Senkyunolide A Attenuates OGD/R-Induced HT22 Cell Injury by Inhibiting Oxidative Stress and Apoptosis

Abstract

Objective

This study aimed to investigate the protective effect and mechanism of Senkyunolide A (SenA) on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in mouse hippocampal neuronal HT22 cells, providing experimental evidence for elucidating the application of SenA in the prevention and treatment of cerebral ischemia–reperfusion injury.

Methods

An HT22 cell injury model was established using the OGD/R method and divided into the Control group, Model (OGD/R) group, Edaravone (EDA) group (OGD/R + EDA), and SenA group (OGD/R + SenA). Cell viability was detected by Cell counting kit-8 (CCK-8) assay; live and dead cells were observed by Calcein AM/PI cell viability assay kit (Calcein-AM/PI) double staining; intracellular reactive oxygen species (ROS) levels were measured using the H2DCFDA (DCFH-DA) fluorescent probe; levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were determined by biochemical kits; apoptosis rate was detected by flow cytometry; protein expression levels of Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), and Cysteine-dependent aspartate-specific protease-3 (Caspase-3) were measured by Western blot.

Results

Compared with the Control group, the OGD/R group showed significantly reduced cell viability (p < 0.001), increased proportions of dead cells, ROS and MDA levels, and apoptosis rate (p < 0.001), decreased SOD activity and GSH levels (p < 0.05; p < 0.001), significantly upregulated protein expression of Bax and Caspase-3 (p < 0.01; p < 0.001), and downregulated Bcl-2 expression (p < 0.001). Compared with the OGD/R group, both SenA and EDA significantly increased cell viability (p < 0.001), reduced the proportion of dead cells, ROS and MDA levels, and apoptosis rate (p < 0.001), upregulated SOD activity and GSH levels (p < 0.01; p < 0.001), downregulated protein expression of Bax and Caspase-3 (p < 0.01; p < 0.001), and upregulated Bcl-2 expression (p < 0.001).

Conclusion

SenA can alleviate OGD/R-induced neuronal injury by mitigating oxidative stress and inhibiting cell apoptosis. This study provides modern experimental evidence for the traditional theory of Chuanxiong in “promoting blood circulation, removing blood stasis, and unblocking brain collaterals,” and offers new insights for the prevention and treatment of ischemia–reperfusion brain injury with traditional Chinese medicine.

Keywords

ischemic stroke - senkyunolide A - oxygen-glucose deprivation/reoxygenation - oxidative stress - apoptosis

Introduction

Stroke is a major global cause of disability and death, characterized by high incidence, disability, and mortality rates in China,[1] [2] with ischemic stroke (IS) accounting for approximately 80% of cases.[3] Although thrombolysis and anticoagulation therapies can restore cerebral blood flow, reperfusion often leads to cerebral ischemia–reperfusion injury (CIRI), exacerbating neurological dysfunction.[4] Due to the narrow therapeutic window and limited efficacy of existing treatments, there is an urgent need to develop safe and effective novel neuroprotective agents.

Modern pharmacological studies have confirmed that oxidative stress is a key mechanism in the pathogenesis of CIRI.[5] [6] During ischemia–reperfusion, excessive generation of reactive oxygen species (ROS) leads to redox imbalance, mitochondrial dysfunction, and lipid peroxidation, ultimately resulting in neuronal apoptosis.[7] [8] Therefore, alleviating oxidative stress and inhibiting apoptosis are critical therapeutic strategies for reducing neuronal damage caused by CIRI. Edaravone (EDA) was initially approved in Japan in 2001 for the treatment of IS[9]; however, recent clinical studies have shown side effects such as hepatotoxicity, increased bleeding risk, and lipid metabolism disorders.[10]

Traditional Chinese medicine (TCM) considers stroke to fall under the category of “wind stroke,” with the core pathogenesis being disorder of qi and blood, and obstruction of collaterals by wind, fire, phlegm, and stasis. The basic treatment principle is “promoting blood circulation to remove stasis, calming wind, and unblocking collaterals.” As stated in the Chapter on the Ultimate Truth in The Yellow Emperor's Inner Classic: Basic Questions (Huangdi Neijing Suwen): “When blood and qi flow disorderly in the meridians and settle in the brain, it affects the marrow,” suggesting that impaired cerebral blood circulation is closely related to mental disorders. Chuanxiong (Chuanxiong Rhizoma), pungent in taste and warm in nature, acts on the liver, gallbladder, and pericardium meridians. It has the effects of promoting blood circulation, moving qi, dispelling wind, and relieving pain, and has been commonly used in TCM for stroke treatment throughout history. Senkyunolide A (SenA) is a major bioactive component extracted from Chuanxiong (Chuanxiong Rhizoma), with anti-inflammatory, antioxidant, and neuroprotective effects.[11] [12] Some studies have shown that SenA can alleviate CIRI-induced central nervous system injury in rats[13] and function by inhibiting NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-mediated ferroptosis.[14] However, its direct protective mechanisms on central neurons remain unclear. This study is the first to investigate the effect and mechanism of SenA on oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury in HT22 hippocampal neurons, revealing that it exerts neuroprotective effects by alleviating oxidative stress and inhibiting apoptosis, providing new evidence for elucidating the modern scientific connotation of Chuanxiong (Chuanxiong Rhizoma) in “promoting blood circulation, unblocking collaterals, and nourishing the brain to protect the spirit.”

Materials

Cells

The mouse hippocampal neuronal cell line HT22 (CL-0697) was purchased from Wuhan Procell Life Science and Technology Co., Ltd.

Drugs and Reagents

SenA (purity >98%) was purchased from Shanghai Yuanye Bio-Technology Co., Ltd.; EDA (purity >99%) was purchased from Merck and Co., Inc.; Dulbecco's modified Eagle medium (DMEM), fetal bovine serum (FBS), and penicillin–streptomycin were all purchased from HyClone Laboratories; glucose-free DMEM was purchased from Gibco (Thermo Fisher Scientific); CCK-8 assay kit was purchased from Absin Bioscience Inc. (Shanghai); Calcein-AM/PI staining kit and ROS assay kit were purchased from Beyotime Biotechnology (Shanghai); malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) assay kits were purchased from Nanjing Jiancheng Bioengineering Institute; Bicinchoninic acid (BCA) protein assay kit and Annexin V-Fuorescein isothiocyanate (FITC)/PI apoptosis detection kit were purchased from Beijing Solarbio Science and Technology Co., Ltd.; Caspase-3 (D3R8Y) antibody was purchased from Cell Signaling Technology; Bax (AB32503) antibody was purchased from Abcam, United Kingdom; Bcl-2 (A19693) antibody, β-actin (AC026) antibody, and goat anti-rabbit secondary antibody (AS014) were all purchased from ABclonal Technology Co., Ltd. (Wuhan).

Instruments

Multimode microplate reader (SYNERGY-LX, BioTek Instruments); chemiluminescence imaging system (ChemiDoc™ Imaging System, Bio-Rad Laboratories); fluorescence inverted microscope (ECLIPSE Ts2-FL, Leica Microsystems); CO₂ incubator (3111, Thermo Fisher Scientific); and flow cytometer (CytoFLEX, Beckman Coulter).

Methods

Cell Culture

HT22 cells were cultured in complete DMEM supplemented with 10% FBS and 100 U/mL penicillin–streptomycin, and maintained in a 37 °C, 5% CO₂ incubator.

Oxygen-Glucose Deprivation/Reoxygenation Model

HT22 cells were seeded in culture dishes at a density of 8 × 10⁵ cells/mL. When cell density reached 60% to 70%, the medium was replaced with glucose-free DMEM, and the cells were placed in a hypoxic chamber (95% N₂ and 5% CO₂) at 37 °C for 10 hours of hypoxia. Subsequently, the medium was replaced with high-glucose DMEM, and the cells were reoxygenated under normoxic conditions for 6 hours. The durations of hypoxia and reoxygenation were based on our preliminary studies.[15] Both SenA and EDA were added to the medium during the reoxygenation phase for intervention.

CCK-8 Assay for Cell Viability

HT22 cells were seeded in 96-well plates at a density of 5 × 10⁴ cells/mL and cultured for 24 hours, followed by OGD/R treatment. During reoxygenation, different concentrations of SenA (5, 10, 20, 40, 60, and 80 μM) or EDA (50 μM) were added and incubated for 6 hours. Then, 10 μL of CCK-8 reagent was added to each well and incubated at 37 °C in the dark for 30 minutes. Absorbance was measured at 450 nm.

Live/Dead Cell Staining

HT22 cells were seeded in 24-well plates (1.5 × 10⁵ cells/mL) and cultured for 24 hours, followed by OGD/R treatment. SenA (40 μM) or EDA (50 μM) was added and incubated for 6 hours. Cells were stained using the Calcein-AM/PI double staining kit, observed under a fluorescence microscope, and the proportion of dead cells was calculated.

Reactive Oxygen Species Level Detection

Intracellular ROS levels were detected using the DCFH-DA staining kit. HT22 cells were seeded in 6-well plates (3 × 10⁵ cells/mL) and cultured for 24 hours, followed by OGD/R treatment. SenA (40 μM) or EDA (50 μM) was added and incubated for 6 hours. The DCFH-DA probe was diluted at a 1:1,000 ratio (final concentration 10 μmol/L) and incubated at 37 °C in the dark for 25 minutes. After washing three times with PBS, images were captured under a fluorescence microscope.

Malondialdehyde, Superoxide Dismutase, and Glutathione Detection

HT22 cells were seeded in 60-mm culture dishes (5 × 10⁵ cells/mL). OGD/R treatment and drug administration were consistent with the above methods. Cells were collected and lysed with radio immunoprecipitation (RIPA) lysis buffer via sonication (300 W, 5 s ON, 10 s OFF, 30 cycles), centrifuged at 12,000 g for 20 minutes, and the supernatant was collected. MDA, SOD, and GSH levels were determined according to the kit instructions. Protein concentration was measured using the BCA method.

Apoptosis Detection

Cell apoptosis rate was detected by flow cytometry using the Annexin V-FITC/PI double staining method. After OGD/R modeling, SenA (40 μM) or EDA (50 μM) was added for intervention. Subsequently, 5 μL each of Annexin V-FITC and PI were added and incubated at room temperature for 5 minutes before detection. Total apoptosis rate = Early apoptosis rate + Late apoptosis rate.

Western Blot

Protein was extracted from the collected cells of each group, and protein concentration was determined using the BCA method. Protein samples were mixed with loading buffer and boiled, then separated by SDS-PAGE and transferred to PVDF membranes. The membranes were blocked with 5% skim milk for 1 hour, then incubated with primary antibodies against Caspase-3 (1:4,000), Bcl-2 (1:500), and Bax (1:2,000) at 4 °C overnight. The next day, membranes were incubated with secondary antibody (1:10,000) at room temperature for 1 hour. After washing, bands were visualized using ECL chemiluminescence. β-actin was used as an internal reference for protein expression quantification.

Statistical Analysis

Data are expressed as mean ± standard error of the mean (mean ± SEM). Statistical analysis was performed using SPSS 27.0 software. Intergroup comparisons were conducted using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test. A p-value of <0.05 was considered statistically significant.

Results

Effect of Senkyunolide A on Oxygen-Glucose Deprivation/Reoxygenation-Induced HT22 Cell Injury

The effect of different concentrations of SenA on cell viability is shown in [Fig. 1A]. SenA significantly reduced cell viability at concentrations greater than 100 μM (p < 0.001). SenA significantly increased the survival rate of HT22 cells induced by OGD/R ([Fig. 1B]), with 40 μM showing the most pronounced effect (p < 0.001), comparable to EDA. Therefore, the concentration of 40 μM was selected for subsequent experiments. Calcein-AM/PI staining results further confirmed that both SenA and EDA significantly reduced the proportion of dead cells (p < 0.001), indicating that SenA effectively alleviates OGD/R-induced HT22 cell injury ([Fig. 1C, D]).

Fig. 1 Effect of SenA on OGD/R-induced HT22 cell injury (×200; n = 3). (A) Effect of different concentrations of SenA on HT22 cell viability (n = 6). (B) Effect of different concentrations of SenA on OGD/R-induced HT22 cell injury (n = 6). (C) Effect of SenA on the proportion of dead HT22 cells induced by OGD/R. (D) Proportion of live and dead HT22 cells detected by Calcein-AM/PI double staining. Compared with the Control group, ***p < 0.001; compared with the OGD/R group, ^# p < 0.05, ^## p < 0.01, ^### p < 0.001. Scale bar: 50 μm. EDA, edaravone; OGD/R, oxygen-glucose deprivation/reoxygenation; SenA, senkyunolide A.

Effect of Senkyunolide A on Oxygen-Glucose Deprivation/Reoxygenation-Induced Oxidative Stress

As shown in [Fig. 2A, B], OGD/R significantly increased ROS levels (p < 0.001), while both the SenA and EDA groups showed significantly reduced ROS levels (p < 0.001). Compared with the Control group, the OGD/R group showed significantly increased MDA levels (p < 0.001) and significantly decreased SOD activity and GSH levels (p < 0.05; p < 0.001). SenA and EDA significantly reduced MDA levels (p < 0.001) while increasing SOD activity and GSH levels (p < 0.01; p < 0.001; [Fig. 2C–E]). These results indicate that SenA can effectively alleviate OGD/R-induced cellular oxidative stress injury.

Fig. 2 Effect of SenA on OGD/R-induced oxidative stress levels in HT22 cells (×200; n = 4). (A) Intracellular ROS levels detected by DCFH-DA staining. (B) Quantification of intracellular ROS (n = 3). (C) Cellular MDA levels. (D) Cellular SOD activity (n = 4). (E) Cellular GSH levels (n = 4). Compared with the Control group, *p < 0.05, ***p < 0.001; compared with the OGD/R group, ^## p < 0.01, ^### p < 0.001. Scale bar: 50 μm. EDA, edaravone; GSH, glutathione; MDA, malondialdehyde; OGD/R, oxygen-glucose deprivation/reoxygenation; ROS, reactive oxygen species; SenA, senkyunolide A; SOD, superoxide dismutase.

Effect of Senkyunolide A on Oxygen-Glucose Deprivation/Reoxygenation-Induced Apoptosis

As shown in [Fig. 3], compared with the Control group, the OGD/R group showed a significantly increased apoptosis rate (p < 0.001). Treatment with SenA and EDA significantly reduced the apoptosis rate (p < 0.001), indicating that SenA can inhibit OGD/R-induced cell apoptosis.

Fig. 3 Effect of SenA on OGD/R-induced apoptosis in HT22 cells (n = 3). (A) Apoptosis of HT22 cells detected by flow cytometry. (B) Total cell apoptosis rate. Compared with the Control group, ***p < 0.001; compared with the OGD/R group, ^### p < 0.001. EDA, edaravone; OGD/R, oxygen-glucose deprivation/reoxygenation; SenA, senkyunolide A.

Effect of Senkyunolide A on Bax, Bcl-2, and Caspase-3 Protein Expression

As shown in [Fig. 4], compared with the Control group, the OGD/R group showed significantly increased protein expression levels of Bax and Caspase-3 (p < 0.01; p < 0.001) and a significantly decreased Bcl-2 level (p < 0.001). Compared with the OGD/R group, the SenA and EDA groups showed significantly reduced protein expression levels of Bax and Caspase-3 (p < 0.01; p < 0.001) and a significantly increased Bcl-2 level (p < 0.001). The results indicate that SenA exerts its antiapoptotic effect by regulating the Bax/Bcl-2 balance and inhibiting Caspase-3 activation.

Fig. 4 Effect of SenA on Bax, Bcl-2, and Caspase-3 protein expression (n = 3). (A) Western blot bands of Bax, Bcl-2, and Caspase-3 in each group. (B) Relative quantification of Bax protein. (C) Relative quantification of Bcl-2 protein. (D) Relative quantification of Caspase-3 protein. Compared with the Control group, **p < 0.01, ***p < 0.001; compared with the OGD/R group, ^## p < 0.01, ^### p < 0.001. EDA, edaravone; OGD/R, oxygen-glucose deprivation/reoxygenation; SenA, senkyunolide A.

Discussion

This study confirms that SenA has a significant protective effect against OGD/R-induced HT22 cell injury. It not only increases cell survival rate but also effectively alleviates OGD/R-induced oxidative stress and apoptosis, which are core pathological links in CIRI, suggesting that SenA has good application potential in CIRI intervention. From the perspective of TCM, Chuanxiong (Chuanxiong Rhizoma) is pungent in taste and warm in nature, acting on the liver, gallbladder, and pericardium meridians. It has the effects of promoting blood circulation, moving qi, dispelling wind, and relieving pain. It has been commonly used by physicians throughout history for patterns such as “wind stroke with unconsciousness” and “headache and dizziness,” which are related to obstruction of the brain collaterals. As an important active component of Chuanxiong (Chuanxiong Rhizoma), modern pharmacology finds that SenA aligns with the traditional efficacy of Chuanxiong (Chuanxiong Rhizoma) in “promoting blood circulation to remove stasis and unblocking the brain collaterals,” providing modern scientific evidence for the TCM treatment of cerebral ischemic diseases.

Apoptosis is a key mechanism leading to neuronal loss in CIRI,[16] and excessive neuronal apoptosis can exacerbate brain tissue damage and impair neurological functional recovery.[17] [18] This study found that SenA significantly enhanced cell viability in the OGD/R model, with the optimal protective effect observed at 40 μM, comparable to the clinical neuroprotective agent EDA. Live/dead cell staining further confirmed that SenA markedly alleviated OGD/R-induced cell injury. Mechanistically, SenA downregulated the expression of proapoptotic proteins Bax and Caspase-3 while upregulating the antiapoptotic protein Bcl-2, thereby inhibiting apoptosis. Caspase-3 is a key executor of apoptosis, and its excessive activation is closely associated with various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and stroke.[19] [20] [21] [22] Bax promotes mitochondrial membrane permeability and activates the caspase cascade, whereas Bcl-2 exerts antiapoptotic effects by antagonizing Bax activity.[23] [24] The results of this study demonstrate that SenA significantly reduces OGD/R-induced neuronal apoptosis by modulating the Bcl-2/Bax balance and inhibiting Caspase-3 activation, thereby maintaining neuronal survival and functional stability.[25]

Oxidative stress is another core mechanism in CIRI injury, characterized by excessive ROS generation and exhaustion of the endogenous antioxidant system.[26] Accumulation of ROS can lead to lipid peroxidation, DNA damage, and cell death.[27] This study revealed that OGD/R treatment significantly increased ROS and MDA levels in HT22 cells while reducing SOD activity and GSH content. However, the SenA intervention markedly improved these indicators, suggesting its potent antioxidant activity. Previous studies have reported that SenA can regulate redox homeostasis and alleviate oxidative stress injury by activating the SIRT6/Nrf2 pathway.[28] Additionally, SenA inhibits NLRP3-mediated ferroptosis and reduces lipid peroxidation.[14] The findings of this study are consistent with these reports, further confirming that SenA mitigates neuronal oxidative stress damage by enhancing cellular antioxidant capacity and scavenging excess free radicals.

Conclusion

In summary, this study demonstrates for the first time that SenA exerts significant protective effects against OGD/R-induced neuronal injury, likely through mitigating oxidative stress and inhibiting apoptosis. As a key active component of Chuanxiong (Chuanxiong Rhizoma), the neuroprotective effects of SenA provide modern pharmacological evidence for its traditional efficacy in “promoting blood circulation to remove stasis and unblocking brain collaterals,” offering new insights and scientific rationale for TCM-based intervention in CIRI.

Conflict of Interest

The authors declare no conflict of interest.

CRediT Authorship Contribution Statement

Roujia Guo: Methodology, investigation, visualization, and writing original draft. Yufang Zhao: Investigation, and data curation. Zhouli Yue: Conceptualization, investigation, formal analysis, and visualization. Yucheng Li: Project administration, supervision, conceptualization, funding acquisition, and writing-review & editing.

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Publication History

Received: 21 July 2025

Accepted: 17 September 2025

Article published online:
30 December 2025