The Pathological Complexity of Stroke and Rational Treatment Principles of Chinese Herbal Medicine

Abstract

This paper first analyzes the complexity of pathological processes involved in acute hemorrhagic or ischemic stroke, including primary and secondary brain injury manifestations and mechanisms, potential transformations between hemorrhage and infarction, and the impact of postbrain injury inflammation on disease progression. Based on decades of extensive clinical and pharmacological research on the usage of Chinese herbal medicine (CHM) monomers or formulas that promote blood circulation and remove blood stasis (such as Angong Niuhuang Wan, Buyang Huanwu Tang, Dahuoluo Wan, and Dushen Tang) for stroke treatment, it proposes that tonifying qi, promoting blood circulation, removing blood stasis, and detoxifying are rational treatment principles of CHM. These principles correspond to the following Western medical implications: tonifying qi corresponds to neuroprotection effects, promoting blood circulation corresponds to anticoagulation and thrombolysis, removing blood stasis addresses hematoma absorption and cerebral edema reduction, and detoxifying corresponds to anti-inflammatory actions. This paper further proposes from a systems medicine perspective that acute stroke is a complex disease requiring individualized CHM treatment with timely modifications rather than a one-size-fits-all approach. CHM monomers or formulas for promoting blood circulation and removing blood stasis, which have various effects such as lowering blood pressure, hemostasis, anticoagulation, antiplatelet, anti-inflammatory, promoting fibrinolysis, and edema reduction, must align with disease progression and be applied within appropriate therapeutic time windows to ensure efficacy and safety. Finally, this paper suggests that a combined use of acupuncture and CHM can potentially synergistically leverage their respective therapeutic strengths. Additionally, acupuncture shows clear benefits in the acute phase of intracerebral hemorrhage (ICH), such as stimulating the vagus nerve to enhance cerebral blood flow, reducing inflammation, as well as triggering hemostatic effects. By applying these rational treatment principles in an integrated approach, better CHM treatment outcomes and higher efficacy of stroke management may be attained.

Keywords

stroke - chinese herbal medicine - tonifying qi - promoting blood circulation - removing blood stasis - detoxifying - anti-inflammatory - therapeutic time windows - treatment with timely modification

Introduction

Hemorrhagic or ischemic stroke is a highly prevalent, high-risk condition with severe sequelae in clinical practice. Despite Western medicine having a series of effective interventions to reduce acute-phase mortality and sequelae, there remains a lack of effective methods with minimal side effects for controlling rebleeding, hematoma resolution, neuroprotection, preventing hemorrhage–ischemia conversion, and sequelae rehabilitation.

Due to the accumulation of extensive and long-standing success in treating stroke with CHM monomers or formulas,[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] backed by modern pharmacological research on active ingredients, the integration of traditional Chinese medicine (TCM) therapies has naturally emerged to the forefront. Though the benefits of Chinese herbal medicine (CHM) in these aspects are becoming apparent, however, due to the complexity of stroke pathophysiology, particularly in the acute phase,[13] [14] [15] [16] [17] [18] significant uncertainties remain regarding how to rationally optimize the application of TCM therapies by targeting disease progression and its pharmacological effects to achieve maximum efficacy. All the while the understanding of CHM treatment principles remains largely rooted in TCM, making it difficult to integrate into Western medicine and posing a significant barrier to advancing research and promoting CHM therapies in stroke treatment.

To overcome such obstacles, this paper first analyzes the complexity of the occurrence and progression of hemorrhagic or ischemic stroke, including the primary and secondary brain injury manifestations and mechanisms, potential transformations or coexistence between hemorrhage and infarction, and the impact of the postbrain injury inflammation development and control on disease evolution. Subsequently, from the diverse TCM treatment principles for stroke, we present four methods that align well with stroke pathophysiological mechanisms and demonstrate clear efficacy: the Fu Zheng method (replenishing/tonifying qi), the Huo Xue method (promoting blood circulation), Hua Yu method (removing blood stasis), and the Jie Du method (detoxifying). This paper then elaborates on the modern medical connotations and rationality of these four treatment principles based on the results of numerous clinical trials and pharmacological studies conducted over the past few decades using CHM monomers or formulas (such as Angong Niuhuang Wan, Buyang Huanwu Tang, Dahuoluo Wan, and Dushen Tang) for stroke treatment. Moreover, this paper analyzes optimal time windows for applying these blood circulation-promoting and blood stasis-removing CHM formulas and their relationship with efficacy and safety, and discusses from a systems medicine perspective whether to adopt differential diagnosis and syndrome-based treatment in TCM therapies for stroke. Finally, this paper highlights key benefits of combining acupuncture with CHM applications. All in all, based on the analysis of the complex pathophysiological processes and mechanisms of stroke, integrating the pharmacological effects and clinical experience of various common CHM used in stroke treatment, this paper presents several rational TCM treatment principles, and provides each with scientific interpretations, respectively.

The Pathological Complexity of Stroke

Stroke is primarily categorized into two main types, based on pathophysiology: ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when the cerebral arteries occlude due to a travelling embolus, such as a cardiogenic embolus, an artery-to-artery embolus, or a vascular stenosis of the artery itself, which has a mortality rate of approximately 30%. Hemorrhagic stroke happens less frequently than an ischemic stroke but has a high morbidity and mortality rate (∼40%). Hemorrhagic stroke primarily occurs due to blood vessel rupture and the extravasation of blood in either the brain parenchyma and ventricles, called ICH, or the subarachnoid space, called subarachnoid hemorrhage. ICH can also occur after an ischemic stroke, and may be associated with hematoma expansion (HE), edema, and intraventricular hemorrhage. The leading causes of bleeding include hypertension and the use of anticoagulants and thrombolytic agents along with head injuries.[16] No matter hemorrhagic or ischemic stroke, the timeliness, appropriateness, and effectiveness of acute-phase intervention all directly relate to patient survival and the degree of poststroke recovery. To choose and implement timely and appropriate interventions, having a fundamental understanding of the pathophysiological mechanisms during the acute phase of stroke is essential, especially when both ischemic and hemorrhagic strokes manifest as neurological dysfunctions due to multiple pathological mechanisms.[13]

Primary and Secondary Brain Injuries

Injuries from ICH are generally categorized into primary injury, the initial damage from the hemorrhage itself, and secondary injury, the damage related to downstream pathways activated in the presence of intraparenchymal blood. During the first day of intracranial hemorrhage, the critical factors determining the post-ICH clinical outcome are the HE and the increase in hemorrhagic volume, where bleeding following ICH causes a disruption of the brain structure merely within hours. Primary injury is usually related to mass effect from the initial hematoma, HE, and hydrocephalus, often occurring immediately after the hemorrhage within the first few days or weeks. Secondary injury typically comes from intraparenchymal hematoma, resulting in multiple injurious events and neurological deficits. Various blood components activate cytotoxic, excitotoxic, oxidative, and inflammatory pathways. Thrombin, iron, and hemoglobin from the hematoma are the major contributors to secondary brain damage post-ICH.[13] Although these primary and secondary pathways of injury are pathophysiologically distinct, there is mechanistic overlap in how they cause injury to the brain parenchyma (for example, edema development leads to additional mass effect, intraventricular blood may cause hydrocephalus both from obstruction and inflammatory effects). Therefore, medical intervention should focus on injuries following ICH as related to early hematoma growth, mass effect, and increased intracranial pressure, intraventricular hemorrhage and hydrocephalus, perihematomal edema and inflammation, and additional medical complications. ICH volume is the strongest predictor of mortality with volume >60 cm³ associated with 91% of 30-day mortality.[16] [Fig. 1] illustrates the mechanisms of primary and secondary brain injuries caused by acute ICH.[19] Based on this figure, we made a rough estimation and labeled the potential pathways through which blood circulation-promoting and blood stasis-removing CHM may treat acute ICH via anti-inflammatory, anti-ischemic, reducing cerebral hematoma and edema, and neuroprotective comprehensive mechanisms.

Fig. 1 Primary and secondary brain damage and action sites of CHM in hemorrhagic stroke. BBB, blood–brain barrier; CHM, Chinese herbal medicine; ROS, reactive oxygen species.

Ischemic stroke occurs when the cerebral arteries occlude due to a travelling embolus. The interrupted cerebral blood flow results in functional and neurological damage. Ischemic and hemorrhagic stroke share different pathophysiological mechanisms, such as oxidative stress and inflammation. Among the other most important mechanisms in ischemic stroke are calcium overload and excitotoxicity, which mainly involves autophagy, apoptosis, and necroptosis.[13] Shortly after focal perfusion insufficiency occurs, excitotoxicity may cause fatal damage to neurons and glial cells. The sheer complexity of these mechanisms during stroke has often led to disappointing show of many pharmaceutical trials but also provides a rare opportunity for exploring the applications of CHM therapies.

Transformation or Coexistence of Hemorrhage and Infarction

Whether primary ICH or cerebral infarction, another complexity during the acute phase is that ICH and cerebral infarction may mutually transform or coexist, also known as mixed cerebral infarction. There are two types: acute brain infarcts after spontaneous ICH and hemorrhagic transformation after cerebral infarction, the latter also referred to as hemorrhagic infarction (HI). The phenomenon of acute brain infarcts after spontaneous ICH is rarely reported, but it has a high incidence rate and can increase patient disability or mortality rates. According to Garg et al.,[20] decreased diffusion consistent with acute ischemia was found on MRI in 39 of 95 patients (41%) during 1 to 7.5 days after ICH, and these patients had a higher risk of disability or death within 3 months. It is now understood that cerebral infarctions complicating the acute phase of ICH often have clinical characteristics such as being subcortical, scattered, and having small infarction areas. Moreover, they mostly present with a subclinical onset (no clinical symptoms but with imaging manifestations, for example, silent brain infarction) and are easily overlooked in clinical practice.[18] The mechanism of its occurrence is not entirely clear, but according to recent studies, in addition to possibly being related to underlying cerebral small vessel disease, inappropriate blood pressure management after ICH is also a significant factor. For example, excessive blood pressure reduction can induce cerebral ischemia leading to cerebral infarction.[20] [21] Additionally, it may also be related to factors such as excessive hemorrhage volume (moderate to large volume ICH), obstructive hydrocephalus leading to increased intracranial pressure, and impaired cerebral blood flow regulation curves.[21] Since ischemic lesions secondary to ICH are associated with disability and mortality rates at 3 months,[22] [23] effective prevention and treatment of cerebral infarction complicating the acute phase of ICH has profound clinical significance, but there is currently no effective method to date. The application of CHM formulas derived from natural plants may help address this issue.

Hemorrhagic transformation occurs when blood reenters the tissue or necrotic tissue regions after vascular occlusion. It is a common complication of acute ischemic stroke, occurring in approximately one-third of cases, and is particularly common after thrombolytic therapy or in cases of large-area infarction. The risk of hemorrhagic transformation limits the applicability of tissue plasminogen activator (tPA), and currently, Western medicine lacks effective interventions for it.[24] Hemorrhagic transformation can be divided into HI and parenchymal hematoma, with the former having a higher incidence rate than the latter, at 9% and 3%, respectively.[25] When large-area cerebral infarction exists, the risk of hemorrhagic transformation significantly increases. Additionally, large-area cerebral infarction is often accompanied by severe cerebral edema, causing compression of surrounding blood vessels. The opportunity for hemorrhagic transformation significantly increases after edema subsides.

To sum up, during acute stroke, hemorrhage and infarction frequently coexist and mutually convert: the larger the hemorrhage area, the more likely to coexist with cerebral infarction, or the larger the infarction area, the more likely to lead to ICH. The complexity of this acute phase in ICH presents significant clinical challenges. Over the long history of TCM, many blood circulation-promoting and blood stasis-removing CHM are shown to possess mild anticoagulant and/or hemostatic effects, thus promoting hematoma absorption during the treatment of acute stroke and its sequelae, showing promise in reducing the risk of post-HI or postinfarction hemorrhage.

Hemorrhage, Ischemia, and Inflammation Coexist

Besides the mutual conversion or coexistence between ICH and infarction, both can lead to neuroinflammation. Inflammation is a double-edged sword, as inflammatory mechanisms play a crucial role in both brain damage and potential repair.[19] This is another complexity in the acute phase of stroke.

Increasing evidence indicates that inflammatory mechanisms participated in both early and delayed phases after ICH. Hemorrhagic stroke can initiate inflammatory responses, induce cerebral edema, and disrupt the blood–brain barrier (BBB) with neurotoxic materials such as thrombin, fibrin, and erythrocytes. Cerebral edema is triggered by the presence of intraparenchymal blood. Immediately upon detection of the presence of blood components within the parenchyma, an inflammatory response occurs, characterized by the mobilization and activation of inflammatory cells. Local microglia and astrocytes are the first cells to respond to the ICH. Their role is to promote, once activated, the influx of circulating macrophages. Subsequently, various proinflammatory cytokines are expressed, further activating lymphocytes and ultimately limiting ICH-induced damage by disrupting the BBB. As the inflammation proceeds, leukocytes are recruited via adhesion molecules to secrete diverse chemokines and cytokines to induce endothelial cell death, recruit more immune cells, and damage the tight junctions in the BBB.

Microglia have two phenotypes: M1 and M2. The initial proinflammatory phase following brain injury involves the activation of M1 microglia, leading to the infiltration of various circulating immune cells, especially macrophages and T cells. This subsequently results in the release of inflammatory cytokines (such as interleukin [IL]-1β [IL-1β]), and tumor necrosis factor-α (TNF-α), chemokines, free radicals, and other potentially toxic chemicals coordinated by transcription factors. These chemicals, along with cell death products, further activate resident and migrating lymphocytes, leading to increased lymphocyte infiltration, enhanced M1 polarization, and exacerbated inflammation. This inflammatory response contributes to the formation of edema by increasing the permeability of the BBB around the hematoma, thereby exacerbating the mass effect, enhancing the cell death process through secondary ischemia, and further causing inflammatory damage to the surrounding brain tissue. Within 7 days after the onset of ICH, the M1 phenotype shifts to the M2 phenotype, which is crucial for hematoma clearance, tissue healing, and the overall resolution of inflammation. Once M2 microglia are activated, they release anti-inflammatory cytokines—IL-4, IL-10, and transforming growth factor-β (TGF-β)—all of which are involved in tissue regeneration and the overall resolution of neuroinflammation. Therefore, the inflammatory response related to injury can be divided into two phases: the proinflammatory/cytotoxic phase and the anti-inflammatory/neuroprotective phase.[26]

During hemorrhagic stroke, the various inflammatory pathways activated by the blood within the parenchyma are remarkably similar to those in ischemic stroke.[27] Following cerebral ischemia, the activation of microvascular endothelial cells throughout the brain and the leakage of the BBB allow various inflammatory mediators to diffuse along the cerebrospinal fluid or interstitial fluid.[28] Concurrently, activated glial cells begin to appear in the infarction area and surrounding tissues, accompanied by the infiltration of various peripheral immune cells, gradually forming a whole-brain inflammatory environment. This whole-brain inflammation may persistently influence the pathological evolution poststroke and have long-term effects on the patient's nervous system.[29] Hemorrhagic transformation following thrombolysis for cerebral ischemia is considered at the molecular level to be caused by the actions mediated by inflammatory cells and the toxicity of the tPA.[30]

In summary, whether acute ischemic or hemorrhagic stroke, focal cerebral inflammation exacerbates secondary brain injury by aggravating BBB damage, microvascular failure, cerebral edema, oxidative stress, and directly inducing neuronal cell death.[19] Therefore, how to prevent and treat this neuroinflammation is a potential therapeutic strategy for stroke, but the treatment of inflammatory cascades has made minimal progress.[29] [31] This has also led clinicians to zero in on blood circulation-promoting and blood stasis-removing CHM formulas discovered in previous studies to have a certain degree of anti-inflammatory effects. The complex pathological mechanisms aforementioned during acute stroke create potential opportunities for applications of CHM therapies,[32] yet achieving grand success with various CHM formulas remains challenging.

Rational Selection of Treatment Principles for Stroke

Throughout history, TCM practitioners have developed various types of treatment for stroke based on different understandings of its etiology and pathogenesis, such as wind–phlegm obstructing the collaterals, liver yang hyperactivity, qi deficiency with blood stasis, or phlegm–heat fu-organ excess. Accordingly, TCM practitioners then proceed to use various principles of dispelling wind, nourishing blood, clearing heat, purging the fu organs, resolving phlegm, opening the orifices, tonifying qi, securing qi to prevent separating and pacifying the liver to extinguish wind to guide their treatments. Through proper syndrome differentiation and treatment, TCM practitioners have accumulated rich clinical experience for stroke, though it comes with plenty of controversies, as practitioners often hold their own individual views or thoughts in higher regard than others. For example, Xu Dachun of the Qing Dynasty stated in his Treatise on the Origin and Development of Medicine · On Stroke: “Since it is a wind disease, the primary treatment must focus on expelling wind-evil as the root.” He opposed “the prevailing practice of immediately using Renshen (Ginseng Radix et Rhizoma), Shu dihuang (Rehmanniae Radix Praeparata), Fuzi (Aconm Lateralis Radix Praeparaia), Rougui (Cinnamomi Cortex), which are all-encompassing tonifying and warming, to treat symptoms of stroke, thereby “tonifying wind, fire, phlegm, and qi” or “believing in a misconception that tonifying the vital qi can expel evil, what a grave mistake.” On the other hand, Wang Qingren of the Qing Dynasty wrote in Corrections on the Errors of Medical Works: “In the disease of hemiplegia…signs of qi deficiency must be seen…using cool and purgative CHM to treat damp-heat leg pain and bi syndrome is acceptable, but not suitable for treating flaccidity syndrome.” Qingren emphasized tonifying qi combined with promoting blood circulation and removing blood stasis to treat hemiplegia, proposing the heavy use of Huangqi (Astragali Radix) in his famous CHM formula of Buyang Huanwu Tang. Clearly, different treatment principles have different indications. Dachun's method of expelling wind-evil is more important in treating acute hemorrhagic stroke, while Qingren's method of tonifying qi and promoting blood circulation and removing blood stasis is particularly suitable for treating ischemic stroke and poststroke sequelae.

Acute hemorrhagic stroke falls under the category of blood syndrome in TCM, with blood stasis obstruction being its most fundamental pathological mechanism and treatment target. Tang Rongchuan of the Qing Dynasty, in his Treatise on Blood Syndromes, proposed a general outline of four methods for treating blood syndromes, namely “stopping bleeding, eliminating stasis, calming blood, and tonifying deficiency,” which are still recognized today as optimal principles for treating blood syndromes, including hemorrhagic stroke. After stopping the bleeding, Rongchuan believed that “even though the blood that has left the vessels is clear and fresh, it is still considered stasis blood.” The cerebral hematoma formed within the brain parenchyma is also considered stasis blood and must be promptly cleared. Therefore, the principle of promoting blood circulation and removing blood stasis can also be applied to ICH. Modern scholars have also discussed the pathological mechanism of hemorrhagic stroke from the perspective of endogenous heat toxins: “After the onset of hemorrhagic stroke, the excess of blood stasis, phlegm turbidity, and heat evil stagnates within the body and cannot be expelled, transforming into toxic evil. Although endogenous toxins are not contagious and differ from the toxins of external epidemic diseases, they still possess the characteristics of being fiercely toxic, prone to change, and likely to attack the zang-fu organs, mostly characterized by fire and heat. They can cause dysfunction or damage to the zang-fu organs, especially damaging the brain tissue, and can even lead to death.”[33] This viewpoint closely aligns with modern medical understanding of excitotoxicity and oxidative stress damage in acute ischemic stroke. Consequently, the application of detoxification methods during the acute phase of ICH is highly necessary.

Since over 90% of patients with acute ICH also suffer from conditions known in TCM as syndromes matching heat-induced constipation, the method of purging the six fu organs (for example, gallbladder, stomach, small and large intestines, urinary bladder, and sanjiao/the triple energizer) to drain heat has been proposed as an important treatment during the acute phase of ICH. Some purgative and heat-clearing CHM can reduce intracranial pressure, promote blood circulation and remove blood stasis, and exhibit significant anti-inflammatory effects. Dahuang (Rhei Radix et Rhizoma) is a typical example. The Treatise on Blood Syndromes states: “Unaccompanied Dahuang (Rhei Radix et Rhizoma) is both a qi medicine and a blood medicine. It stops bleeding without leaving blood stasis, making it a particularly wonderful CHM.”[34] Since the Records of Chinese and Western Medicine in Combination clearly documented the use of Dahuang (Rhei Radix et Rhizoma) for treating ICH, research in its application has drawn increased attention.[35] [36] A clinical study in 1980 found that for patients in the acute phase of ICH presenting with syndrome of “bi zheng” or symptoms of close–shutdown, the addition of 9 g of Dahuang powder mixed with 15 to 20 ml of boiling water and administered in small, frequent doses, or decocted to 200 ml for retention enema in those unable to take it orally, could reduce mortality rates.[37] Modern pharmacological research on Dahuang (Rhei Radix et Rhizoma) has discovered that its effect on the blood system primarily promotes coagulation and hemostasis, rather than anticoagulation. Its effective hemostatic components include rhein and gallic acid, among others.[38]

In short, since the 1980s, research on the treatment of stroke has primarily focused on the methods of purging the six fu organs, promoting blood circulation, removing blood stasis, detoxification, and tonifying qi (replenishing the vital qi).[33] From the pathological processes of the acute phase of stroke aforementioned, these CHM principles each possess considerable rationality. Their modern scientific foundations can be respectively attributed to anti-inflammatory effects, anticoagulation, edema reduction, thrombolysis, antioxidative stress, anti-excitotoxicity, and neuroprotection encompassing these mechanisms. Clinically, the choice of which CHM treatment principle to apply must be consistent with the patient's stroke-onset stage and the complexity of their condition. Below, we analyze the modern medical implications and applications of these treatment principles one by one.

Tonifying Qi: Enhancing Neuroprotection

In the treatment of stroke with CHM, especially in its acute phase, Renshen (Ginseng Radix et Rhizoma) and Huangqi are frequently used. Renshen (Ginseng Radix et Rhizoma) and Huangqi (Astragalus) possess the effects of restoring yang to rescue from collapse and tonifying qi to promote blood circulation. Renshen (Ginseng Radix et Rhizoma) is known to have a strong ability to greatly tonify primordial qi and restore yang to rescue from collapse, often used in emergencies such as sepsis and shock. Huangqi (Astragalus), on the other hand, is milder and primarily used for tonifying deficiency. Ancient TCM practitioners often praised Huangqi (Astragalus) as the “sacred tonic for qi,” and the Compendium of Materia Medica lists Huangqi (Astragalus) as the “chief among all tonics.” Huangqi (Astragalus) not only tonifies qi but also has certain effects for blood circulation-promoting, making it suitable for treating conditions like bi syndrome due to blood stasis, stroke with hemiplegia, and chest bi syndrome. Of course, the importance of tonifying qi has always been emphasized in TCM theory as qi is the driving force behind the generation and movement of blood, while blood is the foundation and carrier of qi, hence the classical TCM proverbs “qi is the commander of blood, and blood is the mother of qi.” In the TCM clinic, methods such as tonifying qi to control blood, moving qi to promote blood circulation, and augmenting qi to secure the body from collapse are all applications of the TCM theory that “qi commands blood.”

A classical CHM formula that greatly tonifies original/primordial qi and restores yang using Renshen (Ginseng Radix et Rhizoma) to rescue from collapse is Dushen Tang (Unaccompanied Ginseng Decoction).[39] The Dushen Tang is renowned for its emergency rescue capabilities and is commonly used in the critical care of severe, life-threatening conditions. It is most suitable for treating severe depletion of original/primordial qi due to “blood loss” or “complete loss of blood,” particularly in cases of sudden collapse nearing death.[40] An example of using Dushen Tang for “blood loss” is in the treatment of uterine bleeding disorders or metrorrhagia. Renshen (Ginseng Radix et Rhizoma) possesses both cholinergic and mild adrenergic-like effects, and its treatment of uterine bleeding is achieved by stimulating the autonomic nervous system to promote uterine contractions. The cholinergic activity of Renshen (Ginseng Radix et Rhizoma) can also explain its beneficial effects in acute hemorrhagic stroke, including lowering blood pressure, dilating cerebral blood vessels, antiplatelet, anti-inflammatory, antistress, and enabling neuroprotection.[41] As a well-known qi-tonifying herb in CHM, modern pharmacological research has found that the main active components of Renshen (Ginseng Radix et Rhizoma) are ginsenosides. To date, more than 40 types of ginsenosides have been isolated from ginseng roots, which exhibit antioxidant, antistress, anti-inflammatory, anticoagulant, anti-ischemic, bidirectional blood pressure regulation, hypoglycemic, antitumor, antiaging, antidepressant, anti-Alzheimer's, and antiatherosclerotic effects, among others.[42] [43] During stroke, ginsenosides not only can increase blood flow in the ischemic reperfused brain, reduce infarct size, and promote recovery of brain electrical activity during reperfusion, but also have a protective effect on neurons damaged by cerebral hypoxia,[44] such as a significant anti-ischemic effect on nerve cells.[45]

The term “neuroprotection” refers to strategies aimed at protecting neurons from damage or degeneration, essentially preserving their structure and function. There are studies indicating that the neuroprotective mechanisms after stroke involve a complex cascade of processes that counteract oxidative stress, mitochondrial damage, cell death related to apoptosis or ferroptosis, inflammatory responses, and disruption of the BBB.[46] While it cannot reverse existing damage, neuroprotection can prevent further neural injury and slow down the degeneration of the central nervous system.

Besides Renshen (Ginseng Radix et Rhizoma), another excellent qi-tonifying CHM, Huangqi (Astragalus), and the CHM formula Buyang Huanwu Tang, which features Huangqi (Astragalus) as its chief ingredient, also exhibit significant neuroprotective effects. Wang Qingren, as the founder of Buyang Huanwu Tang, his innovative approach of heavily using qi-tonifying CHM (Huangqi) combined with blood circulation-promoting and blood stasis-removing CHM to treat hemiplegia has continued to this day and has been validated and developed by modern medicine. In various experimental studies, Buyang Huanwu Tang was found to enhance neural regeneration and neuroprotection through multiple compounds along multiple signaling pathways.[47] Its chief herb, Huangqi (Astragalus), treats ischemic stroke with effective mechanisms related to its neuroprotective effects, improvement of cerebral blood flow, and suppression of inflammation-mediated apoptosis in brain ischemic tissue cells.[48]

When analyzing the treatment principles of CHM for COVID-19,[49] the strategy of “tonifying deficiency throughout the entire course of treatment” is of great significance. The physiological significance of tonifying deficiency or qi deficiency is to enhance innate immunity. Renshen (Ginseng Radix et Rhizoma) and Huangqi (Astragalus) are some of the most commonly used CHMs. On occasion, Renshen (Ginseng Radix et Rhizoma) can also be replaced by Tiazishen (Pseudostellariae Radix) or Xiyangshen (Panacis Quinquefolii Radix), or by CHM formulas such as the Si Jun Zi Tang (Four Gentlemen Decoction) and the Bu Zhong Yi Qi Tang (Tonify the Middle to Augment the Qi Decoction). Generally speaking, the relationship between long-term chronic diseases and deficiency syndromes, as well as the importance of tonifying deficiency, is relatively easy to comprehend and garners attention, but the relationship between acute diseases like COVID-19 and deficiency syndromes (so-called acute deficiency syndromes) is easily overlooked. In fact, a stroke onset typically delivers a severe blow to the body. Since its target is the central nervous system, even a previously robust body can collapse instantly, thus urgently requiring tonification, especially qi-tonifying. In treating stroke, the reason that particularly important in its acute phase, requires qi-tonifying is that such a method can quickly enhance neuroprotective effects, thereby reducing damage to brain tissue and function caused by various factors during stroke. Therefore, the strategy of “tonifying deficiency throughout the entire course of treatment” is equally suitable for the prevention and treatment of stroke from the acute phase to the chronic phase, including sequelae ([Fig. 2]).

Fig. 2 Chronological cellular and molecular consequences of ischemic stroke and the treatment principles of Chinese herbal medicine.

Whether treating hemorrhagic or ischemic stroke, emphasizing neuroprotection is one of the key aspects. Modern medicine's research on stroke neuroprotection has been conducted for many years, but many neuroprotective agents show less than ideal efficacy, and some other neuroprotective agents (such as albumin, uric acid, and magnesium sulfate) face difficulties in translating clinical research. The reason for this is very likely that these potential single neuroprotective agents, targeting a single injury mechanism or molecular event, are insufficient to protect brain tissue damage that develops from complex pathological processes involving multiple injury mechanisms and molecular events.[15] This also suggests that multidrug therapeutic interventions may be necessary to produce clinically effective neuroprotection.[50] [51] Applying CHM formulas or preparations with different active components to provide neuroprotective benefits to brain tissue is clearly a major advantage of CHM over conventional pharmaceuticals in treating stroke.

Sanqi (Notoginseng Radix et Rhizoma), which possesses similar neuroprotective effects to Renshen, may indeed have such an advantage. Sanqi (Notoginseng Radix et Rhizoma), since ancient times, has been used to treat ischemic diseases, with its main active components being ginsenosides and notoginsenosides. Notoginsenosides are composed of multiple active ingredients, namely containing approximately 20 different total saponins, exhibiting various neuroprotective mechanisms.[52] [53] This may precisely be its primary difference from other Western neuroprotective agents. Case and point, one type of soft gel capsule called Xuesaitong, was prepared with notoginsenosides as the raw material, and it was studied in a randomized clinical trial, which showed it significantly increased the likelihood of functional independence at 3 months in ischemic stroke patients, such benefits may be attributable to the synergistic neuroprotective effects of the diverse active components of total notoginsenosides on ischemic brain tissue, including antioxidant, anti-inflammatory, antiapoptotic, and enhanced angiogenesis effects.[54]

It is now understood that there are many other CHMs with neuroprotective effects, and they are not all necessarily qi-tonifying CHMs. For example, CHM formulas that regulate mitochondrial autophagy through various pathways to alleviate cerebral ischemia–reperfusion injury include Taohong Siwu Tang (Four-Substance Decoction with Safflower and Peach Pit), Xiao Xuming Tang (Minor Extend Life Decoction), and Dengzhan Xixin (Erigerontis Herba) injection. Their derived compounds such as ligustilide (LIG), harpagoside A1, baicalin, resveratrol (Res), rhein (Reh), naringin, artemisinin (ART), and chrysophanol (Chry) also exhibit such effects. Resveratrol (Res), a natural extract from Huzhang (Polygoni Cuspidati Rhizoma et Radix), exhibits comprehensive neuroprotective effects in ischemic stroke.[55] These can be CHMs that promote blood circulation and remove blood stasis, or CHMs with anti-inflammatory, analgesic, detoxifying, or heat-clearing properties.

A pathway to neuroprotection is through antioxidant stress. Oxidative stress plays a very important role in brain injury following intracranial hemorrhage. Oxidative stress is described as an imbalance between the production of reactive oxygen species (ROS) by cellular physiological antioxidant mechanisms and the ability to eliminate ROS. Oxidative stress leads to the growth and progression of perihematomal edema in patients with ICH. CHM monomers with antioxidant stress can be roughly divided into two categories: tonifying and blood circulation-promoting/blood stasis-removing. Most tonifying CHMs have effects of reducing free radical damage, antioxidation, and antiaging. CHM with potent antioxidant effects includes Heshouwu (Polygoni Multiflori Radix), Gouqizi (Lycii Fructus), Renshen (Ginseng Radix et Rhizoma), Huangqi (Astragali Radix), Zhenzhufen (Pulvis Pernulae), Sanqi (Notoginseng Radix et Rhizoma), Loulu (Rhaponticiradix), Wuweizi (Schisandrae Chinensis Fructus), Buguzi (Psoraleae Fructus), Tusizi (Cuscutae Semen), Yinyanghuo (Epimedii Folium), Rouconrong (Cistanches Herba), Baishao (Paeoniae Radix Alba), Maimendong (Ophiopogonis Radix), Nvzhenzi (Ligustri Lucidi Fructus), Shanzhuyu (Corni Fructus), Dangshen (Codonopsis Radix), Tianmendong (Asparagus Cochinchinensis), Fupenzi (Rubi Fructus), Chuan Xuduan (Dipsaci Radix), Suoyang (Cynomorii Herba), Machixian (Portulacae Herba), Ciwujia (Acanthopanacis Senticosi Radix et Rhizoma Seu Caulis), etc.[56]

All in all, the pathways to neuroprotection are multifaceted, including detoxification, anti-inflammation, antioxidant stress, anticoagulation, etc. The numerous treatment principles of CHM soon to be shared below can all enable neuroprotection. Similarly, qi-tonifying CHM while protecting nerves, also often possesses anti-inflammatory and blood circulation-promoting, blood stasis-removing functions. Here, we are merely emphasizing the different focuses of these CHM treatment principles.

Blood Circulation-Promoting: Anticoagulation and Thrombolysis

In the treatment of stroke, especially ischemic stroke, the most commonly used CHMs are those that promote blood circulation and remove blood stasis. The concept of “promoting blood circulation and removing blood stasis” in TCM has a rich connotation. When interpreted in terms of Western medicine, promoting blood circulation focuses on anticoagulation, antiplatelet effects, thrombolysis, enhancing blood flow or vasodilation, and angiogenesis. Removing blood stasis emphasizes promoting the absorption of stagnant blood, reducing or eliminating hematomas and edema. These effects may seem conflicting at times, but they often share the commonality of anti-inflammation, which can be present throughout the entire process of promoting blood circulation and removing blood stasis. Below, we will first delve into the anticoagulant, antiplatelet, and thrombolytic functions of blood circulation-promoting CHM.

A recent network analysis study on the rules of CHM usage combined with thrombolysis for the treatment of acute cerebral infarction included 46 CHM formulas involving 116 different CHMs. The top five CHMs observed in frequency were Chuanxiong (Chuanxiong Rhizoma), Huangqi (Astragali Radix), Danggui (Angelicae Sinensis Radix), Honghua (Carthami Flos), and Taoren (Persicae Semen). The top five categories of CHM in terms of frequency were blood circulation-promoting and blood stasis-removing CHM, tonifying deficiency CHM, liver-pacifying and wind-extinguishing CHM, heat-clearing CHM, and phlegm-resolving, cough-suppressing, and asthma-relieving CHM. Common CHM combinations included Chuanxiong–Taoren–Danggui, Taoren–Honghua–Danggui, and Chuanxiong–Danshen–Huangqi. Core CHM formulas included Danggui (Angelicae Sinensis Radix), Chuanxiong (Chuanxiong Rhizoma), Honghua (Carthami Flos), Huangqi (Astragali Radix), Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Taoren (Persicae Semen), Dahuang (Rhei Radix et Rhizoma), Tianma (Gastrodiae Rhizoma), Tiannanxing (Arisaematis Rhizoma), Gancao (Glycyrrhizae Radix et Rhizoma), Chishao (Paeoniaeradix Rubra), Shichangpu (Acori Tatarinowii Rhizoma), Banxia (Pinelliae Rhizoma), Dilong (Pheretima), Shuizhi (Hirudo), and Quanxie (Scorpio). The conclusion was that current CHM combined with thrombolysis for acute cerebral infarction emphasizes the main treatment principle of “qi-tonifying and blood circulation-promoting,” while also focusing on pacifying the liver and extinguishing wind, strengthening the spleen and resolving phlegm, and appropriately using insect-based CHM formulas; presenting a compatible pattern with “Danggui (Angelicae Sinensis Radix), Chuanxiong (Chuanxiong Rhizoma), Honghua (Carthami Flos), Huangqi (Astragali Radix), Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Taoren (Persicae Semen)” as the core CHM formulation.[57] From this observation, we can draw two conclusions; first, the necessity of combining qi-tonifying (neuroprotection) with blood circulation-promoting (anticoagulation, thrombolysis) in the treatment of acute cerebral infarction; second, except for Danshen (Salviae Miltiorrhizae Radix et Rhizoma), the other five core CHM—Danggui (Angelicae Sinensis Radix), Chuanxiong (Chuanxiong Rhizoma), Honghua (Carthami Flos), Huangqi (Astragali Radix), and Taoren (Persicae Semen)—all are components of the Buyang Huanwu Tang, indicating that the Buyang Huanwu Tang remains, to this day, a key CHM formula for ischemic cerebral infarction.

Huangqi (Astragali Radix), the chief herb of the Buyang Huanwu Tang has already been covered in the previous section. Here, we will introduce the other herbs, namely, Chuanxiong (Chuanxiong Rhizoma), Danggui (Angelicae Sinensis Radix), Honghua (Carthami Flos), and Danshen (Salviae Miltiorrhizae Radix et Rhizoma). Chuanxiong (Chuanxiong Rhizoma), known as the “qi-moving herb in the blood,” can be considered a key CHM among blood circulation-promoting and blood stasis-removing CHM. Modern pharmacological research has found that Chuanxiong extracts or its active component ligustrazine exhibit anticoagulant and thrombolytic effects, improve microcirculation, reduce capillary permeability, enhance phagocytic function, and accelerate fibrin dissolution, without direct hemostatic effects.[58] [59] It can inhibit the overexpression of tissue factor (TF), a key factor in physiological hemostasis and pathological thrombosis. Suppressing TF expression can reduce bleeding complications and thrombus formation.[60] Danggui (Angelicae Sinensis Radix), commonly known as “female ginseng,” is also a critical herb for treating ischemic stroke. Its extracts or active compounds possess significant anti-inflammatory, antioxidant stress, antiplatelet aggregation, and antiatherosclerotic effects, as well as protecting blood vessels, promoting angiogenesis, and neurogenesis, aiding in improving neurological function in ischemic stroke.[61] Honghua (Carthami Flos)/Safflower extract has a protective effect on ischemic brain injury. Safflower yellow pigment injection for treating acute-phase cerebral infarction can also effectively improve symptoms.[62] Danhong injection, composed of Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Honghua (Carthami Flos), and water for injection, primarily used to increase coronary blood flow and dilate coronary arteries, has a confirmed therapeutic effect in treating cerebral infarction patients.[63]

In the treatment of ischemic stroke, several plant-based CHMs are commonly used, including Sanqi (Notoginseng Radix et Rhizoma), Yinxingye (Ginkgo Folium), and Tianma (Gastrodiae Rhizoma).[64] Among these, Sanqi (Notoginseng Radix et Rhizoma) stands out for its unique ability to both stop bleeding and prevent blood clots. Historically, Sanqi (Notoginseng Radix et Rhizoma) was first recognized for its hemostatic properties, making it the primary treatment for various types of bleeding. The renowned and versatile CHM formulation, Yunnan Baiyao, primarily consists of Sanqi (Notoginseng Radix et Rhizoma). Additionally, Sanqi (Notoginseng Radix et Rhizoma) has blood circulation-promoting and blood stasis-removing effects, alleviating swelling and pain, making it an excellent choice for treating conditions caused by stagnant blood, such as contusions, fractures, and abscesses. Why can Sanqi (Notoginseng Radix et Rhizoma), a “close relative” of Renshen (both belonging to the Araliaceae family, genus Panax), both can stop bleeding and exert anticoagulant effects? The water-soluble component of Sanqi (Notoginseng Radix et Rhizoma), notoginsenoside, a unique amino acid isolated from the root of Sanqi (Notoginseng Radix et Rhizoma), has been shown to reduce coagulation time in mice and significantly increase platelet count. Meanwhile, primary active components of Sanqi (Notoginseng Radix et Rhizoma) are known as notoginseng total saponins, which has the opposite effect, including markedly inhibiting platelet aggregation, thus exhibiting anticoagulant effects (similar to aspirin), such as manifesting an enhanced cerebral blood flow. Notoginsenosides contain over 20 types of ginsenosides and notoginseng total saponins, with ginsenoside Rb1, Rg1, and panax notoginseng saponin R1 (PNS-R1) being the most abundant. This indicates that Sanqi (Notoginseng Radix et Rhizoma) influences hemostasis or anticoagulation through distinct active components.[65] In summary, Sanqi's hemostatic effect is manifested by shortening bleeding and clotting time, an effect related to the herb's metabolism in the liver, while its anticoagulant (blood-activating) effect is demonstrated by inhibiting platelet aggregation. Modern pharmacological research has revealed that the primary active components of Renshen (Ginseng Radix et Rhizoma) are ginsenosides, polysaccharides, and volatile compounds. Over 40 ginsenosides have been isolated from Renshen roots, all of which possess multiple actions. In the context of stroke treatment, Renshen (Ginseng Radix et Rhizoma) not only serves as a qi-tonifying herb (with antioxidant, anti-inflammatory, and neuroprotective effects) but also demonstrates anticoagulant and anti-ischemic properties akin to blood circulation-promoting agents.[42] [43] It has been reported that Renshen (Ginseng Radix et Rhizoma), Sanqi (Notoginseng Radix et Rhizoma), and Xiyangshen (Panacis Quinquefolii Radix) all prolong plasma clotting time, with anticoagulant activity ranking as Renshen (Ginseng Radix et Rhizoma) > Sanqi (Notoginseng Radix et Rhizoma) > Xiyangshen (Panacis Quinquefolii Radix).[53]

In addition to plant-based CHM, certain insect-derived CHMs also exhibit significant anticoagulant, antiplatelet, and thrombolytic effects. For instance, Tongxinluo capsules, composed of Quanxie (Scorpio), Shuizhi (Hirudo), Wugong (Scolopendra), Tubiechong (Eupolyphaga Steleophaga), and Chantui (Cicadae Periostracum), possess lipid-lowering, anticoagulant, antiplatelet, fibrinolytic, and cerebroprotective effects. They also promote the generation of cerebral microvessels, improve cerebral blood supply, and alleviate neurological deficits caused by ischemic stroke.[64] [66] Therefore, combining blood circulation-promoting and blood stasis-removing plant-based CHM with insect-derived CHM, such as Dilong-containing Buyang Huanwu Tang, enhances vasodilation and thrombolysis, making them suitable for various thrombotic disorders. Several good thrombolytic CHM formulations on the market include Qilong Tongluo capsules, Solutolysin capsules, Naosetong wan, Fufang Xuesaitong capsules, and Xuesuanning capsules.

It is crucial to emphasize that while thrombus formation is a complex process, platelet aggregation is a key factor in thrombus formation, and inhibiting platelet aggregation is one of the most direct and effective strategies for treating thrombotic conditions. The roles of anticoagulation, antiplatelet activity, and hemostasis are distinct, and distinguishing between hemorrhagic and ischemic stroke is critical in determining the appropriate therapeutic approach. Hemorrhagic strokes require immediate blood pressure reduction and hemostasis, while ischemic strokes necessitate anticoagulation and thrombolysis. However, due to the complexity of acute stroke, such as hemorrhagic transformation in ischemic strokes or ischemic downstream regions in hemorrhagic strokes, antiplatelet therapy may be considered after hemostasis. Anticoagulation and thrombolysis must be carefully managed to avoid excessive bleeding.

In 2019, the RESTART trial (Restart or Stop Antithrombotics Randomized Trial) conducted a randomized controlled trial involving 537 survivors of ICH associated with prior antithrombotic use. The study found that over a 2-year follow-up, the use of antiplatelet pharmaceuticals did not increase the risk of recurrent hemorrhagic stroke compared with avoiding their use, contrary to initial expectations.[67] This suggests that antiplatelet therapy may still be safely administered in certain posthemorrhagic stroke patients, particularly those with hemorrhage-related anticoagulant use or secondary ischemic stroke. However, concerns remain regarding the potential for recurrent bleeding. Current antiplatelet pharmaceuticals are limited by suboptimal efficacy and a higher risk of excessive bleeding, whereas blood circulation-promoting and blood stasis-removing CHM exhibit fewer and milder side effects in inhibiting platelet aggregation, all while supplying gentle yet multitarget actions, prompting an outcry from the public to replace antiplatelet pharmaceuticals with minimally invasive CHM.

In recent years, Yu and colleagues conducted a literature review of 149 CHMs with blood circulation-promoting and blood stasis-removing effects. They identified 37 CHMs with significant antiplatelet effects. These CHMs were categorized based on their therapeutic properties, revealing that the proportion of warm-natured CHM is the largest, including Sanqi (Notoginseng Radix et Rhizoma), Yuejihua (Rosae Chinensis Flos), Honghua (Carthami Flos), Shaji (Notoginseng Radix et Rhizoma), Awei (Ferulae Resina), Chuanxiong (Chuanxiong Rhizoma), Dengzhanxixin (Erigerontis Herba), Jixueteng (Spatholobi Caulis), Shanjiang (Alpinia japonica), Yanhusuo (Corydalis Rhizoma), Shanzha (Crataegi Fructus), Ruxiang (Olibanum), Zelan (Lycopi Herba), Jiangxiang (Dalbergiae Odoriferae Lignum), Chaxiong (Ligusticum Sinense Oliv.cv.Chaxiong Mass), and Jili (Tribull Fructus). Neutral-natured CHMs include Sumu (Sappan Lignum), Xingren (Persicae Semen), Hongjingtian (Rhodiolae Crenulatae Radix et Rhizoma), Yinxingye (Ginkgo Folium), Puhuang (Typhaepollen), Sanleng (Sparganii Rhizoma), Shuizhi (Hirudo), and Moyao (Myrrh). Cold-natured CHMs include Mudanpi (Moutan Cortex), Huzhang (Polygoni Cuspidati Rhizoma et Radix), Yujin (Curcumae Radix), Yimucao (Leonuri Herba), Chishao (Paeoniaeradix Rubra), Danshen (Salviae Miltiorrhizae Radix et Rhizoma), and Dahuang (Rhei Radix et Rhizoma), as well as the cool-natured Maodongqing (Ilex pubescens Hook).[68] [69] [70] The antiplatelet mechanisms of these CHMs include inhibiting platelet aggregation, blocking platelet release reactions, influencing platelet metabolism, and modulating intracellular signaling pathways and differential protein expression.[71] Warm-natured CHMs such as Sanqi (Notoginseng Radix et Rhizoma), Yuejihua (Rosae Chinensis Flos, Awei (Ferulae Resina), Jixueteng (Spatholobi Caulis), and Chuanxiong (Chuanxiong Rhizoma) exhibit multitarget characteristics.[70] These findings underscore the potential for developing efficient and safer antiplatelet agents from CHM for clinical application. This research will undoubtedly benefit the clinical application of these CHM by providing a foundation for syndrome differentiation or etiology-based treatment.

Blood Stasis-Removing: Eliminating Hematomas and Edema

In TCM, while “promoting blood circulation” primarily corresponds to anticoagulation, antiplatelet activity, fibrinolysis, and improving microcirculation, “removing blood stasis” can be associated with eliminating hematomas and edema. In the context of treating stroke, this involves promoting the absorption of intracranial hematomas (including intraventricular hemorrhage) and reducing cerebral edema (including perihematoma edema and hydrocephalus).

Effectively promoting the absorption of intracranial hematomas and reducing their volume has always been a critical component of Western emergency treatment for acute hemorrhagic stroke. Based on the size of the hematoma and its space-occupying effect, treatment options may include surgery or conservative therapies with pharmaceuticals. Studies have shown that the speed of hematoma clearance significantly influences patient outcomes; however, promoting endogenous hematoma absorption is preferable, as surgery is only suitable for a small subset of patients and open surgery can cause additional trauma to the patient.[17] While mannitol and other intracranial pressure-lowering pharmaceuticals have proven efficacy, they are not directly correlated with the rate of hematoma absorption. In this regard, Western medicine currently lacks effective pharmaceuticals for promoting the absorption of intracranial hematomas, leaving room for contributions from CHM therapies, especially those CHM that have already demonstrated unique benefits in this regard.[59]

It has been confirmed that numerous single or compound CHM can be used in the clinical treatment of ICH, accelerating the absorption of edema, reducing the volume of hematomas, and significantly improving the neurological function of patients.[72] Some evidence indirectly comes from clinical experience in treating the acute phase of ICH, such as frequent use of heat-clearing and blood circulation-promoting and blood stasis-removing CHM, along with purgative and hemostatic agents. Core CHMs include Dahuang (Rhei Radix et Rhizoma), Sanqi (Notoginseng Radix et Rhizoma), Shuizhi (Hirudo), Shichangpu (Acori Tatarinowii Rhizoma), Shengdihuang (Rehmanniae Radix Praeparata), and Mudanpi (Moutan Cortex).[73] Dahuang (Rhei Radix et Rhizoma) was found to be the most frequently used CHM, with its combination guided by the principle of purging excess while tonifying deficiency.[74] There is also evidence derived from clinical observations, with representative CHM including Sanqi (Notoginseng Radix et Rhizoma), Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Huangqi (Astragali Radix), Shuizhi (Hirudo), Ciwujia (Acanthopancis Senticosi Radix et Rhizoma Seu Caulis), Sodium β-aesculin, Yinxingye (Ginkgo Folium), Chuanxiong (Chuanxiong Rhizoma), and Dengzhanxixin (Erigerontis Herba).[75] Blood circulation-promoting and water-draining CHM, such as Sanqi (Notoginseng Radix et Rhizoma), Sheng Puhuang (Typhaepollen), Fuling (Poria), Zexie (Alismatis Rhizoma), and Dangshen (Codonopsis Padix) have been shown to effectively promote hematoma absorption, reduce inflammatory responses, and demonstrate good safety profiles in clinical applications.[76] The pharmacological mechanisms of these CHM formulas are primarily related to anticoagulation, antiplatelet activity, vasodilation, and improved microcirculation. These mechanisms likely contribute to the common effects of blood circulation-promoting and blood stasis-removing CHM in promoting hematoma absorption and alleviating cerebral edema.

Dahuang (Rhei Radix et Rhizoma) possesses both hemostatic and antiplatelet aggregation properties, making it particularly advantageous in treating complex strokes where hemorrhage and infarction coexist or transition into one another. Current evidence suggests that emodin, one of the primary components of Dahuang (Rhei Radix et Rhizoma), has pharmacological characteristics such as a small molecular weight, rapid onset of action, and fast metabolism. It exhibits multiple effects, including protection of vascular endothelial cells, regulation of platelet aggregation, improvement of coagulation factors and fibrinogen function, and modulation of fibrinolysis. Studies have shown that in cases of sepsis complicated by disseminated intravascular coagulation in its late stages, where widespread microthrombus formation consumes large amounts of coagulation factors and platelets, emodin increases platelet count and aggregation function, thereby correcting coagulation disorders in sepsis.[77] This mechanism may explain how Dahuang (Rhei Radix et Rhizoma) can aid in hemostasis during ICH. On the other hand, experimental observations indicate that emodin significantly reduces platelet aggregation rates, prevents the shortening of prothrombin time, and improves the thrombotic-prone state of small cerebral arteries and veins.[78] The blood circulation-promoting efficacy of emodin and emodin acid, in terms of antagonizing platelet aggregation, is 5.02 and 5.15 times that of aspirin, respectively.[79] This dual action of Dahuang (Rhei Radix et Rhizoma) makes it a versatile CHM that can be used to treat both hemorrhagic and ischemic strokes.

Sanqi (Notoginseng Radix et Rhizoma) improves blood flow through its anticoagulant properties and may promote hematoma absorption.[54] Xuesaitong injection, derived from the total saponins of Sanqi (Notoginseng Radix et Rhizoma), has been shown through pharmacological studies to significantly increase cerebral blood flow, reduce cerebral vascular resistance, promote the opening of collateral circulation, lower intracranial pressure, thereby reducing perihematoma edema, alleviate brain tissue compression, and exhibit inhibitory effects on platelet aggregation, fibrinogen content, blood viscosity, and thrombus formation.[80] A study involving 82 patients in the acute phase of ICH randomly divided them into two groups. Both groups received standard treatments, including dehydration, blood pressure regulation, maintenance of water and electrolyte balance, CHM, and acupuncture. The treatment group additionally received Xuesaitong injection via intravenous drip for 10 to 14 days. The results demonstrated that the treatment group achieved higher clinical efficacy and was a safe method; compared with the control group, the treatment group had a higher rate of complete hematoma absorption, shorter time to complete absorption, higher recovery rate of self-care ability, and no cases of HE.[81] However, it is important to note that while Xuesaitong injection may promote hematoma absorption, its use in the acute phase of ICH might exacerbate cerebral edema. Therefore, it should be used with caution in patients with large hematomas during the ultra-early treatment phase.[82]

The blood stasis-removing function of CHM, in addition to dilating blood vessels and improving microcirculation, also involves the following mechanisms: first, by enhancing the phagocytic action of phagocytes and glial cells, it accelerates the absorption of hematomas and controls cerebral edema; second, by antagonizing the toxic substances released by hematomas, especially the damage caused by thrombin to tissues, such as calcium overload, excitatory amino acid toxicity, and free radical damage, it provides neuroprotective effects against the inherent toxicity of the hematomas themselves. Shuizhi (Hirudo), for instance, contains hirudin, a potent thrombin inhibitor. Studies show that when hirudin is administered alongside blood injection into the brain, it prevents significant cerebral edema formation.[83] Shuizhi's remarkable ability to break down clots and dissipate stagnation is attributed to its anticoagulant properties, anti-free radical effects, and reduction of blood viscosity and fibrinogen levels.[84] A clinical trial by Zhang et al. demonstrated that oral administration of Shuizhi capsules for 1 month in 50 patients with acute hemorrhagic stroke resulted in significantly greater hematoma absorption, reduced neurological deficits, and improved overall efficacy compared with a control group.[85]

Chuanxiong (Chuanxiong Rhizoma), traditionally used for ischemic stroke, has also shown promise in treating acute ICH when used in high doses.[86] A 2022 meta-analysis of 15 randomized controlled trials involving 1,579 participants found that the combination of blood circulation-promoting CHM with Western treatments significantly improved neurological function, daily activity indices, hematoma absorption, cerebral edema reduction, and reduced adverse effects and mortality rates in ICH patients compared with Western treatments alone.[87] The most frequently used CHM in these studies were Chuanxiong (Chuanxiong Rhizoma) and Dahuang (Rhei Radix et Rhizoma). Ligustrazine, an active ingredient of Chuanxiong (Chuanxiong Rhizoma), has shown through research that it possesses the ability to reduce free radicals and exert antioxidant effects, significantly inhibiting platelet aggregation and counteracts cerebral ischemia–reperfusion injury, accelerating the absorption of hematomas. Furthermore, ligustrazine also antagonizes the vasoconstrictive effects of endothelin, markedly alleviating spastic contractions of vascular smooth muscle and improving cerebral arterial spasm following hemorrhage, and increases cerebral blood flow in ischemic regions, mitigates cerebral edema and diminishes neuronal apoptosis, among other beneficial effects.[75]

Danshen (Salviae Miltiorrhizae Radix et Rhizoma) has been shown to significantly improve human hemorheological parameters, reducing blood viscosity and enhancing blood circulation. In a study by Li et al., 30 patients with acute hypertensive ICH were randomly divided into two groups. After 14 days of treatment, CT scans revealed that the group receiving Danshen injection exhibited superior hematoma absorption, reduced hematoma volume, and significant decreases in whole blood viscosity, fibrinogen levels, and hematocrit, effectively preventing secondary ischemic damage.[88]

Dengzhanxixin injection, derived from the active components of Dengzhanhua (Erigerontis Herba), has been shown to significantly dilate blood vessels, increase cerebral blood flow, reduce peripheral vascular resistance, improve microcirculation, decrease plasma viscosity, hematocrit, platelet aggregation rate, and fibrinogen levels while enhancing erythrocyte deformability. Due to these pharmacological effects, clinical use of Dengzhanxixin injection has been effective in promoting hematoma absorption, improving microcirculation, facilitating neural function recovery, and enhancing treatment outcomes for ICH.[75]

Cerebral edema is a secondary symptom in various conditions, including ICH, ischemic stroke, hydrocephalus, and liver failure. The prognosis of hypertensive ICH primarily depends on the location, size of the hematoma, and the severity of cerebral edema, which is positively correlated with hematoma volume.[89] The pathogenesis of cerebral edema is complex, involving cellular swelling, vascular leakage, and impaired fluid absorption pathways, forcing fluid into brain tissue. Cerebral edema following ICH can be either cytotoxic or vasogenic. Similarly, cerebral edema caused by ischemia involves both cytotoxic and vasogenic mechanisms.[90] The shared mechanisms underlying cerebral edema caused by hemorrhage and ischemia may explain why certain blood circulation-promoting and blood stasis-removing CHM, such as ligustrazine, can effectively treat both conditions.[86]

The clinical management of cerebral edema primarily focuses on reducing intracranial pressure, alleviating cellular compression, and restoring viable brain cells, particularly those in the penumbra, from ischemic and hypoxic states. Commonly used pharmaceuticals for treating cerebral edema include hyperosmolar diuretics, diuretics, and corticosteroids, among which mannitol, a hyperosmolar diuretic, is widely utilized. However, mannitol has several adverse effects, including the potential to induce hypokalemia, exacerbate heart failure, or cause hepatorenal dysfunction with prolonged use.[82] Blood circulation-promoting and blood stasis-removing CHM, with their multipathway and multitarget characteristics, offer a novel approach to treating cerebral edema during the acute phase of hemorrhagic or ischemic stroke. These CHMs not only promote hematoma absorption but also reduce cerebral edema and mitigate ischemic injury, providing new insights into cerebral edema management.[82] While the mechanisms of CHM in treating cerebral edema differ from those in treating hematomas, they often employ an approach that combines removing stasis and promoting diuresis.

Commonly used CHM formulations for treating cerebral edema include Danshen-based formulas (such as Danshen injection, Compound Danshen injection, and Danhong injection)[91] and Sanqi-based formulas (including Sanqi granules and Xuesaitong injection), as well as the classical CHM formula Taohe Chengqi Tang (Peach Pit Decoction to Order Qi), composed of Taoren, Dahuang, Gancao, Mangxiao (Natrii Sulfas), and Guizhi (Cinnamomi Ramulus). Pharmacological studies have revealed that these formulations improve cerebral edema not only through their circulatory-enhancing effects but also by promoting diuresis via water and ion channels. For instance, Taohe Chengqi Tang primarily targets aquaporin proteins, ion channel proteins, and matrix metalloproteinases in the blood.[82] A study reported that combining Taohe Chengqi Tang with mannitol for treating acute cerebral edema in patients with hypertensive ICH improved cerebral hemodynamics, shortened hematoma absorption time, effectively reduced secondary cerebral edema, promoted the absorption of perihematoma edema (related to its diuretic and de-swelling effects), and lowered inflammatory cytokine levels, leading to faster recovery of neurological deficits. The overall efficacy of this CHM was superior to mannitol treatment alone.[92]

In clinical studies, Danshen-based formulas, Sanqi-based formulas, and Taohe Chengqi Tang have all achieved favorable therapeutic outcomes. The treatment groups demonstrated significantly better efficacy, improved outcomes, and higher overall effectiveness rates compared with the conventional treatment groups. Clinical studies typically measured indicators such as intracranial pressure in patients with cerebral edema, improvements in the Glasgow Coma Scale scores, and the reduction in cerebral edema volume after the treatment course. However, the current clinical studies are limited by small sample sizes, predominantly nonblinded designs, and single-center trials, which reduce the persuasiveness of the evidence. Future clinical research designs need to address these limitations to enhance the robustness of the findings.[82]

Detoxification: Counteracting Neuroinflammation

In the prevention and treatment of acute stroke, detoxification methods are applied. Essentially, detoxification and qi-tonifying methods share the same objective: to protect the body's neural tissues from being harmed by various toxic substances generated during a stroke. However, the pathways through which they achieve this goal differ. Qi-tonifying aims to “strengthen the vital qi,” as the ancient saying goes, “When vital qi is abundant, pathological factors cannot invade.” By enhancing the resistance of neural tissue, the harmful effects of toxic pathogens are mitigated. On the other hand, detoxification aims to minimize the production of toxic pathogens within the body or to suppress their toxicity (such as excitotoxicity, oxidative stress products, etc.). In Western medicine, the concept of detoxification can be summarized as having anti-inflammatory effects.

It is now well-established that CHMs are effective in the prevention and treatment of various chronic inflammatory diseases, and the underlying mechanisms have been clarified.[93] These chronic inflammatory diseases include Alzheimer's disease, atherosclerosis, arthritis, asthma, diabetes, and inflammatory bowel disease. The CHMs primarily used for these conditions are qi-tonifying, heat-clearing, and detoxifying agents.[94] The aforementioned qi-tonifying CHM, such as Renshen (Ginseng Radix et Rhizoma) and Huangqi (Astragali Radix), also have mechanisms of neuroprotection that involve anti-inflammatory pathways. Ginsenosides, the main pharmacologically active components of Renshen (Ginseng Radix et Rhizoma), have anti-inflammatory mechanisms that can be categorized into three aspects: antioxidant effects, modulation of inflammatory factors and inflammatory signaling pathways, and regulation of gut microbiota.[95] As for heat-clearing and detoxifying CHM, their major active components exhibit anti-inflammatory effects,[96] which is more intuitive since systemic fever or local redness, swelling, and heat are the most common manifestations of acute inflammation. It is particularly noteworthy that most blood circulation-promoting and blood stasis-removing CHM also possess anti-inflammatory effects. This forms the basis for the clinical application of CHM therapies that promote blood circulation and remove blood stasis in treating various inflammatory pain conditions, as well as the foundation for their prevalent use in the prevention and treatment of stroke, and cardiovascular and cerebrovascular diseases.

In the context of treating stroke, why do many single CHM or CHM formulas primarily known for their blood circulation-promoting and blood stasis-removing effects effectively treat both ischemic and hemorrhagic stroke? If we simplistically attribute this to their dual actions of “anticoagulation and hemostasis,” it inevitably leads to self-contradiction. In fact, their traditional functions of promoting blood circulation and removing blood stasis are not limited to the modern medical understanding of anticoagulation, thrombolysis, or the elimination of hematomas and edema. Instead, they largely rely on their anti-inflammatory effects. In other words, blood circulation-promoting and blood stasis-removing effects are inseparable from anti-inflammatory actions. Evidence supporting this can be summarized in the following three aspects.

First, recent studies over the past two decades have revealed that hemostasis, thrombosis, and inflammation are closely interconnected processes, with thrombin or platelets exhibiting a strong relationship with inflammation.[97] [98] [99] There is a complex interplay between inflammation and hemostasis: on one hand, inflammation can cause endothelial damage, leading to the loss of endothelial physiological anticoagulant, anti-aggregatory, and vasodilatory properties; inflammation also increases the release of procoagulant factors and inhibits the activity of fibrinolytic enzymes, thereby promoting thrombus formation.[97] Even in the absence of vascular wall injury, inflammation-induced venous thrombosis may occur. Thromboinflammation, which involves both infectious and noninfectious acute and chronic diseases, includes cardiovascular diseases such as myocardial infarction and ischemic stroke[99]; on the other hand, coagulation exacerbates inflammation, creating a vicious cycle. This is primarily achieved through the induction of proinflammatory cytokine and growth factor secretion by thrombin.[97] Additionally, platelets, in addition to their hemostatic function, play a key role in mediating various inflammatory processes. In thromboinflammation, platelets are critical effector cells, linking all three key processes (hemostasis, thrombosis, and inflammation).[97] [99] In summary, the inflammatory response is the source of secondary damage following stroke and accompanies the entire disease process. Although ischemic and hemorrhagic strokes are two distinct diseases, both may involve neuroinflammation as a secondary injury.[32]

Second, as mentioned earlier, blood circulation-promoting and blood stasis-removing CHM often possess anticoagulant and fibrinolytic functions, and these effects are closely related to anti-inflammatory mechanisms. A network pharmacological analysis of blood circulation-promoting and blood stasis-removing CHM observed that Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Chuanxiong (Chuanxiong Rhizoma), and Honghua (Carthami Flos) are the three most commonly used CHMs in such formulations. Further analysis of the antithrombotic mechanisms of their active components revealed a network relationship involving 25 CHM monomers and 29 thrombus-related molecules. Among these, 23 molecules were associated with inflammatory responses. This suggests that the antithrombotic effects of blood circulation-promoting and blood stasis-removing Chinese patent medicines containing Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Chuanxiong (Chuanxiong Rhizoma), and Honghua (Carthami Flos) are primarily related to their inhibition of inflammatory responses.[100] Moreover, anticoagulant pharmaceuticals also exhibit similar properties. Commonly used anticoagulants such as heparin, pravastatin, and aspirin serve not only as anticoagulants but also possess anti-inflammatory characteristics,[101] with heparin being particularly notable in this regard.[102]

Like anticoagulant pharmaceuticals, most blood circulation-promoting and blood stasis-removing CHM with anticoagulant and fibrinolytic functions also possess anti-inflammatory effects, such as Danshen (Salviae Miltiorrhizae Radix et Rhizoma), Dahuang (Rhei Radix et Rhizoma), Chuanxiong (Chuanxiong Rhizoma), Honghua (Carthami Flos), Danggu i(Angelicae Sinensis Radix), Yimucao (Leonuri Herba), Mudanpi (Moutan Cortex), Chishao (Paeoniaeradix Rubra), Yinxingye (Ginkgo Folium), Sanqi (Notoginseng Radix et Rhizoma), Shanzha (Crataegi Fructus), Mangchong (Tabanidae), Shuizhi (Hirudo), and Dilong (Pheretima). Dahuang (Rhei Radix et Rhizoma), Sanqi (Notoginseng Radix et Rhizoma), and Chuanxiong (Chuanxiong Rhizoma), which are commonly used in the treatment of stroke, exhibit particularly pronounced anti-inflammatory effects. Regarding the anti-inflammatory mechanisms of blood circulation-promoting and blood stasis-removing CHM, numerous in-depth studies at the cellular and molecular levels have already been conducted,[103] [104] and no longer warrant further elaboration.

In summary, based on the understanding of the close relationship between stroke and inflammation, as well as the characteristic anti-inflammatory properties of blood circulation-promoting and blood stasis-removing CHM, their advantages in the prevention and treatment of acute stroke become even more evident. Anti-inflammatory detoxification not only reduces further damage to brain tissue caused by inflammation but also enhances the neuroprotective effects of qi-tonifying methods and increases the efficacy of blood circulation-promoting methods (such as anticoagulation, fibrinolysis, or blood stasis-removing methods for reducing edema). The combination of detoxification methods with qi-tonifying, blood circulation-promotion, and blood stasis-removing methods cannot only reduce brain tissue damage during stroke but also provide a new pathway with fewer side effects to improve treatment outcomes for stroke and its poststroke sequelae. Therefore, in the near future, we should seek out effective CHM therapies that not only target coagulation and thrombolysis mechanisms but also exert anti-inflammatory and detoxifying effects, so that they can provide greater benefits for the treatment of stroke.

One Chinese Herbal Medicine Formula Fits all or Treatment Based on Cause/Symptom Differentiation

In the application of CHM for treating acute stroke, a controversy exists regarding whether to adopt the classical TCM syndrome differentiation and treatment. Modern clinical TCM research emphasizes the repeatability and ease of operation for effective interventions, often favoring the validation of a “single CHM formula for a thousand or even 10,000 people/one-size-fits-all” based on modern disease or cause differentiation, rather than the classical TCM syndrome differentiation and treatment. However, when clinical studies fail, it is often attributed to the deviation from the classical TCM syndrome differentiation and treatment. A recent example is the heated discussion within the TCM field,[105] triggered by a recent study on the use of Zhongfeng Xingnao Tang (FYTF-919) for treating acute ICH, published in the Lancet.[12]

This paper argues that even setting aside the fundamental theories of TCM, the necessity of individualized syndrome differentiation and treatment versus the application of a customized “single CHM formula for a single person” or a generic “single CHM formula for a thousand or even 10,000 people” primarily depends on the nature of the disease being treated. For simple diseases, it is reasonable to apply a single formula for 1,000 or even 10,000 people. However, for complex diseases, it is extremely challenging to adopt a one-size-fits-all approach. Even when based on modern disease or cause differentiation, it is not advisable to rigidly apply a single formula without modification.

How does one differentiate between simple diseases and complex diseases?

The book, Principles of Systems Medicine [106] presents a simple formula:

In the proposed formula, “a” represents the overall impact on the regulatory functions of subsystems, and “b” represents direct external influences. Together, they determine the magnitude of “S.” If we define S ≠ 0 as indicating illness (a sustained deviation from homeostasis), then “b” represents the cause of the disease. Meanwhile, “a” is a factor that can either exacerbate or alleviate the disease and is related to the body's capability of recovering homeostasis. Since this formula applies to all diseases, it serves as the foundation for disease occurrence and progression and can be referred to as the fundamental formula of systems medicine. If both “b” and “a” are generalizable (i.e., their values apply to a specific population), the formula describes a generalized disease. However, if “b” and “a” are specific to an individual and cannot be generalized, the formula describes an individualized disease. Based on this formula, we can make a simple assessment of disease complexity: Diseases caused by a deviation from homeostasis due to a change in only one factor (either “b” or “a”) are relatively simple and can be classified as simple diseases. On the other hand, diseases resulting from the interaction of both factors (“b” and “a”), which may also feedback into the deviation from homeostasis, are classified as complex diseases, as shown in [Fig. 3].

Fig. 3 A perspective of systems medicine about simple diseases and complex diseases. The red letters represent the main causes of the disease; the blue dashed lines represent the feedback impacts of deviations from homeostasis or the disease on the cause.

Fever and heat stroke (overheating) are typical examples of simple diseases. Fever is caused by pathogenic microorganisms that only affect the body temperature set point “b” (increasing it) without impacting the body's temperature regulation mechanisms “a” (heat production and dissipation remain unchanged). In contrast, heat stroke occurs when the body's temperature regulation mechanism “a” changes, while the temperature set point “b” remains unaffected. Thus, the treatment methods for fever or heat stroke can be standardized. An example of the suitability of a single CHM formula for 1,000 or even 10,000 people is the treatment of COVID-19 infectious disease (plague). Plague is an acute disease, and during its acute phase, when the body's resistance is not yet compromised, it only involves changes in “b,” thus still falling under the category of simple disease. Consequently, the treatment methods are relatively straightforward and single–single CHM formula or single–thousands CHM formulas, all have shown good efficacy. Although, for more complex diseases, one needs to timely adjust or modify CHM formulas based on disease progression, such as knowing when to use the famed “San Yao/three medicines” (Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Xuebijing Injection) and “San Fang/three formulas” (Qingfei Paidu Formula, Huashi Baidu Formula, Xuanfei Baidu Formula), all of which are effective antiepidemic CHM formulas, but being selectively used when encountering mild, moderate, and severe disease phases during the height of COVID-19.[107] If interested in learning more, refer to one of the author's previous articles discussing the mechanisms and rationale behind those CHMs effectiveness in combating the epidemic from the perspective of the systems medicine and its derived basic formula.[49]

In contrast to most simple acute infectious diseases, the majority of modern chronic diseases or age-related illnesses are classified as complex diseases, including hypertension, diabetes, metabolic disorders, neurodegenerative diseases, dementia, and cancer. The causes and progressive mechanisms of these diseases are highly complex, involving not only external factors but also changes in the body's homeostatic mechanisms. Stroke, closely related to hypertension and atherosclerosis, is naturally a complex disease. Especially during its acute phase, as previously analyzed, treating acute stroke is much more challenging than treating simple diseases with a standardized approach. In other words, due to the sheer complexity of acute stroke, even a classic CHM formula (such as Angong Niuhuang Wan, Dahuoluo Wan, or Buyang Huanwu Tang) or an empirical CHM formula (like Zhongfeng Xingnao Tang) may lack universal applicability, no matter how reasonable it may be.

It is evident that the use of CHM for complex conditions like acute stroke should differ from its use for simple diseases. Flexible and adaptive measures tailored to the disease's complexity are essential. For example, the selection and combination of effective CHM vary between hemorrhagic and ischemic strokes. Similarly, the treatment approach during the acute phase differs from that during the poststroke recovery phase. Since the intervention goals often shift during the treatment course of the diseases—such as when to stop bleeding, eliminate blood clots, reduce brain edema, or initiate anti-inflammatory or neuroprotective measures—the individual differences in patients' conditions further amplify the need for personalized interventions. Therefore, a standardized “one-formula-fits-all” approach is unlikely to surpass the effectiveness of individualized CHM formulas or symptom-based combinations.

For patients with acute ICH, the initial intervention should prioritize stopping the bleeding and lowering blood pressure. Herbs with blood pressure-lowering and hemostatic effects, such as Renshen (Ginseng Radix et Rhizoma) and Dahuang (Rhei Radix et Rhizoma), could be considered. However, in clinical practice, CHM interventions are often initiated only after the bleeding has largely ceased, making the use of CHM for blood pressure reduction and hemostasis less common. It is recommended to start with CHM which promotes blood clot absorption and neuroprotection. Additionally, to prevent rebleeding, maintaining smooth bowel movements is crucial. Dahuang (Rhei Radix et Rhizoma), which has hemostatic, anti-inflammatory, and laxative properties, could be a suitable choice for this purpose. Since ICH often leads to secondary cerebral infarction, adding CHM with anticoagulant or antithrombotic effects, such as Chuanxiong (Chuanxiong Rhizoma), during the postbleeding phase is both necessary and reasonable. Furthermore, inflammation is inevitably associated with the acute phase of stroke (whether hemorrhagic or ischemic). Inflammation acts as a “double-edged sword,” being both necessary and potentially harmful if excessive. For severe patients with significant bleeding, early administration of Renshen (Ginseng Radix et Rhizoma) can enhance sympathetic nervous system activity, strengthen immune function, facilitate blood clot absorption, and protect neural tissue.[104] In the later stages of stroke, including the recovery phase, selecting CHM with anti-inflammatory, anticoagulant, and blood stasis-removing properties, such as Sanqi (Notoginseng Radix et Rhizoma) is a more reasonable approach.

For acute ischemic stroke, timely anticoagulation and antithrombotic measures are crucial for minimizing poststroke complications. While there is a possibility of ischemic stroke transitioning to hemorrhagic stroke, appropriately selected CHM combinations generally do not increase the risk of bleeding. Buyang Huanwu Tang may be the most effective CHM formula for treating ischemic stroke, both historically and in modern practice. For poststroke sequelae, whether caused by hemorrhagic or ischemic stroke, the primary goal of CHM therapy is to promote functional recovery while preventing recurrent strokes or poststroke complications (for example, dementia or neuropsychiatric disorders). To achieve this, CHMs that improve cerebral blood flow, particularly to damaged brain tissue, should be selected. These CHMs can help revive inhibited or partially viable neurons near the injury site, promote neurogenesis or angiogenesis to establish compensatory pathways, and restore partial functionality. Additionally, CHMs with peripheral effects, such as improving muscle tone and reducing disuse-induced muscle atrophy, are also important. Dahuoluo Wan is a commonly used CHM formula for poststroke sequelae. Buyang Huanwu Tang can also be considered, as it is particularly well-suited for treating acute ischemic stroke.

Of course, the principles of TCM, which emphasize personalized treatment based on syndrome differentiation, are undoubtedly reasonable. However, it is common for the same syndrome to appear in modern cases of stroke with entirely different underlying causes (for example, hemorrhagic vs. ischemic stroke). Combining syndrome differentiation with modern medical approaches—such as identifying the cause (etiology) and symptoms (symptom-based diagnosis)—to select treatment methods or adjust therapeutic plans can lead to more effective and safer outcomes. From the perspective of systems medicine, syndrome differentiation, cause-based differentiation, or symptom-based differentiation can all be summarized as “self-consistency.” This means that the selection and combination of CHM for treating stroke, especially during the acute phase, should not only be based on their pharmacological mechanisms but also align with the patient's condition and the treatment goals at different stages of the disease. These treatment goals include hemostasis, elimination of blood clots and brain edema, anticoagulation, thrombolysis, anti-inflammation, and neuroprotection. For ICH, classification based on the amount and the location of the hemorrhage, and the severity of neuroinflammation is also necessary. One of the challenges in treating acute ICH is the subsequent development of cerebral infarction, which is more likely to occur with larger hemorrhages.[108] Therefore, for patients with significant bleeding, it is often necessary to increase the anticoagulant effects of CHM after bleeding has ceased.

In short, replacing a standardized “one-formula-fits-all” approach with a treatment strategy based on syndrome classification or cause/symptom differentiation is a wiser choice.

The Emergency Treatment Time Window for Acute Stroke using Chinese Herbal Medicine

In Western medicine, to make emergency care for acute ischemic stroke, it is essential to first quickly differentiate between ischemic and hemorrhagic stroke types, emphasizing the critical “golden window period”—the initial hours following symptom onset when treatment is most effective. For ischemic stroke, emergency treatment aims to restore blood flow, potentially involving immediate thrombolytic therapy (for example, tPA or tenecteplase) or mechanical thrombectomy. For hemorrhagic stroke, treatment focuses on controlling bleeding and reducing intracranial pressure. Advanced stroke protocols also incorporate neuroprotective therapies.

A well-rounded CHM formula, even if perfectly tailored to the syndrome or aligned with the individual's condition, requires precise timing for application, especially in the treatment of acute stroke. For example, consider the Zhongfeng Xingnao Tang for acute ICH study recently published in 2024 regarding the optimal therapeutic time window for intervention; a closer examination of the subgroup analysis in the published data shows a relationship between the timing of administration and the efficacy observed 90 days later. The results show that initiating treatment 24 hours after onset yields significantly better outcomes compared with starting between 12 to 24 hours postonset.[12] This is clearly determined by the pharmacological mechanism of the CHM formula in treating acute ICH: its primary goal is not hemostasis but rather addressing potential posthemorrhage complications such as inflammation, cerebral edema, cerebral infarction, and other neural injuries. The immediate inflammatory response following hemorrhage plays a positive role in repairing damage, but by this time window, anti-inflammatory actions and neuroprotection become crucial. Additionally, the CHM formula's effectiveness becomes more pronounced in preventing or mitigating posthemorrhagic cerebral infarction symptoms.

If the use of CHM for treating acute ICH is best initiated after bleeding has been controlled, then for ischemic stroke, is there no such time restriction, or should it also be administered as early as possible, similar to thrombolytic pharmaceuticals? To answer the questions, let us examine two classic CHM formulas commonly used for stroke: Angong Niuhuang Wan and Buyang Huanwu Tang.

Angong Niuhuang Wan, originally formulated by Dr. Wu Jutong during the Qianlong period during the Qing dynasty and recorded in Wenbing Tiaobian (Detailed Analysis of Epidemic Warm Diseases) is primarily used for febrile diseases with pathogenic factors affecting the pericardium, presenting with high fever, convulsions, coma, and delirium. It has the effects of clearing heat and detoxifying, calming the mind, and restoring consciousness. It is often regarded as a “miracle drug” for stroke emergencies, used in cases of early signs of febrile stroke or immediately upon stroke onset. Timely administration can protect the brain and reduce damage. The formula consists of 12 CHM, including Niuhuang (Bovis Calculus Biliaris; 20%), Shuiniu Jiao Nongsuofen (Bubali Cornu extract powder; 20%), Yujin (Curcumae Radix; 15%), Shexiang (Moschus; 5%), as well as Huanglian (Coptidis Rhizoma), Zhenzhu (Margarita), Huangqin (Scutellariae Radix), Zhizi (Gardeniae Fructus), Bingpian (Borneolum Syntheticum), Zhusha (Cinnabaris), and Xionghuang (Realgar). Modern pharmacological studies have shown that not only does its main ingredient, Niuhuang (Bovis Calculus), has clear heat-reducing, sedative, anticonvulsant, antihypertensive, hemostatic, resuscitative, and hepatoprotective effects, but it also increases cerebral blood flow and protects cerebral vasculature.[109] Additionally, some active components in the formula can eliminate key factors that induce inflammation and BBB damage. Clinical trials have demonstrated that when treating acute stroke, combining comprehensive rescue measures with Angong Niuhuang Wan results in significantly better outcomes compared with standard comprehensive rescue measures alone.[6] Animal model studies have also shown that Angong Niuhuang Wan can inhibit inflammatory responses after ICH, protect against tissue damage following hemorrhage, and provide protection during reperfusion after cerebral ischemia.[7] However, some facilities in the West, such as the International Neurosurgical Circle, remain skeptical and do not recommend consuming Angong Niuhuang Wan during the acute phase of ICH.[110]

Because Angong Niuhuang Wan has slight toxicity, and the toxic substance is clearly identified (Xionghuang), it is not suitable as a daily preventive measure for stroke or for treating poststroke sequelae. However, animal studies have demonstrated that short-term, regular use of Angong Niuhuang Wan for treating ischemic stroke is safe and effective.[111] [112] For acute ischemic stroke, the earlier Angong Niuhuang Wan is administered the better the outcomes. Chen et al.'s team simulated a situation in rats where tPA treatment was delayed for 5 hours after the onset of ischemic stroke. In the rat model, Angong Niuhuang Wan (257 mg·kg⁻¹) was taken within 2 hours of cerebral ischemia. This dose for animals is equivalent to the standard daily dose for humans (one pill per day), helping to extend the golden treatment time window by half an hour. It significantly reduced the damage to the BBB caused by delayed tPA injection in rats 5 hours after cerebral ischemia, decreased cerebral edema, neurological deficits, and neuronal apoptosis, lowered the risk of ICH, and reduced mortality. In summary, Angong Niuhuang Wan can serve as an adjunct therapy to Western thrombolytics, extending the golden treatment time window for ischemic stroke patients by half an hour and reducing the risk of ICH and mortality associated with thrombolytic therapy.[110]

As mentioned previously, Buyang Huanwu Tang is another formula suitable for treating acute ischemic stroke and poststroke sequelae. Recorded in Yilin Gai Cuo by Qing dynasty TCM practitioner, Dr. Wang Qingren. According to the text, “For initial onset of hemiplegia, add 1 Qian of Fangfeng (Ligusticum) to the basic formula; after taking 4–5 doses, discontinue it… For cases lasting two to three months, if previous treatments used excessive cold or cooling CHM, add 4–5 Qian of Fuzi (Aconm Lateralis Radix Praeparaia).” Based on Qingren's experience, Buyang Huanwu Tang is primarily used for “initial onset” or “poststroke sequelae lasting 2 to 3 months.”[113] Modern pharmacological studies have shown that Buyang Huanwu Tang can effectively reduce lipid levels, dilate blood vessels, and inhibit platelet aggregation. It also inhibits thrombosis formation and development, promotes thrombolysis, and restores vascular patency.[1] [2] Buyang Huanwu Tang is not only effective in treating acute ischemic stroke[5] but also applicable for early treatment of poststroke sequelae, meaning it has a relatively broader therapeutic time window.

Balancing anticoagulation and hemostasis is a challenging task closely linked to the golden time window. Overintervention can convert ischemic stroke into hemorrhagic stroke, and vice versa. This challenge is not limited to pharmaceuticals but also applies to CHM. However, as “natural” remedies, CHM generally has milder effects compared with pharmaceuticals. Most blood circulation-promoting and blood stasis-removing CHM primarily focus on anticoagulation and promoting the absorption of stagnant blood, rather than lowering blood pressure or stopping bleeding. Therefore, their safety profile is significantly higher than that of pharmaceuticals. For example, Zhongfeng Xingnao Tang has been shown to be safe when used within 72 hours after the onset of hemorrhagic symptoms, without increasing the risk of rebleeding.[104] Recent studies have further demonstrated that continuous use for 28 days is also safe.[12] A meta-analysis has shown that Angong Niuhuang Wan can improve neurological function and is safe for patients with acute ischemic or hemorrhagic stroke.[114] Chen et al. have also confirmed that the standard adult dose (one pill daily for 1 week) is safe.[110] Buyang Huanwu Tang has been used without adverse effects in clinical practice.[3] [4]

However, exceptions can occur. Take Dahuoluo Wan as an example. This CHM formula consists of 50 CHMs, including certain toxic substances like Qishe (Agkistrodon), Caowu (Aconitum), and Niuhuang (Bovis Calculus), and is primarily used to treat hemiplegia caused by stroke.[8] Studies have shown that Dahuoluo Wan can effectively promote the recovery of neurological function in ischemic stroke patients[9] [10] and help prevent recurrent ischemic stroke.[11] However, when using Dahuoluo Wan for stroke, it must be administered after the condition has stabilized. For hemorrhagic stroke patients, it should only be taken after bleeding has been controlled. Even for ischemic stroke patients, extreme care must be taken to avoid excessive anticoagulation or thrombolysis, which could lead to the transformation of ischemic stroke into hemorrhagic stroke. One of the authors recalled that his own paternal grandfather experienced an ischemic stroke in 1953, with only mild hemiplegia. However, during his initial use of Dahuoluo Wan, he developed a secondary hemorrhagic stroke, resulting in severe symptoms such as aphasia that took years to recover. Of course, it is important to note that this second stroke may not have been directly related to the use of Dahuoluo Wan.

The original English Mollet et al. illustrates the temporal progression of cellular and molecular consequences following ischemic stroke: excitotoxicity, necrosis, oxidative, and nitrosative stress occur rapidly in the stroke core immediately after ischemia. Subsequently, over hours to days, apoptosis, neuroinflammation, bioenergetic catastrophe, BBB disruption, and persistent oxidative and nitrosative stress develop.[14] Modifications have been added in the original to incorporate the corresponding time windows and treatment principles of CHM. As shown in our redrawn [Fig. 2], the application of CHM should be tailored to the distinct stages of ischemic stroke, which vary from minutes to weeks. To protect or minimize neuronal damage from various toxicities, tonifying qi CHM should be consistently administered throughout the entire process, from the onset of the stroke to the recovery phase. Anti-inflammatory CHMs are most critical during the acute phase, starting a few hours after stroke onset and continuing for several days. Promoting blood circulation and removing blood stasis CHM, initiated alongside anti-inflammatory agents, can be extended into the recovery phase to support vascular and neuronal regeneration and rehabilitation. This figure succinctly highlights the temporal application of different CHM principles, emphasizing the importance of timing in optimizing therapeutic outcomes.

Chinese Herbal Medicine and Acupuncture Combined Therapy: Synergistic Effects and Complementary Advantages

In the treatment of stroke and its sequelae within the framework of TCM, acupuncture has been extensively utilized in conjunction with CHM, amassing substantial clinical experience.[115] The application of acupuncture during the acute phase of ICH has been extensively researched, focusing on its therapeutic value and underlying mechanisms.[116] [117] Evidence underscores that the integration of acupuncture with CHM frequently yields superior outcomes compared with CHM alone, particularly for acute stroke. A paradigmatic example is the combined use of Buyang Huanwu Tang with acupuncture.

Buyang Huanwu Tang is a well-established CHM formula for managing cerebral infarction.[118] [119] [120] [121] A recent study conducted by Hu[122] involved 60 patients with cerebral infarction and hemiplegia, randomly divided into a control group (receiving only the decoction) and a combined therapy group (receiving the decoction plus acupuncture), with 30 patients in each group. All participants underwent standard therapeutic interventions, including anticoagulation, nutritional support, and rehabilitation guidance. Both groups underwent continuous treatment for one month. The study revealed that the combined therapy group demonstrated significantly greater improvement in neurological function, TCM symptom scores, hemorheological indices, and limb function compared with the control group.

When employing CHM to treat stroke, what advantages does acupuncture offer as an adjunct therapy? Acupuncture possesses several unique benefits that are difficult to replicate with CHM alone, such as facilitating recovery of consciousness and spinal shock.[123] Acupuncture can rapidly modulate cerebral blood flow, resulting in significant instant therapeutic effects in stroke treatment.[124] For example, scalp acupuncture has been observed to produce immediate effects in both hemorrhagic and ischemic strokes, with muscle strength in the paralyzed side increasing by two grades or more within 10 minutes postneedling.[125] A study by Dong et al.[126] [127] demonstrated that 60.71% (34/56) of hemorrhagic stroke patients in the scalp acupuncture group exhibited immediate effects, a phenomenon not observed in the drug or surgical therapy groups. Additionally, acupuncture is highly suitable for controlling inflammation during the acute phase of ICH.[116] [128] Unlike pharmacological interventions, the neural stimulation provided by acupuncture offers bidirectional regulation of inflammation, making it applicable to any stage of the inflammatory process.[129]

In comparison to the direct stimulation of somatic sensory and/or motor nerves by acupunctures, resulting in instant effects, the strength of CHM lies in their sustained and mild effect, including anticoagulant, thrombolytic, and blood circulation-promoting and blood stasis-removing actions. These CHMs can provide a slow, sustained regulation tailored to the patient's constitution and disease manifestations through natural pharmacological agents. Numerous clinical studies have validated that the combination of acupuncture and Buyang Huanwu Tang for the treatment of cerebral infarction and its sequelae yields better outcomes than acupuncture alone. This integrated approach can comprehensively promote the recovery of cerebral infarction patients, significantly improve their neurological deficits, and enhance their quality of life.[130] [131] In a 2022 retrospective study by Tseng et al.,[132] a total of 255 hospitalized patients with hemorrhagic and ischemic stroke were divided into two groups: an acupuncture-only group and an acupuncture + CHM group. The study observed that the combination of acupuncture and CHM, combined with conventional rehabilitation therapy, significantly improved early functional recovery in the subacute phase of stroke compared with acupuncture combined with conventional rehabilitation alone.

The above evidence clearly demonstrates that the combination of acupuncture and CHM offers complementary benefits, enhancing therapeutic efficacy. Of particular note is the role of acupuncture in stimulating the vagus nerve, either directly or indirectly, to improve cerebral blood flow, reduce inflammation, and significantly mitigate brain parenchymal damage caused by stroke. Both ischemic and hemorrhagic stroke progression are influenced by vagal afferent and efferent pathway activity, encompassing peripheral and neuroinflammation, as well as neuroplasticity.[133] Vagal nerve stimulation may exert neuroprotective effects by reducing inflammation, cerebral edema, and oxidative stress.[134] Currently, vagal nerve stimulation is under investigation as a potential treatment for brain injury, particularly traumatic brain injury. Recent research has further revealed that vagal nerve stimulation can induce hemostasis, a mechanism referred to as the “neural tourniquet.”[135] This neurohemostatic mechanism is likely present in the brain, meaning that vagal nerve stimulation may restrict ICH during stroke.[133] Since the auricular concha area contains vagal afferent nerve fibers,[136] transcutaneous electrical stimulation or acupuncture of the auricular vagal nerve distribution area now offers a simple and safe alternative to direct vagal nerve stimulation. It is reasonable to speculate that combining acupuncture targeting the vagal nerve distribution in the auricle with CHM may represent a promising therapeutic approach for stroke.

Conclusion

Stroke, particularly during its critical acute phase, presents significant complexity in its pathological process. The limitations and side effects of Western medical interventions have led to a growing emphasis on integrating CHM into stroke therapy, a trend supported by decades of clinical and pharmacological research. This approach has demonstrated the potential to mitigate brain injuries and poststroke sequelae while enhancing therapeutic outcomes. CHM principles, such as qi-tonifying, blood circulation-promoting, blood stasis-removing, and detoxification, offer a rational foundation for stroke treatment when interpreted through modern medical understanding. These principles align with contemporary therapeutic goals, including neuroprotection and inflammation modulation. Treatment of acute stroke, as a complex disease, requires a personalized approach tailored to individual conditions. The selection and application of CHM monomers or formulas should be guided by individualized syndrome differentiation and administered within optimal therapeutic time windows to maximize efficacy and safety. Additionally, combining acupuncture with CHM may yield synergistic benefits. By adopting these principles, CHM could improve stroke treatment efficacy and practicality.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Guanyuan Jin: Conceptualization, software and methodology, formal analysis, data curation, supervision, investigation, writing—original draft, review, and editing. Louis Lei Jin: Data curation, software and methodology, visualization, supervision, investigation, writing—review and editing. Belinda Jie He: Writing—review and editing.

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Publication History

Received: 02 November 2024

Accepted: 28 December 2024

Article published online:
08 April 2025