Phytochemical Profile, Pharmacological Attributes and Medicinal Properties of Convolvulus prostratus – A Cognitive Enhancer Herb for the Management of Neurodegenerative Etiologies

Convolvulus prostratus Forssk., a nootropic herb used in traditional medicinal systems, is also frequently known by its taxonomic synonym Convolvulus pluricaulis. In Indian medicinal system – Ayurveda – it is named as Shankhpushpi. According to the ancient literature, this herb has been attributed with several therapeutic properties, such as anxiolytic, neuroprotective, antioxidant, analgesic, immunomodulatory, antimicrobial, antidiabetic and cardioprotective activities. This medicinal herb has been reported to contain many bioactive phytoconstituents, such as, alkaloid (convolamine), flavonoid (kaempferol) and phenolics (scopoletin, β-sitosterol and ceryl alcohol), that have been ascribed to the observed medicinal properties. Several research teams across the globe have highlighted the neuro-pharmacological profile of C. prostratus, wherein, the neuroprotective, nootropic and neuro-modulatory roles have been described. Besides, role of C. prostratus extracts in neurodegeneration has been well demonstrated. Despite of such elaborative preclinical pharmacological profile, detailed clinical investigations and mechanistic mode-of-action studies of this important herb are yet to be executed. The present review is attempted to showcase the phytochemical profile, pharmacological attributes and medicinal information of C. prostratus; with comprehensive research gap analysis. It is hoped that the scientific update on the ethnomedicinal aspects of this herb would thrive research propagation and development of the CNS phytopharmaceuticals, originated from C. prostratus.


INTRODUCTION
In recent years, non-communicable diseases (NCDs) have become an emerging cause of morbidity and mortality (~12% global prevalence) (Islam et al., 2014). Neurological disorders constitute a significant proportion as the leading causes of death among all the other non-communicable diseases (Gourie-Devi, 2014). The most common disorders of the nervous system are schizophrenia (~40% prevalence in India) and epilepsy (~45% prevalence in India), which are clinically presented by dysfunction of the interneurons, misbalancing neuronal homeostasis, ultimately leading to neurophysiological disintegration (Gururaj et al., 2005). It is estimated that by next decade, mental and behavioural disorders will lead to a reduction in the average life expectancy, nearly by one-fifth proportion (Lopez and Murray, 1998). In India, an average of 65 people out of 1,000 inhabitants suffer from mental and behavioural disorders, wherein, maximum prevalence has been recorded for alcohol dependency afflicted mental disorders (~6% prevalence), child and adolescent behavioural disorders (~4.3% prevalence) and mood disorders (~1.6% prevalence). These statistics makes it obvious that the prevalence of neurodegenerative disorders is escalating, however, effective and safe treatment modalities are still under infancy (Gururaj et al., 2005).
The chemotherapeutic moieties used currently for the treatment of neurological disorders face a daunting challenge of systemic delivery of the drugs to the central nervous system. Moreover, crossing the blood brain barrier after strenuous systemic administration is another challenge. Ultimately, the bioavailability of these drugs becomes low and therefore, lead to below-optimal efficacies (Tonda-Turo et al., 2018). Several drug delivery vehicles and nano-formulations have been devised so as to facilitate the targeted delivery of the drug to the site of action, i.e., the central nervous system, thereby bypassing the blood brain barrier (Saraiva et al., 2016;Tonda-Turo et al., 2018). However, these strategies have also shown little success. Most of the neurodegenerative disorders are progressive in nature, and the cycle of etiological events usually have an early-onset which might get unnoticed or under-detected. In such a case, the therapies initiated after the onset of neuropathological asymptomatic etiologies will only have limited value for the patients (Solanki et al., 2016). Moreover, the foresaid neuropathological conditions are manifested with several additional etiologies, wherein the chemotherapeutic modalities act typically on a single target, thereby providing only palliative care (Chen and Pan, 2014). Hence, natural compounds serve as the holistic option which act on multiple neural targets and are enriched with free radical scavenging polyphenolic compounds (Park et al., 2018). These phytoconstituents have well-described antioxidant and anti-inflammatory properties which aids in protecting the neuronal cells against oxidative stress. Additionally, the natural compounds, such as flavonoids also aid in modulating the neuronal cell signalling pathways (Solanki et al., 2016).
There are various herbs which are used in traditional medicine for the management of neurodegenerative diseases, for instance: Centella asiatica (L.) Urb., Glycyrrhiza glabra L., Tinospora cordifolia (Willd.) Hook. f. & Thomson, Bacopa monnieri (L.) Wettst. and Nardostachys jatamansi (D. Don) DC. (Kulkarni et al., 2012). One such example is Convolvulus prostratus Forssk. (Syn. Convolvulus pluricaulis Choisy), which is commonly known as Shankhpushpi in Ayurveda and is widely recognized for its anxiolytic, antidepressant and nootropic activities (Kulkarni et al., 2012). As per an ancient Indian medicinal scripture-Charaka Samhita-this plant is superior to other nootropic drugs (Medhya rasayana) of Ayurveda, however, a detailed ethnomedicinal update yet needs to be presented (Dev, 2006). The ensuing sections will provide an ethnomedicinal, phytochemical and pharmacological update of this cognitive booster herb, C. prostratus (CP).
ETHNOMEDICINAL UPDATE ON C. prostratus C. prostratus belongs to Convolvulaceae family and is ubiquitous in the north-western regions of India (Nisar et al., 2012). In Ayurveda, this herb is classically described as a memory and intellect booster. Moreover, it is employed in a variety of formulations used for the treatment of nervous disorders, such as insanity, epilepsy, hysteria, insomnia, and psycho-neurosis (Khare, 2004). Mechanistically, it reduces the spontaneous motor activity, thereby controlling the refluxes and frightening responses. It ultimately acts as a sedative moiety which initiates a persistent fall in blood pressure and cardiac contraction, thereby managing neurological pathologies, such as anxiety, insanity and epilepsy (Chaudhary, 1996). The neuromechanistic aspects of this herb has been elucidated in Figure 1A. Besides, this plant has manifold therapeutic utilities, wherein, a decoction of its shoots is used as a remedy for anaemia and weakness (Singh et al., 2003). More specifically, in ancient texts, this plant has been mentioned as sara, medhya, vrsya and rasayana, which refers to the laxative, nootropic, aphrodisiac and rejuvenator properties of this herb, respectively. Additionally, one of the revered ancient Indian medical practitioner, Acharya Charaka had used whiteflowered variety of C. prostratus (Shankhpushpi) along with the juice of Bacopa monnieri (Brahmi), Acorus calamus (Vacha) and Saussurea lappa (Kushtha) for alleviating insanity and epilepsy. Similar views had been presented in Chikitsasangraha written by Chakradatta; Kaideva Nighantu; and Ayurveda Saar Sangraha (Khare, 2004).
Besides Ayurveda, C. prostratus (CP) has also been used in Siddha system of medicine, wherein an oil obtained from this plant is used as a keratogenic agent for promoting hair growth (Gogte, 2012). It is also believed that a paste prepared from its roots and flowers act as anti-aging agents, thereby indicating its apparent anti-oxidant activity (Adams et al., 2007). Furthermore, in Unani medicinal system, a syrup prepared with C. prostratus and Piper nigrum is prescribed in bleeding piles and venereal diseases (Khare, 2004). All the above mentioned ethnomedicinal uses of C. prostratus have been tabulated in Table 1. INDUSTRIAL SIGNIFICANCE OF C. prostratus C. prostratus is extensively used in pharmaceutical, cosmeceutical and nutraceutical industries (Jalwal et al., 2016). In the pharmaceutical industry, various extracts, syrups and t a b l e t s a r e p r o d u c e d , s p e c i fi c a l l y f o r t a r g e t i n g neurodegenerative diseases, hypertension, hypercholesterolemia and gastric ulcers. A few examples of such marketed herbal pharmaceutical formulations include Patanjali Divya Shankhpushpi Churna™, Divya Pharmacy Shankhpushpi Sharbat™, Baidyanath Shankhpushpi Sharbat™, Dabur Shankhpushpi Syrup™, Biotrex Shankhpushpi™, Maxmind capsule™, Herbal Hills Shankhpushpi Tablets™ and many more (Bhowmik et al., 2012). Similarly, in the cosmeceutical industry, the CP herb is used as a general tonic for rejuvenating FIGURE 1 | (A) Neuro-mechanistic aspects of Convolvulus prostratus (CP). Schematic representations of C. prostratus (CP) target and mode of action in neural system. CP reduces the lesions formed in the hippocampus (A); and amyloid plaque accumulation in hippocampus (A), cortex (P), basal ganglia (M) and cerebellum (E). CP also acts as GABA-A agonists and binds to lateral prefrontal cortex (O) and anterior cingulate cortex (N). CP deactivates the wake promoting areas, namely, tuberomamillary nucleus (J) located in the hypothalamus (K), locus coeruleus (I) and raphe nucleus (H). It also activates the sleep inducing areas of the brain, namely, preoptic nucleus (L). Moreover, CP activates the hypoactive regions situated in the prefrontal cortex (shaded pink area; O), and deactivates hyperactive regions situated in the anterior cingulate cortex (shaded green area; N). CP blocks the excessive production of dopamine as produced via substantia nigra (D). CP also removes the excessive calcification formed at the cranio-cervical junction (F). Additionally, CP removes the formation of thrombus in the carotid artery (G). (B) Main mechanisms and phytoconstituents responsible for neuro-pharmacological activities of C. prostratus (CP). This herb exhibits anti-convulsant, anti-depressant, anxiolytic, sedative, anti-inflammatory, anti-oxidant, analgesic, nootropic, spasmolytic and neuroprotective activities. Phyto-constituents belonging to diverse chemical families, namely, coumarins, alkaloids and polyphenols (see Table 2) are responsible for such evident neuro-pharmacological profile of the CP plant (Nolte, 1999;Carter, 2014). Reported mechanisms of CNS action of CP phyto-constituents has been depicted in these schematics, with putative site of action has been marked with fluorescent green blobs.
the skin and hairs, thereby treating skin related ailments as well as keratogenic disorders. A few examples for elucidating the use of CP (Shankhpushpi) as cosmeceutical ingredients include Econature Shankhpushpi Hair oil™, Khadi Natural Shankhpushpi oil™ and Alps Shankhpushpi hair Mask Powder™. Moreover, the CP powder and juice, such as, Jain Shankhpushpi Powder™ and Axiom Jeevan Ras Shankhpushpi Juice™, are also being used as skin mask for rejuvenating the skin and managing skin problems such as acne, blemishes and sun spots (Hindu, 2012). Additionally, food grade CP powder and syrups are also available in the market for being used as a nutraceutical nootropic supplement, for example, Divya Pharmacy Shankhpushpi Sharbat™, Baidyanath Shankhpushpi Sharbat™, Shivalik Herbals Shankhpushpi Nutraceutical Capsules™ and Veg E Wagon Shankhpushpi Powder (Bhowmik et al., 2012). Such extensive industrial uses of CP further confirms the holistic significance of this nontoxic wonder herb (Jalwal et al., 2016).

PHYTOMEDICINAL FORMULATIONS CONTAINING C. prostratus
The CP herb has also been used as a phyto-ingredient of a polyherbal medicinal formulation: Sankhahauli, which contains leaves of C. prostratus (15 g); seeds of Piper nigrum

Disease Targeted Part(s) used Method of Preparation and Dosage (if any)
Amnesia † Whole plant Decoction of this herb used along with milk (Bhalerao et al., 2014). Anorexia Leaf Intact part used as such (Rizwan and Khan, 2014). Anxiety † Leaf, Flower Intact parts used for treating anxiety neurosis .

Arthritis
Whole plant Whole plant used for the management of arthritis, osteoarthritis and rheumatic pain (Pan et al., 2009). Asthma Leaf Intact part used as such .

Blood disorders
Whole plant Whole plant is used (Nisar et al., 2012). Bone fracture Leaf, Flower Paste of flowers and leaves used for the management of fracture (Singh and Pandey, 1998).

Bronchitis
Leaf Intact part used as such . Burning sensation † Whole plant Whole plant is used (Sethiya et al., 2009). Calculi Leaf Intact part used as such .

Constipation
Leaf, Stem Intact parts used for the management of constipation (Malik et al., 2015). Cough Leaf Intact part used as such (Rizwan and Khan, 2014). Dementia † Root, Flower Paste of roots and flowers administered for the treatment of dementia (Adams et al., 2007). Diabetes Leaf Paste of leaves (100 g) along with black pepper (3-4 grains) is to be administered once daily (Singh et al., 2003). Dyspnoea Leaf Intact part used as such (Rizwan and Khan, 2014). Dysuria Whole plant Jelly obtained from this plant (10 g) is mixed with honey (10 g) and is to be taken thrice a day (Bhutya, 2011). Edema Whole plant Whole plant is used (Sethiya et al., 2009). Emesis Whole plant Whole plant is used (Agarwa et al., 2014).

Enuresis
Whole plant Powder of this plant along with Hyoscyamus niger, Prunella vulgaris, (l-2 g) and milk (100 mL) is to be taken along with twice a day (Bhutya, 2011). Epilepsy † Whole plant Paste of this plant along with cumin seeds (l g) and milk thrice a day (Bhutya, 2011). Gonorrhoea Whole plant Jelly obtained from this plant (10 g) is mixed with honey (10 g) and is to be taken thrice a day (Bhutya, 2011).

Haemoptysis
Leaf Juice of the leaves has to be administered at a dose of 10 mL, thrice a day (Bhutya, 2011).

Haemorrhoid
Whole plant Whole plant is used (Nisar et al., 2012). Headache † Whole plant Powder of plant (3 g) mixed with sugar (5 g) and milk (20 ml) is to be taken twice daily (Bhutya, 2011).

Menorrhagia
Whole plant Paste of this plant is taken along with milk (Gupta, 2016). Neurological disorders †

Whole plant
Decoction of this herb is used along with cumin and milk for treating attention deficit hyperactivity disorder (ADHD), mild convulsions, depression, emotional stress, mental debility, memory loss, mental hypersensitivity, schizophrenia and stress disorders Sultana et al., 2018). Polydipsia Leaf, Stem Intact parts used for the management of excessive thirst (Malik et al., 2015). Pyrexia Root, Leaf Intact parts used for alleviating fever (Bhalerao et al., 2014). Pyrosis Leaf, Stem Intact parts used for the management of heart burn or pyrosis (Malik et al., 2015). Scrofula Whole plant Decoction of this herb is used along with cumin and milk .

Sexual debility
Whole plant This plant (100 g) is ground with little water and taken with sugar or honey once daily, for 21 days (Bhutya, 2011). Snake bite Whole plant Whole plant is used (Sethiya et al., 2009). Stomachache Whole plant One tea spoon powder of dried plant is taken for the management of stomachache (Katewa and Jain, 2006). Syphilis Whole plant Decoction of this herb is used along with cumin and milk . Ulcer Root Intact part used as such (Bhutya, 2011). Urinary diseases Leaf Intact part used as such (Rizwan and Khan, 2014). Vertigo † Whole plant A syrup prepared from this herb is used for the management of vertigo (Gogte, 2012).
In addition, CP is known to be a good source of vitamins and minerals, namely, calcium, copper, iron, magnesium, manganese, phosphorus, potassium, sulphur, zinc, vitamin C and E Babu et al., 2015).

Nootropic Activity
C. prostratus (CP) contains volatile oil; fatty alcohols; flavonoids, i.e. kaempferol; hydroxy cinnamic acid; b-sitosterol; and carbohydrates such as glucose, rhamnose, sucrose etc., which endow this plant with nootropic capabilities. Moreover, an alkaloid, namely, convolvine present in this herb has also been found to block cholinergic muscarinic receptors: M2 and M4. Convolvine also aids in potentiating the effect of another muscarinic memory enhancer, namely, arecoline, thereby imparting nootropic abilities to CP (Sethiya et al., 2009). In a study, Rawat and Kothiyal have also found that the aquomethanolic, ethanolic and petroleum ether extracts isolated from CP (50-400 mg/Kg) exhibited anxiolytic, memoryenhancing and nootropic activity as evaluated by using Elevated Plus Maze (EPM) and step-down models in mice. EPM test has mainly been used to investigate the interactions between aversive memory and anxiety responses of the mice. CP effects on EPM activity has been found to be comparable to the standard of care drug, Piracetam (Rawat and Kothiyal, 2011;Kaushik, 2017). Moreover, treatment with alcoholic extract of CP plant led to an increase in the average time-span spent by mice in the enclosed arm of plus maze model, and an escalation in the mean avoidance response on the jumping box model (Rawat and Kothiyal, 2011).

Neuroprotective Activity
The aqueous extract of the roots of C. prostratus inhibited the activity of acetylcholinesterase (AChE) within the cortex and hippocampus of male Wistar rats, that have been intoxicated with scopolamine. CP extract also posed evident anti-oxidant activity and elevated the levels of glutathione reductase, superoxide dismutase and reduced glutathione within the cortex and hippocampus (Kaushik, 2017). Similar results have been observed in case of aluminium chloride induced neurotoxicity in rat cerebral cortex. Regular administration of the CP root extracts (150 mg/Kg) for 3 months inhibited the decline in Na + /K + ATPase activity and also preserved the mRNA expression levels of muscarinic acetylcholine receptor 1 (M1 receptor), choline acetyl transferase (ChAT) and nerve growth factor-tyrosine kinase A receptor (NGF-TrkA) (Bihaqi et al., 2009;Kaushik, 2017). The Na + /K + ATPase pump aids in maintaining the osmotic equilibrium and membrane potential in neuronal cells (Forrest, 2014). Secondly, the muscarinic receptors bind to the neurotransmitter acetylcholine, thereby facilitating the transmission of electrical signals within the central nervous system (Brown, 2018). Furthermore, the choline acetyl transferase enzyme is essential for the synthesis of neurotransmitter acetylcholine; and the nerve growth factortyrosine kinase A receptor is necessary for binding of the neuronal trophic factors, thereby ensuring the survival of the neurons (Johnson et al., 2018;Indo, 2018).
In another experiments, it has been shown that the oral administration of the aqueous extract of the CP roots (150 mg/ Ayapanin Coumarin Improves scopolamine-induced spatial memory impairment (Zingue et al., 2018); antinociceptive activity (Cheriyan Sr et al., 2017).

Quercetin
Flavonoid Antioxidant activity; stimulator of recombinant SIRT1 and also a PI3K inhibitor; attenuated the function VEGFR, androgen receptor and the expressions of NF-kB, IL Receptor, FAK, ERK, Nrf2 (Xing et al., 2001). Kg) to scopolamine induced rats causes a marked reduction in the mRNA levels of tau protein (Bihaqi et al., 2012). Such reduction in the tau protein expression is responsible for causing an amelioration in the amyloid b-induced deficits in case of neurodegenerative disorders such as Alzheimer's disease (Vossel et al., 2010). Hence, the presence of phytoconstituents such as convolvine might be responsible for endowing CP with the abilities to regulate all the neuronal factors/proteins and enzymes, thereby showcasing its evident neuroprotective status (Sethiya et al., 2009;Ray and Ray, 2015).

Anxiolytic Activity
The ethanolic and chloroform extracts isolated from the aerial parts of CP showed significant anxiolytic activity as recorded using elevated plus maze test on experimental mice. There was increase in the time spent in open arms; and in the number of open arm entries upon the CP oral administration to mice at a dose of 200 mg/Kg (Bhalerao et al., 2014). Similar results have also been observed in case of the ethanolic extract of the CP flower petals at doses 200-400 mg/Kg in mice (Kaushik, 2017).
In another study, CP methanolic extract was evaluated for anxiolytic activity on Obsessive Compulsive Disorders (OCDs) in mice by employing marble burying behaviour analysis, hole board and rota-rod tests. The results have shown that the mice group treated with 200-400 mg/Kg CP methanolic extracts can modulate serotonin or dopaminergic levels, thereby harmonizing the major pathway involving serotonergic or dopaminergic receptors manifesting obsessive compulsive disorders (Subramani et al., 2013). Such anxiolytic activity can be linked with the hypotensive effect of this herb, which in turn is attributed to the presence of GABA-A-benzodiazepine agonists, such as convolamine and scopoletin ( Figure 1B) (Malik et al., 2011;Amin et al., 2014;Siddiqui et al., 2014).

Anti-Convulsant Activity
The chloroform, ethanol and aqueous extracts of CP have been evaluated for anti-convulsant activity against strychnine induced as well as pentylene tetrazol (PTZ) induced convulsive seizures in different animal models. Five hundred mg/Kg concentration of the CP extracts have shown statistically significant (p < 0.001)  (Sun et al., 2014;Nam and Kim, 2015).

Anti-Depressant Activity
Bhalerao and co-workers have found that the chloroform fraction isolated from the CP ethanolic extract reversed the reserpine-induced extension of immobility period of mice in Forced Swim Test (FST), and elicited a significant antidepressant effect by interaction with adrenergic, dopaminergic and serotonergic systems (Bhalerao et al., 2014). Similarly, a polyherbal formulation (Trans-01) containing C. prostratus (30%), Valeriana wallichii (45%), Plumbago zeylanica (7.5%), Boswellia serrata (15%) and Acorus calamus (3.5%) also exhibited similar anti-depressant properties as tested by employing the forced swim test (FST), tail suspension test (TST) and forced swimming stress (FSS)-induced alterations in serum corticosterone levels. In TST and FST, Trans-01 showed a dose-dependent decrease in immobility time. Moreover, Trans-01 significantly attenuated the elevated corticosteroid levels, thereby indicating a significant anti-depressant activity of this formulation (Shalam et al., 2007). CP herb is known to contain alkaloids (convolamine and scopoletin), flavonoids (kaempferol), and steroids (phytosterol and b-sitosterol). These phytoconstituents most probably act as GABA-Abenzodiazepine agonists and bind to the GABA-Abenzodiazepine receptors, thereby causing an increase in the chloride ion flux and consequent hyperpolarization of the postsynaptic membrane. Such hyperpolarization leads to a hypnotic effect and may alleviate depression (Siddiqui et al., 2014).

Anti-Inflammatory Activity
Hydroxy-cinnamic acid is a phenyl-propanoid compound found in CP. It is known to cause a downregulation in the expression of cytokine mediators such as IL-8, MCP-1 and ICAM-1, thereby blocking the expression of cytokine-mediated adhesion molecules and therefore the fundamental process of leukocyteendothelial cell adhesion is deterred (Billore et al., 2005;Rathee et al., 2009). Hence, the CP herb may aid in ameliorating the conditions of neuro-inflammation and consequent cognitive impairment. Indeed, oral administration of the ethanolic extract of the CP leaves at dose of 800 mg/Kg, showed significant inhibition of rat paw edema, in the Carrageenaninduced paw edema and Cotton pellet-induced granuloma animal models (Agarwal et al., 2014).

Anti-Oxidant Activity
The reactive oxygen species are known to deteriorate the cellular physiology of nerve cells and ultimate lead to neurodegenerative disorders. Polyphenols, flavonoids and vitamin E present in the CP plant act as reactive oxygen species (ROS) scavengers and also ameliorate the lipid peroxidation, thereby attributing towards the anti-oxidant activity of CP (Nasri et al., 2015). It has also been observed that the ethyl acetate and methanolic extract of CP have shown appreciable results (IC 50~0 .07 mg/mL and 0.075 mg/mL, respectively), as observed in 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. Similarly, in Ferric Reducing Antioxidant Power (FRAP) analysis, aqueous CP extract has been found to be potentially active with anti-oxidant capacity of 460 ± 8 ascorbic acid equivalent/mg of the extract (Jain et al., 2011). Interestingly, the Shankhpushpi syrup and its isolated compounds (Scopoletin and Bacoside A) also exhibited evident anti-oxidant activity as evaluated by using DPPH assay with average IC 50 value ranging from 0.94 -2.39% v/v (Jain et al., 2017;Rachitha et al., 2018). Furthermore, the aqueous extract of CP roots diminished the endogenous levels of reactive oxygen species in tauopathy flies as i n d u c e d b y o v e r e x p r e s s i o n o f t -p r o t e i n , t h e r e b y substantiating its oxidative stress ameliorative effect (Olakkaran and Antony, 2017).

Analgesic and Spasmolytic Activity
The ethanolic extract of CP at dose 750 mg/Kg showed statistically significant analgesic activity as compared to the standard analgesics like, morphine sulphate, when tested in hot plate method and tail-flick assays in rats (Agarwal et al., 2014). Such evident analgesic activity is cohesively attributed by flavonoids, volatile oils, alkaloids, polyphenols and organic acids by means of prevention of the formation of cyclooxygenase enzyme and prostaglandins, i.e., mediators of pain sensitization. Hence, these CP phyto-constituents ultimately aid in ameliorating the neuronal pain and headache (Aleebrahim-Dehkordy et al., 2017).
The CP ethanolic extract has exhibited spasmolytic activity in isolated rabbit ileum, isolated rat uterus, intact intestine and tracheal muscles of dog (Barar and Sharma, 1965). Such antispasmodic action is linked to the inhibition of acetylcholine production which is mainly brought about by the specific alkaloid present in this CP herb, convolvine (Amin et al., 2014).

Sedative Activity
Interestingly, the ethanolic and aqueous extracts of the CP aerial parts showed statistical significant potentiation of sleeping time in rats induced with thiopental sodium (Siddiqui et al., 2014). In another similar experiment, the aqueous extract of the CP leaves and flowers showed an evident barbiturate hypnosis potentiation in albino rats at a dose of 300 mg/Kg (Mudgal, 1975). Such sedative activity is directly linked to the presence of phytoconstituents like convolamine and scopoletin which act similarly to GABA-A agonists, thereby bringing about the effects of sedation ( Figure 1B) (Siddiqui et al., 2014).
This CP herb has also been reported for several other pharmacological activities, including anti-diabetic, antihyperlipidemic, anti-hypertensive, anti-microbial, anti-platelet aggregation, anti-ulcer, cardio-vascular, hepatoprotective, and hypothyroidism (Barar and Sharma, 1965;Mudgal, 1975;Rizk et al., 1985;Mali, 1995;Jain et al., 2011;Ravichandra et al., 2013;Jalwal et al., 2016). Anti-diabetic activities of this plant might be attributed to the presence of tropane alkaloids which are known as potent inhibitor of a-glucosidases and R-galactosidases (Gaikwad et al., 2014;Rachitha et al., 2018). The polyphenols present in this species act as reactive oxygen species (ROS) quenchers, thereby ameliorating the oxidative stress that is generated as a diabetic manifestation. Additionally, the presence of vitamin E in this herb also aids in controlling the levels of protein oxidation and lipid peroxidation, thereby leading to an escalation in the antioxidant defense system (Cowan, 1999;Nasri et al., 2015;Domínguez-Avila et al., 2016;Foretz et al., 2018). Furthermore, the presence of GABA-A-benzodiazepine agonists, such as convolamine, scopoletin, ceryl alcohol, kaempferol, phytosterol, and b-sitosterol endow this herb with hypotensive and sedative activities (Malik et al., 2011;Siddiqui et al., 2014). More specifically, a compound, namely, 29-oxodotriacontanol, isolated from the CP herb has also been assessed to possess antimicrobial and anti-fungal activity (Amin et al., 2014). Certain flavonoids and phenyl-propanoids from CP have been shown to provide anti-platelet aggregation and anti-ulcerogenic activity by means of inhibition of cyclic nucleotide phosphodiesterase enzyme and clot retraction capabilities (Beretz and Cazenave, 1991;Tognolini et al., 2006). The anti-ulcerogenic effect was largely observed due to upregulation of mucosal defensive factors such as mucin and glycoprotein secretion, which in turn was induced by the flavonoids and steroids present in this herb (Srinivas et al., 2013). These flavonoids also pose the profound effects on the thyroid hormone regulation and deiodinase-1 inhibition, thereby endowing this herb with anti-thyroid activity (Nagarathna and Jha, 2013). Additionally, the fundamental principle responsible for the cardio-vascular activity of this herb has been proposed to be linked with it alkaloid derivative, evolvine hydrochloride, which is known to exhibit lobeline-like action on the cardiovascular system. This phytoconstituent acts as a cardiac depressant, ultimately leading to a fall in blood pressure, which gets gradually normalised (Dwoskin and Crooks, 2002;Sethiya et al., 2009).

Safety Profile of C. prostratus
The ethanolic and aqueous extracts of the CP leaves have been evaluated for acute oral toxicity study in albino Wistar rats. The animals did not show any toxicity or behavioural changes up to the dose of 5,000 mg/Kg (Agarwal et al., 2014). Similarly, the iron oxide nanoparticles of the CP herb exhibited maximum tolerable dose up to 2,000 mg/Kg in Swiss albino mice with no clinical signs of toxicity. The histopathology of brain also did not show any aberrations or degeneration of neurons. Furthermore, no inflammation was observed in the heart and liver (Ravichandra et al., 2013). These toxicological studies, therefore, confirmed that the administration of CP is safe for the vital organs within the respective treatment durations.

Summary and Way Forward
The use of herbal medicines continues to escalate rapidly with about 70% of the world population still relying upon traditional medicines for their primary healthcare needs. The natural plant products have negligible toxicities, if any, and are endowed with a multitude of phytoconstituents which are responsible for their holistic therapeutic action. Cognitive dysfunction is one of the major health problem in today's world, wherein the available synthetic chemotherapeutic modalities have proven to be non-absolute and, at times toxic in nature. In such a scenario, safer herbal alternative medicines play a vital role in managing the neurological etiologies. One such cognitive booster herb is C. prostratus Forssk., commonly known as Shankhpushpi, which is mainly endowed with neuroprotective, nootropic and neuro-modulatory activities ( Figure 1B). Besides, it also possesses several other therapeutic properties, such as immunomodulatory, antimicrobial, antidiabetic and cardioprotective activities. The fundamental bioactive compounds responsible for the nootropic activities of this herb have been identified as 4'-methoxy kaempferol, 7-methoxy quercetin, convolamine, scopoletin, ceryl alcohol, b-sitosterol and hydroxycinnamic acid. Additionally, this herb did not exhibit any signs of toxicity and neurodegeneration up to a dose of 2000 mg/Kg in mice, thereby indicating its safety profile. A few initial clinical trials have conducted for CP, however, more detailed and controlled clinical trials are needed to establish and validate the neuro-pharmacological profile of C. prostratus. In addition, detailed mechanistic studies are yet to be executed to unravel the underlying mechanism of action for this cognition enhancing herb. Taken together, C. prostratus is likely to be the front runner for the clinical phyto-pharmaceutical status for treatment of neurological ailments.

AUTHOR CONTRIBUTIONS
AB conceived the presented research. PT analyzed the information, generated the artwork, and co-wrote the manuscript. AV investigated and supervised the findings of the work. AB and AV provided critical revision of this review article, and approved the manuscript for submission. All authors agreed with the final version of this manuscript.

FUNDING
The presented research work been funded by the research funds of Patanjali Research Foundation Trust (PRFT), Haridwar, India.