Introduction

Plants are sources of myriads of potent bioactive compounds with medicinal properties [1, 2]. Studies show that plants growing under the ocean are also a rich source of bioactive phytochemical and are of immense medicinal importance [3]. Plants have been medicinally important since the beginning of civilization and various medicines used in Ayurveda, Unani, etc. have their sources from plants. Many of the drugs of modern day owe their roots to plant origin. Potent bioactive compounds derived from plant sources are used as potent lead molecules for developing drugs with minimal side effects [4]. Plants of every region have their unique phytochemical. The composition of the phytochemicals is known to vary in quality and quantity depending on the geographic region and soil composition on which the plant grows [5]. Natural products have been in use as drug candidates since ages [6]. Plants growing in a particular region by default find their use in local folk medicine. Mother nature has gifted mankind with a vast reserve of different kinds of plants all around. Most of these plants are rich source of potent bioactive phytochemical. The plants like Murraya koenigii, Moringa olefera, Ocimum sanctum, Terminalia arjuna, Azadirachta indica, and Coriendrum sativum are some of the very common popular potent medicinal plants found in almost all regions of South-East Asia including India [7–11]. Several hundreds of medicinal plants growing in the Indian Sub-continent have been identified to have potent neuroprotective activity. Some of these are Bacopa monnierae, Withania somnifera, Hypericum perforatum, Allium sativum, Centella asiatica, Nicotiana tabaccum, Celastrus paniculatus, Enhydra fluctuans, Ricinus communis, Ginkgo biloba, Angelica sinensis, Uncaria tomentosa, Terminalia chebula, Salvia officinalis, Physostigma venosum, Acorus calmus, Curcuma longa, Huperiza serrata, Glycyrrhiza glabra, Crocus sativus, and Valeriana wallichii, etc. [12].

Neuroprotection refers to the mechanism of protection of neurons from injuries or degenerations and conserving their normal physiological functions [13, 14]. Most common neurodegenerative diseases affect the aging population around the globe. Several plants derived traditional medication are there in use for ages for treating neurodegenerative situations, improving memory and learning as well as delaying the process of ageing [15, 16].

More than one hundred and twenty plants are known to be in use to address neurological ailments in the Asian countries [16]. These plants are rich sources of phytocompounds which have been studied to have potent neuroprotective activities [12]. Thus, the bioactive compounds and their derivatives with neuroprotective potential from these plants are used as lead compounds for developing neuro-psychopharmacological drug formulations. In this review, the neuroprotective compounds and their mechanism of action from four major indigenous plants grown in the state of West Bengal, India has been discussed.

Neuroprotective compounds from Withania somnifera (Aswagandha)

Withania somnifera (Ashwagandha) is a very common medicinal plant of India and has been in extensive use in Ayurveda for ages. The plant has several medicinal properties. Neuroprotective potential of Aswagandha is one of the most important and significant medicinal properties of the plant. It is known to be used as a nerve tonic in Ayurveda [17]. Studies show that Withania somnifera has cognition promoting impact [17]. It is reported to be effective in treating memory deficit in children and is also known to improve memory in aged people [17]. Withania somnifera is useful and effective in treating neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s diseases [17]. Withania somnifera is commonly known as the “Indian Ginseng” and “Indian Winter Cherry” [18]. The plant is known to have γ-aminobutyric acid (GABA) mimetic effect and is reported to promote dendrites formation [19]. The plant is also known to improve energy levels. It has positive effects on mitochondrial health. The plant is also reported to have anxiolytic and antidepressant effects [20]. This effect of Withnia somnifera is reported to be by virtue of the glycowithanolides present in Withania somnifera [20]. Alkaloids like anaferine, isopelletierine, anahygrine, cuseohygrine have been reported to be present in Withania somnifera (Table 1). The plant has been known to be a source of saponins and steroidal lactones like withaferins, and withanolides [21]. Other bioactive compounds reported to be present in Withania somnifera are acylsterylglucosides, Withaferin A and sitoindosides (Table 1). These compounds have anti-stress effects [22]. Compounds like 5-dehydroxy withanolide-R and withasomniferin-A have been isolated from the aerial parts of the plant [23].

Neuroprotective compounds from Bacopa monnieri (Brahmi)

Bacopa monnieri popularly known as Brahmi is a common medicinal herb grown abundantly in parts of West Bengal, India [28]. It is a small succulent herb grows naturally in wet soil. The herb was used by the ancient Vedic scholars to memorize lengthy scriptures and sacred hymns. A phytochemical namely Bacosides, is known to be present in Brahmi (Table 1), and causes an increase in the cerebral blood flow. This compound is extensively used as brain health supplement and is remarkably used in the treatment of Alzheimer’s disease [28]. The herb is primarily composed of bioactive compounds like dammarane-type triterpenoid saponins that are called Bacosides and they have jujubogenin or pseudo-jujubogenin moieties as their aglycone units [29]. Bacosides have been reported to promote nerve impulse transmission, repair damaged neurons by stimulating kinase activity and also stimulate neuronal synthesis [29]. Bacosides are also reported to restore nerve impulse transmission [29]. Studies conducted on murine model of schizophrenia reveals that administration of Brahmi resulted in restoration of the memory impairment by decreasing NMDAR1 in certain brain areas in the rats [30]. Another study shows that memory impairment induced by streptozoticin is restored by Brahmi in murine model [31]. Studies report that Brahmi has the ability to enhance the expression of 5-hydroxytryptamine type 3A (5-HT3A) receptors, the level of serotonin, and also the level of cyclic adenosine monophosphate response element binding protein (CREB) in hippocampus of postpartum rats and these facilitates the learning abilities of the experimental animals [32]. The fact that Brahmi has the potential to bring improvements in cognitive abilities, has now been well established with supporting experimental and clinical data [33, 34]. Studies show that during clinical trials using Brahmi, there has not been any toxicity in the human subjects [34]. The studies reveal that Brahmi has the ability to improve nervousness, concentration and memory in adult subjects [34]. A study using 60 healthy human adults, reveals that Brahmi improves cognitive processing, attention, and working memory partly through the decrease in acetylcholinesterase (AChE) activity [35].

Bacoside A (dammarane-type triterpenoid saponins), the primary neuroprotective compound group recognised from Brahmi is composed of bacopaside III, bacopaside X, Bacoside A3, and bacopasaponin C (Table 1) [33–35]. Through structural analysis, 12 analogues derived from the Bacosides have been reported, different saponin types have also been identified as essential ingredients which are known as bacopasides I–XII [36]. Other components of Bacopa are apigenin, monnierin, cucurbitacin, hersaponin, azlkaloids brahmine, monnierasides I–III, D-mannitol, nicotine and herpestine [37, 38].

Studies show that Bacosides have the potential to prevent amyloid beta peptide (Aβ) aggregation, and formation of fibrils [38] and also protect neurons from toxicity induced by Aβ [39]. The compounds are reported to directly interact with the neurotransmitter and thus bring changes in memory and learning [40, 41]. Bacosides isolated from Brahmi, are non polar glycosides in nature and they easily cross the blood brain barrier [42–44]. This has been confirmed by radiopharmaceuticals biodistribution studies [45]. Thus, the Brahmi, rich in Bacosides have potent neuroprotective potentials and may be explored for utilizing the phytocompounds as lead molecules for developing more potent and effective neuroprotective drugs. Computational study predicts ebelin lactone as the most important compound from Bacopa monnieri. The study claims ebelin lactone as the most promising drug candidate and that it can be utilised to develop a drug against Alzheimer’s disease, post pre-clinical and clinical validations [46]. The herb has also been found to have potent neuroprotective and neurorescuing effects against neurodenerative disese like Parkinsons’s disease [47].

Neuroprotective compounds from Centella asiatica

Centella asiatica is a small perennial plant that grows abundantly in hot humid tropical and sub-tropical regions around the globe. The plant grows extensively in West Bengal, India [48] (Figure 1). Some of the primary bioactive phytocompounds identified and reported from Centella asiatica are phenylpropanoid derivatives (eugenol derivatives, flavonoids, and caffeoylquinic acids) and isoprenoids (plant sterols, sesquiterpenes, saponins, and pentacyclic triterpenoids) (Table 1) [49].

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Figure 1. 

Centella asiatica

Several studies have been conducted in rodent models and some in human models to investigate the neuroprotective potentials of Centella asiatica [49]. The medicinal plant Centella asiatica is traditionally known for enhancing the cognition and improving memories [50]. The plant is also known in folk medicine as an anxiolytic agent and anticonvulsant [51]. In Ayurveda the plant is known as “medhyarasayana” by virtue of its ability to improve memory and cognition [52]. Centella asiatica is reported to have neuroprotective effect and it has also been established in several in vitro models. Administration of Centella asiatica has been reported to improve antioxidant status, inhibit pro-inflammatory enzyme namely phospholipase A2 and protect against beta amyloid toxicity [49]. Centella asiatica is known to impose its neuroptropic effects by modulations of the signal transduction pathways including ERK1/2 and PKB pathway [53]. Increased dendritic arborization and synaptogenesis are the prime neuroptopic effects of Centella asiatica [53]. Most of these neurotropic and neuroprotective potentials of Centella asiatica are due to the potent phytocompounds present in the plant which include triterpene compounds asiaticoside, asiatic acid, and madecassoside [54]. The new group of compounds reported from Centella asiatica are caffeoylquinic acids and these have the potential of inducing the Nrf2-antioxidant response pathway and HO-1 signaling [55]. Studies show that by virtue of its ability to improve the antioxidative signaling pathway, the plant Centenella asciatica improves memories in experimental rats [55].

Other medicinal properties of Withania somnifera, Bacopa monnieri and Centella asiatica

All these three plants are known to possess several other medicinal properties besides that of neuroprotective actions. The plant Withania somnifera, popularly known as Aswagandha and the phytocompounds namely Withaferin A, withanolide A, withanolide D, and withaniamides are known to play significant pharmacological roles. Glycoproteins from Withania and lectin like-protein are reported to possess potent antimicrobial, anti-snake venom poison and antimicrobial therapeutic potentials [56]. In folk medicine, the plant Withania is known to be in use for treating ailments like hypothermia, diabetes, cancer, hepatitis, arthritis, asthma, ulcer, eyesores, heart problems, haemorrhoids, etc. The plant Withania is known to have anticancer, antimicrobial, and muscle strengthening activities. It is also reported to have potential in treating low back pain [57]. Several important secondary metabolites like steroids, alkaloids, phenolics, flavonoids, saponins, and glycosides have been reported from the Withania and these have potent medicinal properties [57]. Phytocompounds from different parts of the plant Withania, specially the roots have been extensively explored for their medicinal properties like treating male infertility, antianxiety, obsessive-compulsive disorder, etc., and several of these experimental studies have been evaluated successfully for clinical trials [56, 57]. A bitter alkaloid named Somniferin has been isolated from Withania somnifera and is known to have hypnotic activity [58].

The plant Bacopa monnieri, is also known to be a rich source of medicinal phytocompounds with various medicinal properties. Memory enhancing ability of the plant is well documented [59]. The plant is known to add years to life and also promotes rejuvenation [59]. Several potent medicinal phytochemicals namely triterpenoid saponins, monnierinalkaloids flavonoids, glycosides and other phytochemicals namely betulinic acid, betulic acid, oroxindin, wogonin, stigmasterol, beta-sitosterol, sapogenin, Brahmic acid, brahminoside, brahamoside, isobrahmic acid, etc., have been isolated from the leaves of the plant Bacopa monnieri [59]. Studies reveal broad therapeutic potentials of the Bacopa monnieri that include analgesic, anxiolytic, antioxidant, anti-inflammatory, anti-microbial, anti-depressant, anti-convulsant, adaptogenic, hepatoprotective, immunostimulatory, anti-ulcerative and anti-neoplastic, etc. [60–70]. Extracts of the plant Centella asiatica are reported to have extensive use in folk medicine in China and India and has potentials in boosting memory, preventing cognitive deficits and improving brain functions [71]. Certain potent phytochemicals namely pentacyclic triterpenoid glycosides, madecassoside and asiaticoside have been reported from the plant. Corresponding aglycones, asiatic acid and madecassic acid of the mentioned compounds have also been reported to have potent medicinal properties. Asiaticoside and madecassoside are reported as marker compounds of Centella asiatica and are known to have wide pharmacological potentials. The triterpene compounds, asiaticoside and madecassoside have been reported to have anti-inflammatory, antioxidant, anti-allergic, wound healing, cardioprotective, hepatoprotective, neuroprotective, anxyiolytic, anti-fibrotic, antibacterial, anti-arthiritic, anti-tumor, anti-ulcerative properties. The compounds are also widely used for addressing issues of skin abnormalities and for treating burn injuries, asthma, lupus, psoriasis and scleroderma, etc. [71–76].

Conclusions

Neurological diseases are usually long term disturbances that may occur in any stage of life. The common degenerative neural diseases includes Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, insomnia, loss of cognitive ability, etc. The primary causes of these diseases are stress, ageing, inflammation, compromised immunity and neural injury. The chief neurotransmitter systems disabled in such illness are cholinergic, GABAergic, dopaminergic transmitter pathways. The plants discussed in this review work on several target molecules effecting these neurotransmitters, metabolism of the brain or checks oxidative stress mediated neural damage. The potent phytocompounds from these plants are also known to be affecting various signaling pathways and all together they have been found to be potent neuroprotective agents. There are extensive literature revealing in vitro, in vivo, and in silico studies and also successful clinical trials of some of the potent bioactive neuroprotective compounds from the plants namely Withania somnifera, Bacopa monnieri and Centella asiatica. These studies taken together, show that these indigenous West Bengal, India may be explored to utilise their rich source of bioactive neuroprotective compounds for developing new potent, effective and affordable neuropharmacological formulations and drugs which are expected to have minimum or no side effects.