Pistacia Genus as a Potential Source of Neuroprotective Natural Products

Neuroprotective agents are able to defend the central nervous system against acute or chronic neuronal injuries. Even with the progress made over the last decades, most of the medications prescribed for the management of neurodegenerative diseases can only reduce their symptoms and slow down their progression. Based on natural product research, there are potential effective medicinal plants and phytochemicals for modulating neuronal functions and protecting against neurodegeneration. Plants in the genus Pistacia are also among valuable natural resources for neuroprotection research based on experiences in traditional medicine. Studies have supported the value of bioactive compounds of the genus Pistacia for central nervous system disorders such as Alzheimerʼs, Parkinsonʼs, multiple sclerosis, cerebral ischemia, depression, and anxiety. Related literature has also revealed that most of the evidence on neuroprotection in the genus Pistacia is in the form of preliminary studies, mainly including models of behavior, motor function, and memory impairments in animals, neural toxicity, cerebral ischemia and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid β aggregation, and acetylcholinesterase as well as investigations into some cellular pathways. Along with the phytonutrients in kernels such as pistachios, various phytochemicals, mostly terpenes, and phenolic compounds have also been identified in different plant parts, in particular their oleoresins, of species in the genus Pistacia. In this review, the pharmacology of neurological effects and related molecular mechanisms of the plants belonging to the genus Pistacia and its active constituents, as well as pharmacokinetics aspects, are discussed.

Key words

Alzheimer - flavonoids - neurodegenerative diseases - Pistacia - phenolic compounds - terpenes

Abbreviations

6-OHDA: 6-hydroxydopamine

ABTS: 2,2′-azino-bis(3-ethylbenzothiazoline-6- sulphonic acid

AD: Alzheimerʼs disease

BDNF: brain-derived neurotrophic factor

CAT: catalase

CNS: central nervous system

COX-2: cyclooxygenase-2

DCF-DA: 2′,7′-dichlorofluorescin diacetate

DPPH: 2,2-diphenyl-1-picrylhydrazyl

GABA: gamma-aminobutyric acid

GPx: glutathione peroxidase

IL: interleukin

NF- k B: nuclear factor kappa-light-chain-enhancer of activated B cells

NO: nitric oxide

Nrf2: nuclear erythroid 2-related factor 2

PC12: pheochromocytoma cells

PD: Parkinsonʼs disease

PPAR: peroxisome proliferator-activated receptor

PTZ: pentylenetetrazole

SOD: superoxide dismutase

TBARS: thiobarbituric acid reactive substances

Introduction

As one of the remarkable modalities of complementary medicine, natural products create a potential platform for drug discovery and development, especially for chronic diseases and major health problems associated with aging. Concentrating on neuroprotective activity of natural products to control or prevent neurodegenerative diseases (NDs) is relatively a new research area [1]. It should be noted that neuroprotective agents are able to defend the CNS against acute (e.g., stroke or trauma) or chronic (e.g., AD and PD) neuronal injuries [2] resulting from the breakdown and deterioration of neurons [3]. Despite differences in anatomic distribution of NDs, leading to various manifestations, it seems that their pathologies have numerous similarities at subcellular levels [4]. In this respect, aggregation of proteins, inflammation, oxidative stress, as well as loss of neurotransmitters are considered among common pathologies of NDs [3]. Even with the progress made over the last decades, most of the clinically prescribed medications for the management of NDs can merely reduce ND symptoms and slow down their progression, and, conversely, lead to unavoidable adverse effects [5].

In recent years, plant-based products have received considerable attention. Hence, there is a strong tendency towards research on phytochemicals for modulating neuronal functions and protecting against neurodegeneration [6]. Numerous medicinal plants have also been recommended for the prevention and treatment of various diseases of the CNS in traditional medicine across the world [7]. Many of these herbs have been extensively studied regarding their neuroprotective effects. In addition, they have been reported to modulate multiple signal transduction pathways through direct effects on enzymes such as kinases, regulatory proteins, and receptors [8]. Panax ginseng C. A. Mey., Ginkgo biloba L., Curcuma longa L. and Bacopa monnieri (L.) Pennell. are among the most prominent plants examined in this field [7]. Plants in the genus Pistacia, belonging to the family Anacardiaceae [9], are also considered one of the valuable natural resources for neuroprotection research based on experiences in traditional medicine. This genus consists of at least 10 species in which Pistacia vera L., Pistacia lentiscus L., Pistacia terebinthus L., Pistacia atlantica Desf., and Pistacia integerrima J. L. Stewart ex Brandis. [Pistacia chinensis subsp. integerrima (J. L. Stewart ex Brandis) Rech. f.] are regarded as the most known ones. Among them, pistachios are more widely known because of the edible nature of their seeds. Although some others may also be suitable for eating, they are most often recognized for their oleoresin with industrial, pharmaceutical, and cosmetic uses [10]. In this study, along with elucidating traditional usage and evidence related to neuroprotective effects of these herbs, their major active ingredients and possible mechanisms of action as well as pharmacokinetic aspects were reviewed.

Traditional Medicinal Usage of the Pistacia Genus

Hippocrates, Dioscorides, and Galen reported the distinctive characteristics of mastic gum (P. lentiscus oleoresin), such as taste and odor as well as therapeutic properties. Based on historical documents, this substance was the first natural chewing gum of the ancient world of Europe that was used to clean the teeth and to freshen the breath [11]. P. lentiscus has traditionally been used for memory improvement, as well as the treatment of stomachache, burn skin, asthma, and bronchitis in Algeria [12]. Even though the most important use of this oleoresin was the treatment of digestive problems such as gastric pains, it was introduced as a brain booster and protector in Greek and Persian traditional medicines, both having the same roots according to historical references. Its oleoresin, especially with olibanum, has also been prescribed orally for this purpose, especially for memory improvement. It has similarly been recommended for treating some types of headaches, psychiatric disorders, and management of stroke [13]. Leaves of the plant are traditionally used for toothaches, mycosis, herpes, abdominal and intestinal pain, rheumatism, antiseptic, cicatrizant, and as an astringent in Italy [14], [15]. The fruits have been used in Tunisia as a condiment and also for the treatment of scabies, rheumatism, and diarrhea [16].

Most therapeutic applications and reported uses of P. atlantica are related to traditional Persian medicine since the western region of Iran is one of the largest centers for producing this species, and its oleoresin is being used as chewing gum [17]. This oleoresin has therapeutic uses similar to mastic gum according to the written documents in traditional Persian medicine [18], [19]. In fact, in these documents, it has been prescribed to strengthen the stomach and the teeth, and also to cleanse the brain from waste materials interfering with brain activity such as memory. Its processed trunk exudate is used to clear mouth, gum, and teeth diseases, improving memory, and reducing stress [20]. In the western regions of Iran, the fruit of this plant, named bane, is also used as a nut, usually after grinding [21].

Records of the consumption of fruits of P. vera (pistachio) as a food date back to 7000 BC. Now it is cultivated in the Middle East, especially in Iran and Mediterranean countries as well as Turkey and the United States [22]. The oleoresin is used in folkloric medicine as chewing gum in Europe and the Middle East. In India, pistachios have been reported as a remedy for liver disorders, abscesses, and poor circulation [23]. In Turkey, pistachio gum has been used as a treatment for asthma, stomachaches, and hemorrhoids [24]. The fruits and fruit kernel of P. vera are used for strengthening the liver, heart, and stomach and as a brain tonic in traditional Persian medicine, as well [18]. In some areas of Jordan, the oil of the fruit has been used as a facial skin cleanser [25]. P. integerrima (P. chinensis subsp. integerrima) is known as kakra shingi in India. Its gall is currently being utilized to treat hepatitis and liver problems in Pakistan [26]. It is also known as an aromatic, astringent, expectorant, sedative, and spasmolytic agent in Ayurveda, and is being employed to treat asthma and chronic bronchitis, dysentery, and fever, as well as skin diseases [27]. The fruit of P. terebinthus has been recommended for the treatment of colds, flu, stomachaches, rheumatism, and urinary inflammations. It has also been used as a diuretic, stimulant, antitussive, and appetizer, and as coffee in Turkey [28], [29], [30].

Evidence Related to the Neuroprotection in the Pistacia Genus

Search strategy

To obtain articles that directly assessed the neuroprotective activity of the plants in the Pistacia genus, databases including Scopus, PubMed, and Google Scholar were searched from 2000 to February 2019. Key words included “brain”, “memory”, “neuron”, “nootropic” “neuroprotective”, “neurodegenerative”, “cognition”, “dementia”, “Alzheimer”, “Parkinson”, “amyotrophic lateral sclerosis”, “stroke”, “seizure”, “anxiety”, and “depression” along with the word “Pistacia” and also with each full scientific name of the plants. All studies that were in English and had full text were selected. The strategy was run by two researchers and then the findings of both were combined and duplicates were deleted. Obtained studies are classified in [Table 1] regarding the details of each study, including plant part, type of study, dose, duration, and results.

Table 1 Pharmacological evidence related to the neuroprotection in the Pistacia genus.
Scientific name	Plant part	Extract/essential oil/active compound	In vivo/in vitro	Animal species	Dose/duration	Assay/method/model	Results	Ref
AChE: Acetylcholinesterase; i. p.: intraperitoneal; DPPH: 2,2-diphenyl-1-picrylhydrazyl; PTZ: pentylenetetrazol; MDA: Malondialdehyde; ABTS: 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid); DMPD: N,N-dimethyl-p-phenylenediamine; SOD: Superoxide dismutase; CAT: catalase; GSH: Glutathione
P. vera	Hull	Aqueous-methanolic extract	In vitro	–	100 µg/mL	AChE inhibitory assay.	AChE inhibitory activity	[34]
	Kernel	Oil	In vivo	Male rats	1 and 4 mL/kg; p. o.; 21 days	Morris water maze (MWM) and Y-CAT maze.	Improved memory performance in Y-CAT maze test. The extract did not affect spatial learning and memory parameters in MWM.	[32]
	Oleoresin	Hydroalcoholic extract	In vivo	Mice	0.25, 0.5, and 1 g/kg; i. p.	Pentobarbital model of sleep induction. Traction and rotarod tests. Elevated plus maze and open field tests.	Hypnotic, antianxiety, and muscle relaxant activities.	[40]
	Fruits	Pistachio suspension	In vivo	Male rats	10% dietary pistachio daily; 5 weeks	Model of motor and cognition impairments induced by cisplatin or vincristine. Rotarod and grasping tests; open field test. MWM	↓ Some learning, memory, and motor impairments.	[31]
	Hull	Methanolic extract	In vitro	–	–	AChE inhibitory assay.	AChE inhibitory activity.	[35]
	Kernel	Hydroalcoholic extract	In vivo	Rats	10, 50, and 100 mg/kg/day; p. o.; 14 days	Avoidance learning test using the shuttle box.	↑ The latency to enter the dark room. ↓ Time spent in the dark room improved learning and memory.	[33]
	Leaves	Aqueous and ethanolic extracts	In vivo	Mice	0.4 g/kg and 0.5 g/kg; i. p.	Hot plate and writhing tests. Xylene-induced ear edema. The cotton pellet test.	Antinociceptive.	[194]
	Ripe pistachio hulls	Hydroalcoholic extract	In vivo	Female Wistar rats	Single dose of 0.1, 1, 10, 50, 100, 250, 500 mg/kg; i. p.	Elevated plus maze model of anxiety.	Percentage of time spent in the open arms (%OAT), percentage of the number of entries into the open arms (%OAE).	[36]
	Seed	Hexan extract	In vitro	–	PC12 cells were pretreated with extract for 48 h (10%, v/v).	Measurement of intracellular oxidative stress. DPPH assay with Trolox. Measurement of cell viability by the MTT reduction assay.	↑ Cell viability. ↓ Intracellular ROS.	[37]
	Kernel	Hydroalcoholic extract	In vivo	Male rats	50 and 100 mg/kg, p. o.; every day (30 days)	Convulsive model induced by PTZ injection.	↓ Seizure scores, stage 4 latency and stage 5 duration.	[41]
	Gum	Hydroalcoholic extract	In vivo	Male NMRI rats	0.1, 0.25, 0.5 g/kg; i. p.	Thiobarbituric acid (TBA) and ferric reducing antioxidant power (FRAP) tests.	↓ Brain MDA. ↑ Antioxidant power of brain.	[38]
P. atlantica	Leaves, flowers	Essential oil	In vitro	–	500 µg/mL	β-Carotene-linoleic acid assay; DPPH and ABTS assays; AChE inhibitory assay.	Antioxidant activity. Anticholinesterase activity against acetylcholinesterase and butyrylcholinesterase.	[52]
	Fruits	Hydroalcoholic extract	In vivo	Gonadectomized rats	100 mg/kg of bane extract; p. o., daily for 20 days	Elevated plus maze model of anxiety.	↑ The percentage of time spent and entries in the open arms.	[53]
	Fruits	Hydroalcoholic extract	In vivo	Male rats	400 mg/kg/bw pistachio + fluvoxamine 120 mg/kg/bw	Immobilization stress radial arm maze test.	↓ The time of reaching to target. ↓ MDA, corticosterone and blood glucose level. ↑ CAT.	[54]
	Leaves	Aqueous extract	In vitro	–	–	AChE inhibitory assay. Radical scavenging activity.	AChE inhibitory activity. ↓ Hydroxyl, DMPD, superoxide and ABTS.	[50]
	Leaves	Methanolic extract, ethyl acetate extract	In vitro	–	–	Total antioxidant and free radical scavenging activity. β-Carotene bleaching test. AChE inhibitory assay.	Considerable antioxidant property. Slight AChE inhibitory activity.	[51]
	Oleoresin	Methanol and dichloromethane extracts	In vitro	–	–	AChE inhibitory assay.	Dichloromethane extract: AChE inhibitory activity.	[45]
	Fruit	Essential oil	In vivo	Rats, mice	200, 300, and 500 mg/kg	Hole-board, rotarod, catalepsy, hypnotic, light/dark tests.	CNS depressant, anxiolytic, sedative and anti-inflammatory properties.	[195]
	Leaves	Aqueous, ethyl acetate, and butanol extracts	In vitro	–	–	DPPH; AChE inhibitory assay.	Antioxidant activity (maximum in the ethyl acetate extract). AChE inhibitory activity (ethyl acetate and aqueous extracts).	[49]
	Leaves	Aqueous extract	In vitro	–	–	AChE inhibitory assay	AChE inhibitory activity.	[43]
P. lentiscus	Leaves	Essential oil	In vivo	Rats	200 mg	Bilateral common carotid artery occlusion model. Analysis of levels of the enzyme COX-2, as assessed by Western blot.	↑ DHA. ↓ COX-2s. ↑ Palmytoylethanolamide and oleoylethanolamide levels in plasma.	[48]
	Leaves	Alcoholic extract	In vitro	–	25, 50, 100 µg/mL	SK-N-BE (2)-C cells injury induced by H₂O₂, and Aβ (25 – 35) by the MTT assay.	Protected the cells against Aβ (25 – 35) and H₂O₂-induced toxicity.	[47]
	Oleoresin	Ethanolic extract	In vitro	–	2, 4, 6, 8, 10 µg/mL	AChE inhibitory assay.	Competitive inhibitor of acetylcholinesterase.	[44]
	Fruits	Methanolic extract	In vitro	–	–	DPPH; ABTS. Thioflavine T assay (ThT); dynamic light scattering (DLS); transmission electron microscopy analysis (TEM).	Antioxidant activity. Inhibited Aβ42 aggregation and related neurotoxicity.	[46]
	Leaves	Aqueous extract	In vitro	–	–	AChE inhibitory assay.	AChE inhibitory activity	[43]
	Fruit	Oil	In vivo	Male rats	3.3 mL/kg orally, daily for 15 days	Model of memory dysfunction and oxidative stress induced by lipopolysaccharide. Open field and spatial object recognition tests. AChE inhibitory assay.	↓ Spatial memory deficit. ↓ Brain acetylcholinesterase activation. ↓ Brain MDA, H₂O₂. ↑ Brain CAT, SOD.	[42]
	Oleoresin	Methanol and dichloromethane extracts	In vitro	–	–	AChE inhibitory assay.	Dichloromethane extract: AChE inhibitory activity	[45]
P. integerrima	Gall	Crude extract, ethyl acetate, aqueous, n-hexane and chloroform fraction; quercetin, pyrogallol	In vitro	–	1000, 500, 250, 125, 62.5 µg/mL	DPPH; ABTS; AChE inhibitory assay.	Ethyl acetate fraction: the most powerful radical scavenging activity. Quercetin and pyrogallol: antioxidant properties. Crude extract and ethyl acetate fraction: highly inhibited acetyl cholinesterase activity.	[57]
	Galls	Ethanolic extract	In vivo	Rats and mice	0.5 mL/kg; i. p.	Five behavioral experimental models. Convulsion experimental models induced by PTZ, strychnine. Maximal electroshock seizures (IVIES).	↑ Pentobarbitone-induced sleeping. ↑ Time of loss of righting reflex. ↑ Reaction time of 24 h fasted rats placed in a Hebb-William maze.	[56]
	Galls	Essential oil	In vitro	–	10 and 50 µg/mL	Pharmacological assays on rabbit jejunum spontaneous contractions, guinea pig ileum.	↑Isoprenaline induced relaxation of rabbit jejunum, relaxation of basal tone of K⁺ induced contraction, ↓ Ca²⁺ induced contraction of isolated guinea pig ileum in Ca²⁺ free medium. ↑ The reversal of a KCl-induced tonic contraction observed in Ca²⁺ free medium.	[196]
P. terebinthus	Flowers	Aqueous extract	In vivo	Male rats	250 mg/kg every other day by gavage	Measuring the lipid peroxidation (LPO), total protein, glutathione, and enzyme activities in blood.	↓ Lipid peroxidation in brain. ↑ Glutathione and total protein. ↑ GSH-Px and SOD.	[197]
P. terebinthus	Fruits	Ethyl acetate and methanolic extracts	In vitro	–	–	AChE inhibitory assay. Tyrosinase activity assay. DPPH, DMPD, FRAP and metal chelation tests and PRAP test as radical scavenging activity assay.	Methanolic extract moderately inhibited butyrylcholinesterase activity. The extracts did not inhibit acetyl cholinesterase and tyrosinase enzymes. Both extracts: DPPH and DMPD scavenging activity and antioxidant activity.	[59]

Most of the evidence related to neuroprotection activity in the genus Pistacia is in the form of preliminary in vitro/vivo studies; mainly including models of memory, motor function, and behavioral impairments in animals, neural toxicity, cerebral ischemia, and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid-β (Aβ) aggregation, acetylcholinesterase (AChE), as well as investigations into some cellular pathways ([Figs. 1] and [2]).

Fig. 1 Pharmacological aspects of the Pistacia genus on the brain.

Fig. 2 Molecular mechanisms of Pistacia in neuroprotection.

Even with the widespread presence of pistachios as the most commonly used phytonutrient-dense species of this genus, no clinical studies have directly aimed at investigating their effects on neurodegenerative disorders. In the following, studies on the neuroprotective effects of each individual plant are presented.

Pistacia vera

In this domain, most of the studies have been carried out on pistachioʼs kernel, hull, and its gum (oleoresin). In this respect, the neuroprotective effects of P. vera kernel was specified in a study through its administration for 5 weeks in rats, which could inhibit cognitive and motor impairments caused by cisplatin or vincristine and specifically reverse spatial memory disturbances by these neurotoxic anticancer drugs. However, pistachio has not indicated any effects on anxiety as monitored by the open field test. Its cognitive improvement effects might have been also related to high flavonoids and phenolic content of the pistachio fruit [31]. P. vera seed oil has been further reported to improve memory and cognitive impairment, as suggested by Y-maze test results in rats. However, it has not revealed any effects on spatial memory parameters in the Morris water maze test [32]. Moreover, one study found that the hydroalcoholic extract of pistachio nut (orally; 14 days) had significantly caused improved learning and memory in rats through the avoidance learning test [33]. In parallel, the aqueous-methanolic extract of P. Vera hull has been able to inhibit AChE activity to a certain extent. In this case, the IC₅₀ of 204.1 ± 6.33 µg/mL was compared with physostigmine (IC₅₀ of 0.093 µM) [34]. Moreover, the AChE inhibitory activity of its fruit hull methanol extract was proven in another study by a percentage of 5.5% in enzyme inhibition [35]. The anxiolytic effect of the hydroalcoholic extract of its hull (10 mg/kg) has been shown in female rats, which might be concluded due to the role of GABA and estrogen receptors in its antianxiety effect [36].

The protective potency of the hexane extract of the pistachio nut against oxidative stress has also been confirmed in a neuronal cell line via MTT and DCF-DA assays through focusing on its fatty acid composition [37].

With regard to antioxidant activity, the neuroprotective effects of P. vera gum extract have also been shown in rats with oxidative damage following cerebral ischemia. In this respect, the given extract could reduce the malondialdehyde (MDA) level and increase antioxidant capacity of the brain in comparison with those in the control group [38], [39]. In another study, the hydroalcoholic extract of P. vera gum had been suggested to prolong sleep duration (at all doses: 0.25, 0.5, and 1 g/kg) and to shorten sleep onset latency (1 g/kg). In addition, the administration of the extract in mice demonstrated its antianxiety effects and consequently suppressed locomotor activity in the open field test [40]. The antiepileptic effects of the hydroalcoholic extract of P. vera fruit have also been validated to be comparable with diazepam in a chronic PTZ-induced model of epilepsy in rats [41].

Pistacia lentiscus

It has been reported that pretreatment by the essential oil of P. lentiscus fruit can attenuate lipopolysaccharide-induced memory impairment in rats in the open field and spatial object recognition tests. It can also induce a decrease in AChE activity as well as oxidative stress markers in brain tissues. The major components of the essential oil identified in this domain have been 4-(3-[(2hydroxybenzoyl) amino] aniline)-4-oxobut-2-enoic acid, β-myrcene, 3-pentadecylphenol, P-tolyl ester, aminoformic acid, and β-sitosterol [42]. Other studies have also demonstrated that the aqueous extract of P. lentiscus leaves and the ethanolic extract of its oleoresin possessed AChE inhibitory activity with IC₅₀ values of 13.67 ± 0.69 µg/mL and 6.5 µg/mL, respectively [43], [44]. Additionally, the dichloromethane extract of P. lentiscus oleoresin has also been shown to inhibit AChE activity [45]. In this respect, Dhouafli et al. [46] investigated P. lentiscus for its ability to counteract amyloid (Aβ42) aggregation, commonly considered a pathological hallmark of AD [47]. The results of this study indicated that pretreatment in SH-SY5Y cells with 100 µg/mL of defatted methanol extract of P. lentiscus (10 µg/mL) for 24 h could increase cell viability and reduce Aβ-mediated cellular toxicity. However, P. lentiscus extract did not have a significant cytoprotective effect. In contrast, cells treated with the same amount of Aβ42 aggregates grown in the presence of the extract showed significant retention of viability, reaching 81.65% for P. lentiscus [46]. The alcoholic extract obtained from P. lentiscus leaves has also been demonstrated to contain substantial amounts of phenolic components as effective agents for preventing disorders induced by oxidative damage. This extract could significantly protect SK-N-BE(2)-C neuronal cells against oxidative injury by H₂O₂ and Aβ (25 – 35) and almost entirely protect the given cells against Aβ-induced neuronal toxicity with the dose of 100 µg/mL [47]. Besides, ischemia of the brain causes free radical formation, neuroinflammation, and neuronal injury. In an ischemic model of bilateral common carotid artery ligation, the essential oil of P. lentiscus leaves was able to reverse ischemia-induced decrease of docosahexaenoic acid (DHA) and COX-2 expression in the frontal cortex. It is noteworthy that DHA is the predominant fatty acid of neuronal cell membrane affected by oxidative damage. It also acts through stimulating PPAR-α, which results in diminishing neuroinflammation. Moreover, COX-2 overexpression induced by ischemia can contribute to neuronal injury. Additionally, the essential oil increases the amount of palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) as well as DHA biosynthesis in plasma, which counteract neuroinflammation. The increase in DHA biosynthesis can be induced by elevated levels of PEA and OEA followed by PPAR-α activation. This potential mechanism eventually leads to a neuroprotective effect of P. lentiscus essential oil against ischemia/reperfusion brain injury [48].

Pistacia atlantica

The most effective AChE inhibitory activity of the extracts of P. atlantica leaves has been reported by ethyl acetate and aqueous extracts, probably due to the high phenolic components in these substances [49]. The results of two studies in this domain demonstrated that the aqueous extract of P. atlantica leaves possessed remarkable AChE inhibitory activity with an IC₅₀ of 0.87 ± 0.55 µg/mL [43] and 58.05 ± 0.12 µg/mL [50], respectively. It should be noted that P. atlantica consists of large amounts of phenolic compounds, possibly associated with the strong AChE inhibitory effect [43], [50]. In addition, anticholinesterase and antioxidant activities of methanolic and ethyl acetate extracts of P. atlantica leaves have been assessed. In this regard, powerful antioxidant properties have been observed by both extracts compared with known synthetic antioxidants. It should be noted that the antioxidant properties of P. atlantica leaf extracts can be attributed to their constituents, including total phenols, total flavonoids, anthocyanins, chlorophyll, and carotenoid contents. In addition, the extracts have demonstrated slight inhibitory activity against AChE. However, ethyl acetate extract could inhibit the enzyme much stronger than the methanolic extract [51].

Essential oils obtained from P. atlantica leaves and flowers have further been found to be protective against free radicals and oxidative stress. They can also inhibit the AChE enzyme. It is worth noting that the essential oils consist of large amounts of monoterpenes and oxygenated sesquiterpenes contributed to the antioxidant and anticholinesterase properties. Moreover, the effects of P. atlantica leaf essential oil on both free radical scavenging and anticholinesterase activities have been reported to be, to some degree, better than its flower oil. P. atlantica leaf oil has also shown an IC₅₀ of 18.5 ± 0.5 compared with P. atlantica flower oil, which has an IC₅₀ of 20.5 ± 0.5 µg/mL against AChE [52].

In one animal study, anxiety-like behaviors were assessed using the elevated plus maze (EPM) test in intact and gonadectomized rats submitted to a chronic unpredictable stress (CUS) paradigm and treated with hydroalcoholic extracts of P. atlantica fruit (100 mg/kg, orally for 20 days). The results of this study revealed that P. atlantica treatment increased the percentage of both time spent and entries in the open arms of EPM in intact and gonadectomized rats. Moreover, the effects of chronic stress were reversed by P. atlantica treatment [53]. Administration of the hydroalcoholic extract of P. atlantica fruit (400 mg/kg) in combination with fluvoxamine in rats under immobilization stress also improved spatial memory via decreasing the time of reaching the target as well as reducing the MDA, corticosterone, and blood glucose levels and increasing the catalase level [54].

Pretreatments with noncytotoxic P. atlantica extract at 100 µg/mL have similarly been reported to reduce starvation-induced apoptosis in vitro. Pretreatments with P. atlantica have also been demonstrated to be neuroprotective against PD-inducing neurotoxins, including 6-OHDA and rotenone [55].

Pistacia integerrima

In this domain, Ansari et al. [56] found that pretreatment of rats with the ethanolic extract of P. integerrima galls could possess a CNS-depressant activity once administered (0.5 mL/kg; i. p.) in rats. It could also extend the duration of sleeping in a pentobarbiton-induced sleeping model. Moreover, its extract could remarkably inhibit aggressive behaviors in isolated mice. As well, the administration of the given extract had significantly protected the mice against tonic-clonic convulsion and death induced by PTZ. Its major identified constituents were α-terpineol, β-terpineol, α-pinene, β-pinene, A3-carnene, α-phellandrene, β-phellandrene, 6-pinene, α-terpenene, limonene α-ocemene, and β-ocemene.

In another study, several types of P. integerrima gall extracts had been studied in order to identify radical scavenging and cholinesterase inhibitory activity. Among them, ethyl acetate extract demonstrated the best radical scavenging activity in both DPPH and ABTS assays as well as the most potent AChE and butyrylcholinesterase inhibitory activities compared with other tested extracts. P. integerrima crude extract also showed both AChE inhibitory and radical scavenging activities, which were approximately closer to the ethyl acetate extract. Free radical scavenging activity of quercetin and pyrogallol as pure compounds isolated from P. integerrima was also confirmed, with higher antioxidant properties for pyrogallol [57].

It has also been reported that the petroleum ether extract of P. integerrima gall could display anticonvulsant activity in zebrafish through prolonging the onset of hyperactivity and tonic-clonic seizure in PTZ-induced seizures (50, 100, 200 mg/kg). Additionally, anticonvulsant effects of the petroleum ether extract have been confirmed in mice at doses of 100 and 150 mg/kg. Besides, petroleum ether extract delayed or prevented hind limb extension onset in maximal electroshock models of epilepsy in a dose-dependent manner. In contrast, methanolic extract proved to have no protection against seizures in both PTZ and MES models [58]. The essential oil of P. integerrima gall also revealed relaxant and spasmolytic effects in one study, probably mediated by modulating β-adrenoceptors and calcium channels [27].

Pistacia terebinthus

The anticholinesterase and antioxidant properties of ethyl acetate and methanolic extracts of P. terebinthus fruit and four terebinth coffee brands were investigated in an in vitro study. The results showed that both extracts had moderate inhibitory effects on butyrylcholinesterase activity (at the concentration of 200 µg/mL). Moreover, they showed radical scavenging activity at a higher concentration (2000 µg/mL) without inhibiting the activity of AChE and tyrosinase enzymes. It has been reported that phenolic and flavonoid contents of terebinth coffee brands are higher than P. terebinthus fruit, which results in higher antioxidant and neuroprotective activities. The increase in phenolic and flavonoid content may be due to the roasting process, which implies that the roasting process of fruit may improve the antioxidant properties of the extracts. It has also been reported that oleic acid is the major fatty acid found in P. terebinthus fruits, while α-pinene is the main constituent in the essential oil followed by β-ocimene and limonene [59].

Neuroprotective Phytochemicals in Pistacia Genus

Herbal medicine or phytotherapy generally refers to the medicinal usage of plant parts with their secondary metabolites for their curative properties. Different usable plant parts in the Pistacia genus also contain a variety of bioactive phytochemicals [9]. Phytochemicals are biologically active compounds that are not considered essential nutrients but seem to contribute to protection against degenerative disease [60].

Among the edible parts of the herbs in this genus, pistachio fruits (i.e., kernels) are the most extensively used nuts as food. From a nutritional point of view, Pistacia species have fruits with remarkable contents of fatty acids. The main fatty acid in kernels of P. vera, P. atlantica, P. lentiscus, and P. terebinthus fruits is oleic acid [22], which has been proven to be protective as an unsaturated fatty acid against AD as well as other neurological disorders [61]. Besides the other fatty acids identified in these species, linolenic has been known as the precursor of DHA and eicosapentaenoic acids (EPAs) and it has been reported to possess antioxidative and neuroprotective effects [62]. Polyunsaturated fatty acids (PUFAs) have been shown to play a central role in the maintenance of neuronal functions and brain development, contributing to neurogenesis and neuroplasticity. Moreover, these PUFAs also exert significant protective effects against inflammatory damage to the neurons and glial cells. Omega-3 fatty acids have also been reported to show promising effects as antidepressant agents [63].

The presence of other nutrients such as glutamic and aspartic acids, vitamins (vitamin E), choline, and phytosterols (i.e., β-sitosterol, campesterol, and stigmasterol) could also emphasize the potential of these seeds (especially pistachios) in the prevention and control of neurological diseases [64]. Along with the nutrient dense kernels, various groups of phytochemicals, mostly terpenes (mono-, sesqui-, and triterpenes) and phenolic compounds, have been identified in different plant parts of Pistacia species. Many studies have shown a neuroprotective effect of Pistacia chemical constituents. Selected studies examining the key components in this domain are summarized in [Table 2] and are shown in [Fig. 2].

Table 2 Selected phytochemicals in the Pistacia genus and their neuroprotective activity.
Scientific name	Plant parts [22]	Constituents	Experimental model	Observation/mechanism
6-OHDA: 6-Hydroxydopamine; ΔΨm: Mitochondrial membrane potential; AChE: Acetylcholinesterase; AD: Alzheimerʼs disease; AIF: Apoptosis-inducing factor; Akt: Protein kinase B; AMPKα: AMP-activated protein kinase; BAX: BCL2 associated X; BBB: Blood-brain barrier; Bcl-2: B-cell lymphoma 2; BDNF: Brain-derived neurotrophic factor; CAT: Catalase; CAV: Caveolin; CB2: Cannabinoid receptor type 2; CI-R: Cerebral ischemia-reperfusion; COMT: catechol-O-methyltransferase; COX2: Cyclooxygenase 2; CRBE: Cyclic-AMP response element binding protein; DHE: Dihydroethidium; DMPD: N,N-dimethyl-p-phenylenediamine; ERK1: Extracellular signal-regulated kinases 1; GFAP: Glial fibrillary acidic protein; GPx: glutathione peroxidase; GR: glutathione reductase; GSH: Glutathione; GSK3β: Glycogen synthase kinase 3β; HMGB-1: High-mobility group box 1. HO-1: heme-oxygenase 1; Iba-1: Ionized calcium binding adaptor molecule 1; ICAM-1: Intercellular adhesion molecule-1; IGF-1: Insulin-like growth factor 1; IL-1β: Interleukin 1 beta; IKK: IκB kinase β; JNK: c-Jun N-terminal kinases; MAP-2: Microtubule-associated protein 2; MAPK: Mitogen-activated protein kinase; MCP-1: Monocyte chemoattractant protein-1; MCAO: Middle cerebral artery occlusion; MDA: Malondialdehyde; MLKL: Mixed lineage kinase domain-like pseudokinase; MMP: Matrix metalloproteinase; MOG: Myelin-oligodendrocyte glycoprotein. MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NADPH: Nicotinamide adenine dinucleotide phosphate; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; NO: Nitric oxide; NOS2: Nitric oxide synthase 2; NPT: Nonprotein thiols content; NQO1: NAD(P)H quinone dehydrogenase 1; Nrf2: Nuclear factor erythroid 2-related factor 2; OGD/R: Oxygen glucose deprivation/reoxygenation; OS: Oxidative stress; PC12: pheochromocytoma cells; PD: Parkinsonʼs disease; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator 1 alpha; PGE2: Prostaglandin E2; PHF: Paired helical filament; PI3K: phosphoinositide 3-kinase; PKB: protein kinase B: PPAR: Peroxisome proliferator-activated receptors; PTZ: pentylenetetrazol; RIPK: Receptor-interaction protein kinase; ROS: Reactive oxygen species; SAH: Subarachnoid hemorrhage; Ser9: Phospho-GSK-3bβ; SIRT: Sirtuins; SOD: Superoxide dismutase; TBAR: Thiobarbituric acid-reactive. TIMP1: Tissue inhibitor of metalloproteinases; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-α; TUNEL: Terminal deoxynucleotidyl transferase dUTP nick end labeling; VGEF: Vascular endothelial growth factor; WT: Wild type
P. vera	Leaf, unripe fruit, resin	α-Pinene	H₂O₂-induced oxidative stress in rat PC12	↑ Cell viability ↓ Intracellular ROS ↑ CAT, SOD, GPx, GR, HO-1 ↓ Apoptosis ↓ Capase-3 ↑ Nrf2 [71]
P. terebinthus	Fruit, aerial part, leaf, gall		6-OHDA-induced PD in rat	Improvement of the movement disorder and avoidance memory ↓ MDA in striatum and hippocampus [73]
P. lentiscus	Resin, leaf fruit, aerial part		Inhalation of α-pinene in mouse	↓ Anxiety Accumulation of α-pinene in the brain and liver [198]
P. atlantica	Leaf, fruit, gall, resin		Inhalation of α-pinene in mouse	↑ BDNF in the olfactory bulb and in the hippocampus [74]
			Scopolamine-induced cognitive dysfunction in mouse	↑ Choline acetyltransferase ↑ Nrf2 Improvement of cognitive dysfunction [72]
			Dizocilpine-induced schizophrenia-like behavior	↓ Behavioral alteration ↓ Total distance travelled in the Y-maze test ↓ Activity of mice in the spontaneous locomotor activity test [75]
P. lentiscus	Mastic water	Linalool	Acrylamide-induced neurotoxicity in rat	↑ GSH ↓ Lipid peroxidation [77]
			OGD/R-induced cortical neuronal injury in microglial cell	↓ Cells death ↓ Intracellular ROS ↑ SOD, CAT ↓ Microglial migration [78]
			Triple transgenic model of AD (3 × Tg-AD) in aged mouse	Improvement of learning and spatial memory ↓ Extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis ↓ p38 MAPK, NOS2, COX2, IL-1β [76]
			MCAO-induced ischemic neurodegeneration in rat Glutamate induced toxicity in glial cell	↓ Infarct volume Better neurological and motor skills and relearning performance ↓ Microgliosis, COX-2, IL-1B and Nrf2 markers ↓ NF-κB, IL1-β, COX-2, and Nrf2 immunostaining and microglial changes under glutamate toxicity [79]
			Expression of recombinant T-type Ca2+ channels (Ca_V3.2) in HEK-293 T cells using whole-cell patch-clamp technique	↓ Ca_V3.2 Inhibition of TTCCs [199]
P. terebinthus	Leaf	β-caryophyllene	OGD/R-induced ischemia in human neuroblastoma SH-SY5Y	Significant neuroprotection effect (more than MK 801, the positive control) [93]
P. lentiscus	Leaf, galls		OGD/R-induced ischemia in human neuroblastoma SH-SY5Y
			LPS-induced toxicity in a proliferative oligodendrocyte cell line (OLN-93)	↓ Toxicity Involvement of CB2R through different pathways including Nrf2/HO-1/antioxidant axis, and PPAR-γ [200]
			High-fat/fructose diet-induced neurobehavioral changes in rats	↓ OS ↓ Neuroinflammation and behavioral changes Involvement of CB2R in antidepressant and memory improvement by upregulation of PGC-1α and BDNF Involvement of PPAR-γ and CB2R in anxiolytic, antioxidant, and anti-inflammatory effects [87]
			CI/R injury in C57BL/6 mice. OGD/R-induced ischemia in vitro	↓ Necroptotic neurons and MLKL protein ↓ Infarct volumes, neuronal necrosis, RIPK1 and RIPK3 expression, and MLKL phosphorylation. ↓ HMGB1, TLR4, IL-1β, and TNF-α levels [91]
			CI-R injury in rat	↓ Neurological deficit scores, infarct volume, MDA, LPO, NO, Bax ↑ SOD, CAT and Bcl-2 ↑ Nrf2, HO-1 [92]
			MPTP-induced murine model of PD	↓ Motor dysfunction ↓ Glia activation ↓ Dopaminergic neuronal losses ↓ Inflammatory cytokines in the nigrostriatal system. Involvement of the CB2R [88]
			Rotenone-induced oxidative stress and neuroinflammation in a rat model of PD	↓ Dopaminergic neurons death ↓ Microglia and astrocyte activation ↓ Iba-1 and GFAP expression ↓ COX-2, iNOS, lipid peroxidation, glutathione depletion ↑ Antioxidant enzymes [201]
			Kainic acid-induced seizure activity in mouse	↓ Seizure activity score ↓ Mortality ↓ MAO, TNF-α, and IL-1β ↑ GPx, SOD, CAT [202]
			Pentylenetetrazol-induced seizures in mouse	↑ Latency to myoclonic jerks Improvement of recognition index No behavioral changes in open field, rotarod, or forced swim tests No effect on TBAR and NPT [203]
			Transgenic APP/PS1 model of AD in mouse	↓ Cognitive impairment ↓ β-amyloid ↓ Astrogliosis and microglial activation ↓ COX-2 protein and the mRNA levels of TNF-α and IL-1β in the cerebral cortex [84]
			MCAO-induced ischemia OGD/R in cerebral cells	↓ Neurological deficits ↓ iNOs, IL-1β, IL-6, and COX-2 in C6 microglial cells ↓ NO and PGE₂ [90]
			Animal model of vascular dementia in rat	↓ Learning and memory deficits ↑ Recovery of cerebral brain flow ↑ Expression of CB2 ↑ Expression levels of PI3K and Akt [82]
			Glutamate-induced cytotoxicity in the C6 glioma cell line	↓ ROS Reestablishing ΔΨm ↑ Nuclear translocation of Nrf2 ↑ GSH Involvement of CB2R activation [85]
P. lenticus	Fruit, resin, leaves, twigs	Myrcene	Global CI/R by carotid occlusion in C57BL/J6 mouse	↑ GSH, GPx, and SOD ↓ TBARs ↓ Histopathological damage and apoptosis in brain tissue [96]
P. atlantica	Fruit, resin, leaves
P. vera	Fruit, leaves, hulls
P. atlantica	gum	Limonene	Corticosterone-induced neurotoxicity in PC12	↓ Neurotoxicity ↓ MDA, NO, NADPH oxidase, iNOS, COX-2, IL-6, IL-1β, and TNF-α, ↓ Bax and cleaved caspase-3 ↑ SOD1, HO-1, Bcl-2 ↓ Number of TUNEL-positive cells ↑ AMPKα and ↓of NF-κB nuclear translocation through upregulation of SIRT1 [97]
P. terebinthus	fruit		Corticosterone-induced neurotoxicity in PC12
P. lentiscus	Resin, fruit		Chronic immobilization stress-induced high anxiety in male rat	↑Percentage of open arm entries and stay in these arms ↓ Stress-induced damage in CA1 pyramidal neurons [98]
			Transient cerebral ischemia in stroke-prone spontaneously hypertensive rats	↓ Cerebral infarct size ↓ mRNA expression of IL-1β, MCP-1, and COX-2 ↑ mRNA expression of VEGF in the brain ↑ SOD, CAT ↑ Glutathione ↓ MDA Improvement of behavior [99]
			Scopolamine-induced dementia	Improvement of associative and non-associative memory ↑ Dopamine ↓ AChE activity [100]
P. lentiscus	Resin [103]	Ursolic acid	Transient MCAO-induced focal cerebral ischemia in the mouse	Improvement of neurological deficit ↓ Infarct size ↓ Lipid peroxidation ↑ Nrf2 pathway ↓ TLR4, NF-κB More severe neurologic deficits, infarct size and inflammatory damage [125]
P. vera	Kernel [104]		Aβ (25 – 35)-induced toxicity in PC12 cells	↓ iNOS and COX-2 through inhibition of NF-κB activity ↓ ERK1/2, p-38, and JNK phosphorylation [117]
	Resin		Aβ-induced neurotoxicity in PC12 cells	↓ ROS, LPO ↓ Caspase-3, apoptosis [118]
			Aβ memory impairment in the mouse	↓ Memory impairment ↓ MDA ↑ Glutathione in hippocampus ↓ IL-1β, IL-6, TNF-α [115]
			Spinal cord injury model in the mouse	↑ Motor functions and axonal regrowth ↓ Astrogliosis ↓ IL-6, TNF-α ↑ Activation of MAPK and PI3K/PKB/mTOR pathways in the injured spinal cord [123]
			D-galactose-induced neurotoxicity and learning and memory impairment in the mouse	Improvement of memory ↑ SOD, CAT, GPx, and GR ↓ MDA, caspase-3 ↑ Neural growth-associated protein GAP43 [119]
			Model of aging mice (C57BL/6)	↑ SIRT1 and SIRT-6 Enhancement of α-Klotho and PGC proteins levels [120]
			Ellmanʼs assays for evaluating acetylcholinesterase and/or butyrylcholinesterase inhibitory activity	↓ Butyrylcholinesterase [121]
			MPTP-induced PD in mouse	Improvement of behavioral deficits ↑ Dopamine ↑ Dopaminergic neurons [122]
			High-fat diet-induced cognitive impairment in C57/BL6J mouse	Improvement of behavioral performance ↓ Endoplasmic reticulum stress and IKKβ/NF-κB-mediated inflammatory signaling ↑ Insulin signaling and PI3K/Akt/mTOR pathway ↑ Memory-related protein expression in the hippocampus [124]
			Traumatic brain injury-induced cerebral ischemia in wild-type (WT) and Nrf2(-/-) mouse	↓ Brain edema and the neurological insufficiencies ↑ Nuclear translocation of Nrf2 protein ↑ Expression of NQO1 and HO1 ↑ Expression of AKT Involvement of Nrf2-ARE signaling pathway No effect on Nrf2(-/-) mice [126]
			Endovascular puncture model of subarachnoid hemorrhage	↓ Expressions of TLR4 pathway-related agents, such as ICAM-1, TLR4, NF-κB, P65, IL-1β, TNF-α, IL-6, iNOS, and MMP-9 ↓ Apoptosis [127]
			MCAO and reperfusion model in rats	Improvement in neurological deficit score ↓ Infarct volume ↑ Intact neurons ↑ PPARγ protein and PPARγ-positive cells ↓ Protein levels of MMP2, MMP9, and activated MAPKs ↑ TIMP1 [128]
			Pentylenetetrazole-induced seizures in the mouse	Positive modulation of α1β2γ2 L GABA-A receptors Anticonvulsant, antidepressant, and anxiolytic activities [129]
			Pentobarbital-mediated sleeping model in the mouse	Enhances sleep duration through GABA-A receptor activation [130]
P. lentiscus	Resin	Oleanolic acid	Cobalt chloride-induced focal cortical hypoxia in rats	↓ Neuronal degeneration and cytoskeleton changes ↓ Astroglial and microglial reaction ↑ Brain tissue recovery [112]
P. terebinthus	Resin
P. atlantica	Resin
			Neural stem cells	↑ Proliferation and neural differentiation ↑ MAP2 expression ↓ Nestin ↑ Phosphorylation of GSK3β at Ser9 and expression of active forms of β-catenin [111]
			6-OHDA induced Parkinsonian in rats 6-OHDA-induced intracellular ROS in PC12	↓ Microglial activation Improved motor symptoms ↑ Striatal dopamine ↓ Amount of intracellular ROS in PC12 cells [110]
			Experimental mouse model of MS (experimental autoimmune encephalomyelitis)	↓ Encephalomyelitis ↓ Activation of microglial cells, BBB disruption and infiltration of inflammatory cells within the CNS ↓ Proinflammatory cytokines and chemokines ↑ Anti-inflammatory ones (modulatory role in Th1/Th2 polarization) ↓ Anti-MOG antibodies [106]
			SAH induction by a standard intravascular puncture model in rats	↓ Permeability of BBB ↓ Brain edema by protein expression of TJs and AJs ↓ SAH grades ↑ Protein expression of HO-1 ↓ Upregulation of VEGF and the phosphorylation of p38 MAPK, ↓ p38MAPK/VEGF/Src signaling pathway [107]
P. integerrima	Bark	Pistagremic acid	In vitro β-secretase, AChE, and butyrylcholinesterase inhibition assay	↓ β-secretase No obvious AChE activity [131]
P. vera	Seed and skin	Gallic acid	Oxidative stress induced with 6-OHDA in PD model in rats	↑ Passive avoidance memory, total thiol, and GPx contents ↓ MDA in the hippocampus and striatum [144]
P. lentiscus	Leaf, fruit		Aβ-induced toxicity in neuronal cells Aβ-induced cognitive dysfunction in mouse	↓ NF-κB ↓ Cytokine production in microglia cells ↓ Neuronal cell death ↓ Expression of cytokines ↓ NF-κB acetylation Improvement of cognitive dysfunction [141]
P. atlantica	Gall, leaf
			Traumatic brain injury in rat (Marmarouʼs method)	Improvement of neurological score, memory, and long-term potentiation from hippocampal dentate gyrus ↓ Brain lipid peroxidation and cerebral proinflammatory cytokines [145]
			Glutamate-induced neurotoxicity in primary rat cortex neurons culture	↓ Neurotoxicity ↓ Cortex neurons antioxidant profile ↓ Proinflammatory cytokine Maintenance of Ca2+ homeostasis, IGF-1 expression [146]
P. vera	Seed, skin	Catechin	Doxorubicin-induced memory deficit in Wistar rats Doxorubicin-induced neurotoxicity in IMR-32 neuroblastoma cells	↑ Viability of undifferentiated IMR-32 cells ↑ Neurite length of differentiated cells ↓ OS ↓ Neuroinflammation ↓ AChE [152]
P. vera	Seed, skin		Aβ-induced BACE-1 upregulation in neuronal culture	↓ ROS and beta-sheet structure formation ↓ Aβ-induced BACE-1 upregulation [142]
P. lentiscus	Leaf		Aβ-induced BACE-1 upregulation in neuronal culture
P. lentiscus	Leaf		Traumatic brain injury model in rats	Protection of BBB integrity ↑ Junction proteins ↓ Local inflammatory reactions [153]
			Streptozotocin-induced diabetes in rats	Improvement of alternation score and retention and recall in passive avoidance test ↓ MDA and nitrite [155]
			Streptozotocin-induced model of dementia in rats	Improvement of cognitive deficit, S100B content and secretion, AChE activity, GPx activity, NO metabolites, and ROS content [156]
			MPTP-induced PD in mice	Prevention of neurotoxicity ↓ Dopaminergic neuron loss in substantia nigra [157]
P. vera	Skin, nuts	Cyanidin-3-O-glucoside	Aβ-induced neurotoxicity in a human neuronal cell line (SH-SY5Y).	↓ Apoptosis and Necrosis ↓ Aβ oligomer binding to plasma membrane, ↓ Membrane integrity loss [158]
P. vera	Seed, skin	Quercetin	Radiation-induced brain injury in rats	↓ Cellular degeneration and infiltration parameters ↓ OS [171]
			MPTP-induced PD in mice	Improvement of the motor balance and coordination ↑ Activities of GPx, SOD, and Na/K-ATPase, AChE, dopamine ↓ 4-Hydroxy-2-nonenal immunoreactivity in the striatum of brains [204]
			Aged triple transgenic AD model in mice	↓ Extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis ↓ PHF, βA 1 – 40 and βA 1 – 42 levels ↓ BACE1-mediated cleavage of APP antibody Improvement of performance in learning and spatial memory [162]
			Cadmium-induced memory impairment and anxiogenic-like behavior in rats	↓ Impaired memory and anxiogenic effect ↑ Na/K-ATPase activity ↓ ROS, TBARS, protein carbonyl content, dsDNA fractions ↑ T-SH, GSH, and GR activities and the rise of GST activity ↓ AChE activity [163]
			Aβ (1 – 42)-induced oxidative cell toxicity in cultured neurons	↓ Aβ (1 – 42)-induced cytotoxicity, protein oxidation, lipid peroxidation and apoptosis [164]
			Mouse model of AD, hippocampal neuronal culture	↑ Cell proliferation in the hippocampal neurons ↑ Neurogenesis, synaptogenesis and cell proliferation ↓ Aβ-induced synaptic loss ↑ Phosphorylation of CREB ↑ BDNF ↑ Dendritic processes in hippocampal neurons [166]
			Perphenazine and reserpine-induced catalepsy in rats	↓ Catalepsy ↓ Activity of COMT and MAO ↑ Bioavailability of L-dopa in the brain [168]
			MPPT-induced oxidative stress in PC12 cells	↓ Apoptotic death ↓ Phosphorylation of STAT Modulation of mRNA levels and protein expression of Bax and Bcl-2 Release of cytochrome c and nuclear translocation of the AIF [169]
			Rotenone-induced hemi-Parkinson in rats	↓ Amphetamine- or apomorphine-induced unilateral rotations ↓ Rotenone-induced loss in striatal dopamine, and nigral oxidized ↓ Glutathione ↑ CAT and SOD ↑ Mitochondrial complex-I activity [170]
			Transient bilateral common carotid artery occlusion and reperfusion in rats	↓ Microvascular permeability, leukocyte adhesion and ROS Protection of capillary perfusion. ↓ Arteriolar dilation [172]

Terpenes

Terpenes and terpenoids (modified terpenes) are the principal constituents of the essential oils in many types of plants. Their classification is commonly based on isoprene units. Essential oils mostly contain mono- (with two isoprene units) and sesquiterpenoids (with three isoprene units) [65]. Monoterpenes are the predominant constituents of the essential oil obtained from leaves, oleoresin, and fruits of different Pistacia species [22]. The galls are also rich in terpenes. The galls usually contain higher levels of total terpene, especially monoterpenes like α-pinene and limonene, while the healthy leaves possess higher contents of sesquiterpenes with a predominance of caryophyllene, germacrene D, and d-cadinene [66].

α-Pinene

α-Pinene is a bicyclic monoterpene widely found in nature, especially in essential oils with a strong turpentine odor [67], [68]. This substance forms a large part of the essential oil of the Pistacia genus from 57.06% [69] in P. atlantica to 75.6% in P. vera [70].

Antioxidant activity of α-pinene has been shown through its beneficial effect on the equilibration of oxidant/antioxidant to protect against H₂O₂-induced oxidative stress in rat PC12 cells. Reactive oxygen species scavenging and induction of the Nrf2 were determined as the main mechanisms of action [71]. In another study, α-pinene was administered in C57BL/6 mice with scopolamine-induced cognitive dysfunction. Increasing mRNA expression of choline acetyltransferase, hemeoxygenase-1 (HO-1) and activation of Nrf2 were the main mechanisms of the α-pinene beneficial effect for management of dementia [72]. In addition, in mice with 6-OHDA-induced PD, administration of α-pinene improved the movement disorder and avoidance memory. It led to a reduction in the MDA level in the striatum and hippocampus [73]. This substance has been shown to exert anxiolytic effects as well. Inhalation of α-pinene in mice increased BDNF mRNA and tyrosine hydroxylase mRNA in the olfactory bulb and in the hippocampus. It also increased locomotor activity and acted as an anxiolytic agent based on the elevated plus maze test [74]. Another animal study evaluated the effects of α-pinene inhalation on mice with dizocilpine-induced schizophrenia-like behavior. Inhalation of α-pinene suppressed the dizocilpine-induced increased total distance travelled in the Y-maze test, whereas it did not alter the MK-801-induced reduced threshold of antinociception in the hot plate test. Inhalation of α-pinene suppressed the activity of mice in the spontaneous locomotor activity test and although it did not suppress the dizocilpine-induced increased locomotor activity in the open field test, it remarkably decreased the time that the mice remained in the central area. In the tail suspension and grip strength tests, there was no effect on mouse behavior by administration of MK-801 (dizocilpine) and inhalation of α-pinene [75].

Linalool

Linalool (3,7-Dimethyl-1,6-octadien-3-ol) refers to two enantiomers of a naturally occurring terpene alcohol that is a major volatile component of over 200 essential oils of several aromatic plants. It has remarkable effects as a sedative, antinociceptive, anticonvulsant, and anxiolytic natural product [76]. Linalool administration in rats that were exposed to acrylamide, as a neurotoxic agent, led to an increase of glutathione content and reduction of acrylamide-induced lipid peroxidation in rat brain tissue [77].

In an in vitro study, (−)-linalool also demonstrated neuroprotective effects against neuronal injury induced by oxygenglucose deprivation/reoxygenation (OGD/R). Antioxidant and anti-inflammatory properties of (−)-linalool might be related to this effect [78].

Oral administration of this monoterpene led to an improvement in learning and spatial memory and greater risk assessment behavior in old triple transgenic AD mice. A significant reduction in microgliosis, astrogliosis, extracellular β-amyloidosis, and tauopathy were detected in hippocampi and amygdalae from linalool-treated mice. Proinflammatory markers p38 mitogen-activated protein kinase (MAPK), NOS2, COX-2, and IL-1β also decreased [76]. Moreover, intranasal administration of linalool after focal-induced ischemia in rats led to a reduction in infarct volume, and better neurological and motor skills. In this study, attenuation of microgliosis and COX-2, IL-1β, and Nrf2 markers in the cerebral cortex and hippocampus was detected [79].

β-Caryophyllene

β-Caryophyllene, also known as caryophyllene or (−)-β-caryophyllene, is a natural bicyclic sesquiterpene that is a constituent of many essential oils. It is usually found in nature as a mixture with small amounts of isocaryophyllene (the cis double bond isomer) and α-humulene (α-caryophyllene) isomers [80]. Various studies have shown neuroprotective effects of β-caryophyllene in animal models of cerebral ischemia, PD, and AD. It has also been shown as an anxiolytic, anticonvulsant, analgesic, immunomodulator, and antispasmodic agent. Machado et al. [81] have recently reviewed the neuroprotective perspective of this natural product. β-Caryophyllene appears to act as a neuroprotective agent by controlling inflammation and oxidative stress as well as various effects on cannabinoid receptor 2 (CB2) [80], [81], [82]. In a vascular dementia rat model study, Lou et al. [82] reported that β-caryophyllene-hydroxypropyl-β-cyclodextrin inclusion complex could alleviate cognitive deficits by increasing the expression of CB2 in the brain, along with the expression levels of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt). β-Caryophyllene also acted as agonist for CB2 and PPAR-α receptors in an animal hypoperfusion-reperfusion model of oxidative stress, and modulated activation of the endocannabinoid system and lipoperoxidation as well as COX-2 in brain tissue [83]. The role of CB2 was revealed in another study as well. In a mouse model of AD, β-caryophyllene ameliorated the Alzheimer-like phenotype in mice with reducing Aβ in brain tissue. It also reduced astrogliosis and microglial activation as well as the levels of COX-2 and proinflammatory cytokines in the cerebral cortex; its protective effect was associated to CB2 receptor activation and the PPARγ pathway [84]. The cytoprotective effect of this sesquiterpene has also been indicated to be mediated through the amelioration of cellular antioxidant responses via Nrf2 activation, which is, in part, dependent on CB2R activation [85]. Similar results were obtained after evaluating the effect of β-caryophyllene against lipopolysaccharides-induced oligodendrocyte toxicity in vitro. There were remarkable correlations between β-caryophyllene concentration and selective modulation of CB2, Nrf2, sphingomyelinase (SMase), and PPARγ c pathways [86]. Moreover, β-caryophyllene was shown to alleviate high-fat/fructose-diet-induced neurobehavioral changes in rats. The role of PPAR-γ and CB2R in the anxiolytic, antioxidant, and anti-inflammatory effects of β-caryophyllene was proven in this study as well. Its memory-enhancing and antidepressant effects are probably mediated via CB2R, mainly by the upregulation of BDNF and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) [87].

β-Caryophyllene might exert its neuroprotective effects in PD via multiple mechanisms as well. It showed an ameliorative effect in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced murine model of PD by decreasing the levels of inflammatory cytokines in the nigrostriatal system and involvement of the CB2 receptors [88]. In a rotenone-induced oxidative stress/neuroinflammation rat model of PD, β-caryophyllene reversed the loss of dopaminergic neurons and decreased microglia and astrocyte activation, as evidenced by reduced ionized calcium-binding adaptor molecule-1(Iba1) and glial fibrillary acidic protein (GFAP) expression. Attenuation of proinflammatory cytokines and inflammatory mediators such as COX-2 and inducible nitric oxide synthase (iNOS), restoration of antioxidant enzymes, and inhibition of lipid peroxidation and glutathione depletion were also reported [89].

It has been reported that β-caryophyllene alleviates cerebral ischemia injury through its potent neuroprotective activity in vivo via inhibiting neuronal death and inflammatory responses [90]. It has been shown to reduce necroptotic cell death via the downregulation of receptor-interaction protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain like pseudokinase (MLKL) expression in vivo, as well as alleviation of inflammation through inhibiting the high-mobility group box 1(HMGB1)-toll-like receptor (TLR4) signaling pathway [91]. This compound also reduced the mRNA expression of iNOS, IL-1β, IL-6, and COX-2 in microglial cells, and decreased the levels of NO and prostaglandin E2 [90]. In another study, Nrf2/HO-1 was introduced as an involved pathway in β-caryophyllene protection against cerebral ischemia injury in vivo [92]. Chang et al. [93] investigated the neuroprotective effect of different terpenoids on human neuroblastoma SH-SY5Y, in vitro, by using a simulated ischemia model, and trans-caryophyllene was identified as the most potent neuroprotective agent. In the mentioned study, terpinen-4-ol, one of the other terpenes of the Pistacia genus, was also found as a neuroprotective substance.

Myrcene

β-Myrcene is a monoterpene that forms about 40% of the essential oil of P. lentiscus leaves [94] and has been notably (41%) identified in the methanolic extract of P. atlantica fruits [95]. In an animal model of cerebral ischemia/reperfusion-induced oxidative stress, myrcene treatment protected against neurotoxicity, which occurred via an increase in TBARS formation and a decrease in the antioxidant defense systems, including glutathione (GSH), CAT, GPx, and SOD. Myrcene also eliminated the histopathological damage and apoptosis in brain tissue [96].

Limonene

Limonene, another monoterpene, which has a cyclic structure, forms about 10% of essential oil obtained from P. lentiscus leaves [94], and 4 – 5% of the methanolic extract of P. atlantica fruits [95]. Evaluation of the effects of d-Limonene on a PC12 cellular model of corticosterone-induced neurotoxicity showed that it has antioxidant and anti-inflammatory effects via decreasing the levels of MDA and NO, activities of NADPH oxidase, and expression of proinflammatory markers such as iNOS, COX-2, IL-6, IL-1β, and TNF-α. It also reduced the expression of BCL2-associated X protein (Bax), cleaved caspase-3, and increased antiapoptotic protein Bcl-2. d-Limonene significantly activated AMP-activated protein kinase (AMPKα) and inhibited nuclear translocation of NF-κB through upregulating sirtuin (SIRT)1 [97]. In an animal model of high anxiety induced by chronic immobilization stress, limonene reduced stress-induced damage in CA1 pyramidal neurons and reversed adverse effects of anxiety [98]. Moreover, impairment in cognitive and memory functions following cerebral ischemia was reversed by D-limonene in rats. It decreased the cerebral infarct size following stroke, along with decreasing mRNA expression of IL-1β, monocyte chemoattractant protein-1 (MCP-1), and COX-2, and increasing the activities of antioxidant enzymes in rats following stroke [99]. In another in vivo study, administration of s-limonene attenuated the memory deficits resulting from scopolamine. It improved dopamine reduction induced by scopolamine [100]. s-Limonene has shown also AChE inhibitory activity in vitro [100].

Triterpenoids

Some triterpenoid derivatives have recently been identified as potential neuroprotective agents with their ability to protect the brain against neurodegenerative and neuroinflammatory processes [101], [102]. Some triterpenes such as oleanolic acid (OA), masticadienonic acid, morolic acid, ursonic acid [22], and ursolic acid (UA) [103], [104] have been identified in different Pistachia species, and pistagremic acid has been isolated from galls of P. integerrima [22].

Oleanolic acid

OA is a pentacyclic triterpenoid compound with a widespread occurrence either as a free acid or as an aglycone precursor for triterpenoid saponins throughout the plant kingdom. Besides its anti-inflammatory and antioxidant activities, OA has been shown to possess neuroprotective effects in several studies [105]. In an experimental mice model of multiple sclerosis, OA inhibited the development of autoimmune encephalomyelitis (EAE), and reduced activation of microglial cells, blood-brain barrier (BBB) disruption, and infiltration of inflammatory cells within the CNS [106]. Its effect in protecting the integrity of the BBB has been shown to be associated with an increase in protein expression of tight and adherent junctions in a rat model of subarachnoid hemorrhage. This compound also suppressed the p38MAPK/VEGF/Src signaling pathway, which is involved in BBB disruption [107]. In a mice model of MS, OA also showed a modulatory role in T helper cell polarization [106]. EAE mice treated with OA had a decrease in the cytokine osteopontin level and TNF-α in CNS tissue. Moreover, EAE mice treated with OA had lower levels of anti-myelin-oligodendrocyte glycoprotein (anti-MOG) antibodies than untreated animals [106]. In vitro, OA decreased the inflammatory stimuli-induced proliferative response, phagocytic properties, and synthesis of proinflammatory mediators in microglia; it also inhibited extracellular signal-regulated kinases (ERK) and ribosomal protein S6 (rS6) phosphorylation as key factors of the MAPK and mammalian target of rapamycin (mTOR) pathways, which play a crucial role in the regulation of cell growth and proliferation [108].

As a beneficial natural product in PD, OA ameliorated forelimb use asymmetry in a 6-OHDA-induced PD rat model and inhibited the reduction of dopamine in the striatum of PD animals. It also decreased membrane depolarization and attenuated mitochondrial apoptosis [109]. OA exerted its neuroprotective effects in 6-OHDA-induced PD in rats by attenuating microglial activation [110]. In vitro, it inhibited the accumulation of intracellular ROS in PC12 cells, resulted in promoting cell survival [110]. In another study, migration, proliferation, and differentiation of neural stem cells (NSCs) were elevated by OA. The mechanism of action was determined as suppressing glycogen synthase kinase 3β (GSK3β) activity, which has a role in peripheral and CNS inflammation in various neurological disorders [111].

Pretreatment of rats with OA before focal cortical hypoxia induced by brain injection of cobalt chloride resulted in a reduction of neuronal damage and glial reaction as well as recovery of brain tissue after injury [112]. OA mitigated cognitive deficits in a rat model of Aβ-induced AD. Related to this, in a model of beta-amyloid-stimulated astrocytes, OA ameliorated primary neuron death and neuroinflammation (via inhibiting transcription and secretion of IL-6, TNF-α, and IL-1β) in secretory phopholipase type A2 (sPLA2)-IIA-mediated calcium signals [113].

Ursolic acid

UA as another naturally derived pentacyclic triterpene acid derives from a hydride of an ursane. It is widely found in fruits, spices, and medicinal herbs [114] such as in the Pistacia genus [103], [104]. Several studies have evaluated the neuroprotective effects of this compound against Aβ to show the therapeutic potential of this phytochemical for AD. It has been reported that Aβ-induced memory and learning deficits in mice were reversed by UA, along with a decrease/increase in MDA/glutathione levels in the mouse hippocampus. Besides its antioxidant effect, UA also reduced the levels of inflammatory markers (IL-1β, IL-6, and TNF-α) [115]. In vitro, UA was also shown to attenuate Aβ-induced neurotoxicity in PC12 neuronal cells through modulation of the NF-κB signaling pathway [116]. In these cells, it has also been shown to inhibit the Aβ-induced expression of iNOS and COX-2 through inhibition of NF-κB activity, along with reduced ERK1/2, p-38, and Jun N-terminal kinases (JNK) phosphorylation [117]. Moreover, UA reversed the increase in ROS, LPO, and apoptosis induced by Aβ via inhibiting caspase-3 activity [118].

Treatment with UA in aged mice subjected to D-galactose-induced neurotoxicity resulted in improved memory as well as elevated the levels of antioxidant enzymes SOD, CAT, GPx, and glutathione reductase (GR) and decreased the level of MDA. In addition, the activation of caspase-3 was inhibited by UA, while the level of neural growth-associated protein GAP43 was elevated [119]. Anti-aging effects of UA might also be considered through increasing the levels of anti-aging biomarkers such as SIRT1, SIRT-6, α-Klotho, and PGC-1β protein [120].

UA has also been reported as an AChE inhibitor, which is one of the characterized targets in a therapeutic approach to AD. The synthetic hydroxyl-propinyl derivatives of UA were shown as more potent AChE/butyrylcholinesterase inhibitors [121].

In an experimental PD mouse model, UA was shown to protect dopaminergic neurons in MPTP-intoxicated mice. It also improved behavioral deficits and restored the altered dopamine level. UA mitigated the MPTP-induced increase of MDA and NO levels [122].

UA has been shown to mimic the human natural killer (HNK)-1 and promote the regaining of motor functions and axonal regrowth in mice with a spinal cord injury via activation of MAPK and PI3K/Akt/mTOR pathways. It also reduced astrogliosis and levels of proinflammatory markers (IL-6 and TNF-α) in the acute phase of inflammation in injured spinal cords [123]. Additionally, UA administration has been indicated to reverse high-fat diet-induced cognitive impairment via inhibition of endoplasmic reticulum stress and NF-κB signaling and activating the PI3K/Akt/mTOR pathway in the mouse hippocampus [124].

UA treatment in mouse models of cerebral ischemia [125] and traumatic brain injury [126] led to a decrease in oxidative stress [125], [126] by enhancing the expression of antioxidant enzymes (NQO1 and HO1) as well as Akt, as an Nrf2 upstream factor, suggesting a possible mechanism via activation of the Nrf2-ARE pathway [126]. It also decreased inflammatory factors (TLR4 and NF-κB) after stroke in the mouse brain [125]. In a subarachnoid hemorrhage rat model, UA treatment reduced early brain injury via reducing apoptosis and suppressing TLR4-mediated inflammatory factors, such as intercellular adhesion molecule-1 (ICAM-1), TLR4, NF-κB, IL-1β, TNF-α, IL-6, iNOS, and matrix metalloproteinase (MMP)-9 [127]. It also showed neuroprotective effects as an activator of PPARs in a rat model of cerebral artery occlusion and reperfusion and modulated the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the MAPK signaling pathway [128]. UA has also been shown to have anxiolytic, anticonvulsant, and antidepressant activities in mice via affecting the GABA-A receptor, especially acting on the benzodiazepine binding site of GABA receptors [129], [130].

Pistagremic acid

Pistagremic acid, another triterpenoid compound isolated from P. integerrima, was evaluated for b-secretase (BACE 1) enzyme inhibition and showed significant activity against BACE1, which plays an important role in APP (amyloid precursor protein) cleavage and subsequent formation of Aβ 40 – 42. However, the effect of pistagremic acid was selective for BACE1 and its inhibitory activity was insignificant against acetylcholinesterase and butyrylcholinesterase enzymes [131].

Masticadienonic acid

Although masticadienonic and masticadienolic acids are among specific triterpenoids identified in the resins of the Pistacia genus [22], there are limited studies on the neuroprotective activity of these natural products. In one study, these triterpenoids showed anti-inflammatory effects in vivo by preventing PMA-induced ear edema, and also the synthesis of lipooxygenase products [132]. In a recently published clinical study, Hazan et al. [133] reported the safety and tolerability of RPh201 in a phase 1, placebo-controlled, double-blinded trial in healthy subjects. RPh201 has been introduced as a botanical formulation, mainly containing masticadienonic acid and isomasticadienonic acid from mastic gum. They also reported that based on their previous in vivo studies, RPh201 promoted neurogenesis and synaptogenesis, and increased functional recovery of cognition, memory, and sensorimotor impairments (unpublished data) [133]. Next they designed a phase 2 clinical trial (NCT02045212) for the assessment of the effect of RPh201 in subjects with previous non-arteritic anterior ischemic optic neuropathy, which is a neurodegenerative disease resulting in vision loss. As a result, improvement in visual acuity was reported in the RPh201 group compared to placebo. The phase 3 clinical trial is in recruiting status (NCT03547206) [134].

Phenolic Compounds

Gallic acid

Gallic acid, a phenolic compound, is a well-known trihydroxybenzoic acid found abundantly in free and conjugated (hydrolysable tannins) or esterified forms in many plants [135]. Gallic acid and its derivatives have also been isolated from different Pistacia species [22]. As a polyphenolic compound in dietary and medicinal plants, its pharmacokinetic characteristics have been partially studied [136], [137]. It has been shown that when 50 mg gallic acid was orally administrated to healthy volunteers, its metabolites concentration in plasma reached 4 µM and the urinary level was about 37% of the ingested amount [136]. One animal study also indicated that gallic acid exhibited slower absorption in myocardial infarcted rats than those in normal rats. However, there is still uncertainty about its pharmacokinetic profile under pathological conditions [138].

As a phytochemical with antioxidant and anti-inflammatory activities, the neuroprotective effect of gallic acid against neuroinflammation, neurodegeneration, and neurotoxicity has been reviewed in some studies [135], [139], [140]. It has been indicated that gallic acid inhibits Aβ-induced neurotoxicity via suppressing microglial-mediated neuroinflammation and decreasing cytokine generation and levels of NF-κB acetylation [141]. The ester derivative of gallic acid, epigallocatechin gallate, also plays a positive role in the modification of AD through suppressing Aβ-induced beta-site APP cleaving enzyme-1 upregulation [142]. Furthermore, it has been shown to regulate the amyloid precursor protein and increase the transferrin receptor in H-SY5Y neuroblastoma cells. These findings seem to be related to its metal (especially iron) chelating activity [143]. Gallic acid has been demonstrated to reduce memory deficit and cerebral oxidative stress in a 6-OHDA-induced Parkinsonʼs disease model in rats [144]. Also, its neuroprotective effect has been shown in models of traumatic brain injury [145], and glutamate-induced neurotoxicity [146] in rats, which was due to improvement of the antioxidant profile and inhibition of proinflammatory cytokine generation [145], [146].

Catechin

Catechin (a flavan-3-ol) belongs to the flavonoids and is well recognized as an antioxidant [147]. Catechin isomers and their gallic acid conjugates are naturally occurring constituents in various plants [148], in which the Pistacia genus is also among them [22]. Despite their therapeutic effects, catechins have been shown with low systemic bioavailability, poor membrane permeability, and rapid metabolism. In this regard, some strategies have recently been used for their structural modifications to improve pharmacokinetic properties [149].

There have been several reviews to date on the neuroprotective properties of catechins, which were mostly through antioxidation and anti-inflammation effects mainly involving Nrf2 and NF-kB signaling pathways [147], [150], [151]. One in vivo study has revealed that it can improve cognitive impairment induced by doxorubicin via increasing antioxidant defense, preventing neuroinflammation, and inhibiting AChE [152]. Another study showed that catechin has neuroprotective activity in a rat model of traumatic brain injury. An anti-inflammatory effect and intervention in the self-perpetuating procedure of BBB disruption were underlying mechanisms [153]. Catechin has also been indicated to inhibit the late stages of Aβ-soluble aggregate growth change in the fibrillar form of Aβ [154]. In streptozotocin-induced diabetes [155] and dementia [156] models in rat, catechin treatment resulted in the improvement of behavioral alternations, along with a decrease in the levels of MDA and nitrite [155], and reduction in cognitive deficit, S100B content, AChE activity, NO, and ROS content [156]. It also prevented neurotoxin-induced dopamine neuron loss in substantia nigra in a mouse model of PD [157].

Cyanidin 3-O-glucoside

Cyanidin 3-O-glucoside has also been shown to inhibit the formation of Aβ oligomers in a human neuronal cell line (SH-SY5Y) [158].

Quercetin

The well-known and widespread flavonoid quercetin has frequently been reviewed as a neuroprotective polyphenol in several studies [159], [160], [161]. Various evidence showed that quercetin can exert neuroprotection, mostly via countering oxidative stress, which is known as one of the important causes of neurodegenerative conditions [161]. Also, quercetin protects neuronal cells through modifying some of the main features involved in AD including Aβ aggregation, and the APP cleaving enzyme (BACE1) [162], as well as AChE inhibition [163]. It has been reported that quercetin attenuated Aβ (1 – 42)-induced cytotoxicity, lipid peroxidation, and protein oxidation as well as apoptosis in primary hippocampal neuron cultures [164]; it also improved the emotional and cognitive impairments in AD models [165]. Quercetin treatment in the hippocampal neurons resulted in the elevation of neurogenesis, synaptogenesis, and cell proliferation as well as restoration of Aβ-induced synaptic loss. It also increased phosphorylation of the cAMP response element-binding protein (CREB) in these cells and enhanced the levels of pCREB in the mouse brain [166].

Furthermore, as a potential effective natural product in PD [167], quercetin has been shown to possess inhibitory activity on catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) enzymes, which can lead to an increase of the bioavailability of L-dopa in the brain [168]. It has been able to inhibit the phosphorylation of the signal transducer and activator of transcription (STAT) and prevent apoptosis in dopaminergic cells via the down/upregulation of Bax/Bcl-2, respectively [169]. Considering its free radical scavenging activity, quercetin also adjusted the electron transport defect of mitochondria and upregulated Complex I in a rotenone-induced rat model of PD [170]. Its protective effect in an animal model of radiation-induced brain injury was also reported through the antioxidant mechanism [171]. Moreover, quercetin decreased rat pial microvascular permeability, leukocyte adhesion, and ROS production during transient bilateral common carotid artery occlusion and reperfusion [172]. The neuroprotective effects of quercetin are manifested through different signaling pathways, including regulation of cytokines via Nrf2, JNK, protein kinase C, MAPK signaling cascades, and PI3K/Akt pathways [173]. Moreover, quercetin has been indicated to be effective in attenuating diabetes-induced neurodegeneration and inflammation due to inhibition of the STAT [150].

Phytochemistry and Pharmacokinetics

Terpenes

Terpenes are derived from isoprene units with five carbons, and based on the number of isoprene units, terpenes can be classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), and tetraterpenes (C40) [174]. Triterpenoids are mostly found as tetra- or penta-cyclic structures, but acyclic, mono-, bi-, tri- and hexa-cyclic triterpenoids also exist. The pentacyclic triterpenes are divided into three major classes: lupane, oleanane, and ursane [175].

Various pharmacological activities of terpenes have been reported so far, but the clinical relevance of these effects depends on the systemic availability of these natural compounds. However, for monoterpenoid compounds, more pharmacokinetic data in humans are needed. In addition, based on studies supporting the effects of volatile compounds of essential oils on cognitive function via aromatherapy, it is important to evaluate their absorption through the skin, or following inhalation, and crossing the BBB [176], [177]. (+)-α-Pinene, (+)-limonene, and (−)-linalool have been shown to be transported to the brain in different amounts following inhalation in mice, indicating that even their low concentrations are capable of exerting effects on the brain [177]. Bicyclic monoterpenoids easily transport to the brain both by inhalation and through blood. β-Caryophyllene is a volatile bicyclic sesquiterpene with extensive biological activities, occurring in the essential oil of numerous plants. However, its poor water solubility and physiochemical sensitivity might decrease its bioavailability. These potential complications have resulted in the use of various drug delivery systems for β-caryophyllene, mostly including inclusion complexes and nonoemulsions, which have been shown to improve its oral bioavailability and neuropharmacological activity in vivo [178].

Various studies on the bioavailability of pentacyclic triterpenes showed that several factors can affect the oral bioavailability of these natural products. Their bioavailability can be improved by increasing the low solubility in the gastrointestinal fluid for better absorption, and, in some cases, by inhibiting their metabolism. It has been shown that high-fat meals enhance triterpene absorption [179]. As a triterpenoid compound, oral administration of OA in rats resulted in low gastrointestinal absorption and hepatic microsomal metabolism [174]. UA is also known to be almost insoluble in water, with a low oral bioavailability. These compounds require some modifications to improve their bioavailability. For example, in the form of self-micro/nano emulsion, the intestinal absorption and bioavailability of UA/OA has been improved. After absorption, OA is transported to the liver where it is converted to its glucuronic acid conjugate. Conjugated OA is transported via the bile to the gut. Then it is hydrolyzed to OA again. UA is mostly distributed in the liver, spleen, stomach, and kidney after intravenous administration, and is rapidly removed by metabolism and in small amounts through the excretion of the kidneys [180].

Phenolic compounds

Studies revealed that (poly)phenols and their metabolites can enter the brain at detectable levels in mammals, which supports their direct neurological action [181]. As a hydroxybenzoic acid, gallic acid has been shown to be effectively accumulated in the brain. It has been detected in trace amounts in the mouse brain after repeated oral administration of a polyphenolic grape extract [182]. Some studies focusing on the bioavailability of gallic acid in humans also showed that compared with other polyphenols, this compound is relatively well absorbed [182].

The chemical structures of flavonoids are based on a diphenylpropane (C6-C3C6) skeleton with two aromatic rings as part of a six-member heterocyclic ring. These compounds can be divided into three classes, including flavonoids, neoflavonoids, and isoflavonoids, based on the connection of the aromatic ring to the heterocyclic ring. Depending on the degree of oxidation and saturation in the heterocyclic C-ring, flavonoids might be divided into different subclasses and minor subclasses [183], [184]. Among different dietary flavonoids, flavanols, flavanones, and flavonol glycosides have intermediate rates of absorption and bioavailability, while proanthocyanidins, flavanol gallates, and anthocyanins have the lowest absorption [183]. Dietary flavonoids occur mainly as glycosides and need to undergo enzymatic deglycosylation before absorption. The only subclass of flavonoids that could be present in the non-glycosylated form in the diet are flavan-3-ols [i.e., (+)-catechin, (−)-epicatechin], which are absorbed mainly in the small intestine [184]. –(−)Epicatechin and quercetin as flavan-3-ol and flavonol compounds, respectively, enter the circulatory system after ingestion, in only trace amounts, and appear mostly as phase II glucuronide, sulfate, and methyl metabolites [185]. Based on limited animal studies, (−)-epicatechin metabolites seem to reach the brain of rodents at levels that might be physiologically effective [186]. Some conjugated forms of quercetin can also accumulate in the brain after oral administration, while aglycone quercetin is scarcely distributed in the CNS [187], [188].

Anthocyanins are the glycosides of 2-phenyl-benzopyrylium or flavylium salts, which have different hydroxy or methoxy groups. As major anthocyanin flavonoids, glycosides of cyanidin (particularly cyanidin-3-glucoside) are primarily present in most of the herbs [189]. Several in vitro/in vivo studies have shown the pharmacokinetic characteristics of anthocyanins and their passage through the BBB. Studies showing that anthocyanins and some of their metabolites are able to cross the BBB have recently been reviewed in detail by Manolescu et al. [190]. Cyanidin-3-glucoside has been shown as the most absorbed anthocyanin through the jejunum and ileum in rats followed by cyanidin-3-galactoside and cyanidin-3-rutinoside [191]. Anthocyanins are hydrolyzed to anthocyanidins through removal of the 3-O-glycosidic part by colon microbiota. Phase I and II reactions mainly occur in the small intestine and liver, and the anthocyanidins become glucuronide, sulphate, or methyl derivatives. Anthocyanins metabolites are eliminated from the body by urine, bile, feces, and breath [192], [193].

Conclusion

The genus of Pistacia has demonstrated various activities such as antioxidant, anti-inflammatory activities, and inhibitory effects on the progression of neurodegeneration together with promoting neuronal growth. These mentioned bioactivities along with their modulatory roles in functions of neurotransmitters, and modulation of signaling pathways as well as maintenance of BBB integrity support promising action of the plants for development in neuroprotective approaches. Phenolic compounds and terpenes as the two main groups of phytochemicals have been identified in different species of the genus Pistacia. α-Pinene, β-caryophyllene, and oleanolic, ursolic, and masticadienonic acids as well as gallic acid, quercetin, and catechins are among the most abundant compounds in Pistacia. They demonstrated notable neuroprotective effects against different neurotoxic agents. The characteristic feature of these species is the production of remarkable essential oils from different parts of plants as well as large quantities of oleoresin. The obtained oleoresins are rich in terpenes, which have been supported by substantial evidence for their antioxidant, anti-inflammatory, and neuroprotective effects.

In this study, we reviewed the neuroprotective efficacy of the genus Pistacia and the related molecular mechanisms of these herbs in various in vitro and in vivo models. The supporting scientific evidence shows that the Pistacia genus might be considered a potential source as a therapeutic agent for the treatment of NDs due to the multitargeted mechanism of action. However, further detailed investigations are essential to assess their safety, efficacy, bioavailability, and probable molecular evaluation experiments.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Correspondence

Zahra Memariani, Pharm D, PhD

Department of Traditional Persian Medicine

Faculty of Traditional Persian Medicine

Babol University of Medical Sciences

P. O. Box

4717647745 Babol

I. R. Iran

Phone: + 98 91 28 23 95 67

Fax: + 98 11 32 19 01 81

Email: z.memariani@mubabol.ac.ir

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Pistacia Genus as a Potential Source of Neuroprotective Natural Products

Correspondence

Publication History

Abstract

Key words

Abbreviations

Introduction

Traditional Medicinal Usage of the Pistacia Genus

Evidence Related to the Neuroprotection in the Pistacia Genus

Search strategy

Pistacia vera

Pistacia lentiscus

Pistacia atlantica

Pistacia integerrima

Pistacia terebinthus

Neuroprotective Phytochemicals in Pistacia Genus

Terpenes

α-Pinene

Linalool

β-Caryophyllene

Myrcene

Limonene

Triterpenoids

Oleanolic acid

Ursolic acid

Pistagremic acid

Masticadienonic acid

Phenolic Compounds

Gallic acid

Catechin

Cyanidin 3-O-glucoside

Quercetin

Phytochemistry and Pharmacokinetics

Terpenes

Phenolic compounds

Conclusion

Conflict of Interest

References

Correspondence

References