INTRODUCTION:

The medicinal plants are often used as an alternate source to improve health and to overcome side effects of contemporary medicine. There has been an increase in the evidence-based reports on the benefits of number of medicinal plants¹and their biochemical and molecular effects. A large number of patients in the world use medicinal plants and herbs for health purpose. Therefore, scientific scrutiny of their therapeutic potential, biological properties, and safety will be useful in making wise decisions about their use.^2-3There are hundreds of significant drugs and biologically active compounds developed from the traditional medicinal plants. Herbal medicines have been extensively used since the ancient times in different forms of traditional medical practices such as Ayurveda, Yoga, Unani, Siddha and by folklore healers. Ayurveda, the Indian traditional holistic health management system describes a number of such herbal preparations which are known to promote health and longevity. One such group of herbal preparations is ‘Rasayana’.

They are classified based on the scope, treatment modality, types and tissue specificity. Tissue specific rasayana are preferred for the improvement of tissue functions in addition to their role as micronutrients.⁴Medhyarasayana is a group of Ayurveda preparations made from a selected group of plants and their extracts for properties to rejuvenate the brain by acting on the nervous system.⁴Clitoria ternatea Linn (CT) a perennial twing herb, steams are terete, more or less pubescent belongs to the family Fabaceae. There are two varieties of Clitoria ternatea white-ﬂower and blue ﬂower varieties. Clitoria ternatea Linn. locally known as shankhpushpi. Shankhpushpi is one of the medhyarasayana plant and is reported to promote intellectual capacity, rejuvenate the body and nervous tissue, enhance the aura of the body and improve general health to elicit quality ageing.

The roots, seeds and leaves of Clitoria ternatea Linn. have long been widely used as a brain tonic and is believed to endorse memory and intelligence.⁵It is reported to have antidepressant, anticonvulsant,⁶anti-inflammatory, analgesic and antipyretic,⁷ local anesthetic,⁸ purgative⁹and anti-diabetic¹⁰activity. It is also used for treatment of snakebite and scorpion sting in India.¹¹ In order to provide the scientific validation for the reported traditional uses many researches done many pharmacological and phytochemical studies on various parts of Clitorea ternatea Linn. Present review is trying to summarise the neuropharmacological effects of Clitoria ternatea Linn.

MORPHOLOGICAL CHARACTERS:

It is a perennial herbaceous plant, with elliptic, obtuse leaves. It grows as a vine or creeper, doing well in moist, neutral soil. The most striking feature about this plant is the colour of its flowers, white flowers; solitary, with light yellow markings. They are about 4 cm long by 3 cm wide. Some varieties yield deep blue flowers.¹²The fruits are 5–7cm long, flat pods with six to ten seeds in each pod. They are edible when tender. It is grown as an ornamental plant and as a revegetation species (e.g., in coal mines in Australia), requiring little care when cultivated. As a legume, its roots forma symbiotic association with soil bacteria known as rhizobia, which transform atmospheric N2 into a plant-usable form (a process called nitrogen fixing), therefore, this plant is also used to improve soil quality through the decomposition of nitrogen rich plant material.¹³

VERNACULAR NAMES¹⁴:

The shape of flowers of the Clitoria plant is a reflection of its genus name. The flowers of this plant resemble in shape with human female clitoris, hence the Latin name of the genus “Clitoria” belongs to “clitoris” and “Ternatea”, the name of the species, which comes from Ternate, an Eastern Indonesian island, similarly in different languages various vernacular names of the flowers are based on reference to a woman’s genital organ.

Sanskrit: Ashphota, Aparajita Saukarnika, Girikarnika,

English: Butterfly pea, Blue pea vine, Mussel-shell climber, Pigeon wings.

Chemical Constituents:

The preliminary phytochemical screening showed that the plant contained tannins, phlobatannin, carbohydrates, saponins, triterpenoids, phenols, flavanoids, flavonol glycosides, proteins, alkaloids, antharaquinone, anthocyanins, cardiac glycosides, Stigmast-4-ene-3, 6-dione, volatile oils and steroids.^15-17

Flower:

The flowers contained flavonol glycosides, quercetin, and phenolic compounds.^18-19 3-O- (2"-O-alpharhamnosyl- 6"-O-malonyl)-beta-glucoside, 3-O- (6"-O-alpha-rhamnosyl-6"-O-malonyl)-betaglucoside and 3-O-(2", 6"-di-O-alpharhamnosyl)- beta-glucoside of kaemferol, quercetin and myricetin were isolated from the petals. Delphinidin glycosides, 3-O-b-glucoside, 3-O(2"-O-a-rahmnosyl)-bglucoside, 3-O-(2"-O-a-rahmnosyl-6"-Omalonyl)- b-glucoside of delphinidin, and eight anthocyanins (ternatins C1, C2, C3, C4, C5 and D3, and preternatins A3 and C4) were also isolated from the flowers.^20-22 Three flavonol glycosides, kaempferol 3-O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)-beta-glucoside, quercetin 3O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)-beta-glucoside, and myricetin 3-O-(2", 6"-di-O-alpha-rhamnosyl)beta-glucoside were isolated from the petals of Clitoria ternatea. Double Blue, together with eleven known flavonol glycosides. They were characterized as quercetin 3-(2(G)- rhamnosylrutinoside)s, kaempferol, quercetin, myricetin 3-neohesperidosides, 3-rutinosides, and 3-glucosides. In addition, the presence of myricetin 3-O-(2"-O-alpha-rhamnosyl-6"-O-malonyl)-beta-glucoside was inferred from LC/MS/MS data for crude petal extracts.²³

Leaf:

From ethanolic extracts of leaves, clitorin and kaempferol have been isolated.²⁴ The leaves also contain 3-monoglucoside, 3-rutinoside, 3-neohesperidoside, 3-o-rhamnosyl-glucoside, 3-o-rhamnosylgalactoside of kaemferol, besides kaemferol-3-o-rhamnosylo- rhamnosylglucoside. It also contains aparajitin and β- sitosterol.²⁵

Root:

Taxaxerol and taxaxerone are present in the roots of plant. The bark of roots contains resin, tannin, starchand flavonol glycosides. The root nodule contains glycine, alanine, valine, leucine, α-aminobutyric acid, aspartic acid, glutamic acid, arginine, ornithine, histadine, γ-aminobutyric acid.^26-27

Seed:

The seed contains bitter acid resin as an active principle with fixed oil, tannic acid and glucose, also contains a cotyledon, which is full of granular starch and bitter in taste. There are two chemicals which are isolated from seeds viz. Sitosterol and anthoxanthin. Other than that seed-oil yields palmitic, stearic, oleic, linoleic and linolenic acids. Oils from blue and white-flower varieties have been found to have almost similar composition. Seeds also contain cinnamic acid, hexacosanol, nucleoprotein with its amino acid sequence somewhat similar to insulin.²⁸

Neuro pharmacological properties of Clitoria ternatea linn.:

Antioxidant effect:

The different solvent extracts of Clitoria ternatea leaf were assessed by Mukhopadhyay et al (2012) for their in vitro free radical scavenging potential by 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging assay. All extracts exhibited potent in vitro free radical scavenging activity that increased with extract concentrations. The methanol extract was found to be the most potent, followed by the chloroform and petroleum ether extracts.²⁹Petroleum ether, chloroform and methanol extracts of roots of blue and white flowered varieties of Clitoria ternatea were studied by Patil AP (2011) for their antioxidant potential. DPPH free radical scavenging assay, reducing power assay, hydroxyl radical scavenging assay were used for evaluation of antioxidant potential. Petroleum ether, chloroform and methanol extracts of roots of blue and white flowered varieties of Clitoria ternatea (CT) significantly inhibited the DPPH free radical at concentrations ranging from 50-600 µg/ml. Petroleum ether, chloroform and methanol extracts of roots of blue flowered variety of CT showed highest inhibition (49.11, 35.42 and 70.67% at 600µg/ ml), respectively. Petroleum ether, chloroform and methanol extracts of roots of white flowered variety of (CT) showed highest inhibition (54.48, 39.21 and 78.13% at 600µg/ml), respectively. Methanol flower extracts of blue and white flowered varieties of CT showed a very powerful antioxidant activity in DPPH radical-scavenging assay. Methanol extracts of CT also showed significant reductive ability as well as hydroxyl radical scavenging activity. Methanol extract of white flowered variety of CT showed more significant antioxidant activity as compared to blue flowered variety of CT. All the concentrations of methanol extract of CT (MECT) showed antioxidant activity when compared to control (p<0.001).^30-31 The antioxidant activity of the leaves as well as blue and white flowers of Clitoria ternatea was investigated. They exhibited significant antioxidant activity and the sample from the blue flower bearing plant showed better scavenging activity.³² The antioxidant activity and protective ability of Clitoria ternatea flower petal extract (CTE) was investigated. CTE showed antioxidant activity as measured by oxygen radical absorbance capacity (ORAC) method and 2, 2diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. CTE (400µg/ml) remarkably protected erythrocytes against AAPH-induced hemolysis at 4 h of incubation. Moreover, CTE (400µg/ml) reduced membrane lipid peroxidation and protein carbonyl group formation and prevented the reduction of glutathione concentration in AAPH-induced oxidation of erythrocytes. The AAPH-induced morphological alteration of erythrocytes from a smooth discoid to an echinocytic form was effectively protected by CTE.³³The antioxidant effects and apoptotic study of the leaves of Clitoria ternatea was studied using the yeast cell. The yeast cells were isolated from the sugar factory effluents and the yeast cell DNA was isolated. The leaves extract from different solvents were tested for their scavenging activity against the stable free radical DPPH (2, 2’-diphenyl-1-picryl hydrazyl) in dot plot rapid screening assay method and quantified using a spectrophotometric assay method. Oxidative damage was induced in vitro by treating yeast DNA and analyse the effects of the leaf extracts. Genomic DNA samples were isolated from YBD broth culture. DPPH scavenging activity was highly elicited by the methanol extract of Clitoria ternatea. The Clitoria ternatea leaf extracts treatment effectively decreased the extent of DNA damage.³⁴

Neurogenic potential:

In Indian Ayurvedic system of medicine, extracts derived from C. ternatea Linn have been used as an ingredient of “Medhyarasayana”, intentionally used for improving memory and longevity in humans and also in treatment of various neurological conditions. Earlier experimental studies with oral intubation of C. ternatea aqueous root extract had shown significant increase in learning and memory of postnatal and young adult Wistar rats.³⁵ In another study it was designed to elucidate the in vitro effects of 200mg/ml of C. ternatea aqueous root extract on proliferation, differentiation and growth of anterior sub ventricular zone neural stem cells derived from prenatal and postnatal rat pups. Results shown significant increase in proliferation and increase in the yield of differentiated neurons of a SVZ neural precursor cells at 7 days in vitro and growth of neurospheres when treated with 200ng/ml of C. ternatea aqueous root extract as compared to age matched control. Results indicate that CTR has growth promoting neurogenic effect on a SVZ neural stem cells and their survival similar to neurotrophic factors like Survivin, Neuregulin 1, FGF-2, BDNF possibly the basis for enhanced learning and memory.³⁶

Nootropic Potential:

Seeds and leaves of Clitoria ternatea have been widely used as brain tonic and believed to promote memory and intelligence. The activity of Clitoria ternatea in Alzheimer’s disease was studied to investigate its efficacy and to identify the major bioactive constituent attributing the activity. The result showed that the aqueous extract of Clitoria ternatea was beneficial in Alzheimer’s disease through many mechanisms. The isolated compounds may act as a lead compounds for identifying new derivatives which could use for improving memory.³⁷

Significant increase in Acetylcholine (ACh) content in hippocampi as compared to age matched controls after the treatment with 100mg/kg of C. ternatea aqueous root extract (CTR), for 30 days in neonatal and young adult age groups of rat. Increase in ACh content in their hippocampus may be the neurochemical basis for their improved learning and memory.³⁸

Researcher has reported the alcoholic extract of roots of C. ternatea on spatial memory retention and associated changes in Acetylcholine (ACh) and Acetylcholinesterase (AChE) activity in the brain after electroshock or scopolamine induced amnesia. The preselected trained rats were administered with either alcoholic extract of C. ternatea or standard Shankhapushpi syrup for 10 days once a day. The animals of respective groups were subjected to electroshock or scopolamine treatment followed by radial arm maze task performance1 h after the last dose. Thereafter, the brain were immediately isolated and ACh as well as AChE levels were estimated. Study shows significant memory retention against scopolamine and electroshock induced amnesia in root extract treated rats. The extract was found to be more effective in scopolamine induced amnesia model. This action was found to be associated with significant decrease in AChE activity and increase in ACh content of whole brain in different regions of the brain compared to respective controls qualitatively.³⁹For studying the mechanisms of memory enhancement of the Clitoria ternatea aqueous root extract, young adult (60 day old) Wistar rats of either sex were orally intubated with 50 and 100mg/kg body weight of aqueous root extract of Clitoria ternatea (CTR) for 30 days, along with age-matched saline controls. These rats were then subjected to passive avoidance tests and the results showed a significant increase in passive avoidance learning and retention. The amygdala of these rats were processed for Golgi staining and the stained neurons were traced using a camera lucida and analysed. The results showed a significant increase in dendritic intersections, branching points and dendritic processes arising from the soma of amygdaloid neurons in CTR treated rats especially in the 100mg/kg group of rats compared with age-matched saline controls.⁴⁰

The effectiveness of alcoholic extracts of aerial and root parts of Clitoria ternatea at 300 and 500mg/kg doses orally was studied in attenuating electroshock-induced amnesia in rats. Extracts at 300mg/kg dose produced significant memory retention, and the root parts were found to be more effective. In order to delineate the possible mechanism through which Clitoria ternatea elicited the anti-amnesic effects, its influence on central cholinergic activity was studied by estimating the acetylcholine content of the whole brain and acetylcholinesterase activity at different regions of the rat brain (cerebral cortex, midbrain, medulla oblongata and cerebellum). The results showed that Clitoria ternatea extracts increase rat brain acetylcholine content and acetyl cholinesterase activity, in a similar fashion to the standard cerebro- protective drug, Pyritinol.⁴¹

Neonatal rat pups (7 days old) were intubated with either 50mg/kg body weight or 100mg/kg body weight of aqueous root extract of Clitoria ternatea (CTR) for 30 days. These rats were then subjected to open field, two compartment passive avoidance and spatial learning (T-Maze) tests (i) immediately after the treatment and (ii) 30 days after the treatment, along with age matched normal and saline control rats. Results showed no change in open field behaviour, but revealed improvement of retention and spatial learning performance at both time points of behavioural tests, indicating the memory enhancing property of CTR which implicates a permanent change in the brain of CTR treated rats.⁹

The effectiveness of Clitoria ternatea in the treatment of obsessive-compulsive was carried out experimentally. The influence of ethanolic extract of Clitorea ternatea was evaluated in marble-burying behavior in mice. The results revealed that ethanolic extract of Clitorea ternatea (EECT) (100, 200 and 400mg/kg) reduced the marble burying behavior in mice. It was clear that EECT exhibited significant anti-compulsive effect in marble-burying behavior test in mice and the effect may be attributed to enhanced serotonergic function and might have influence on 5-HT reuptake.⁴²

The effect of aqueous and hydroalcoholic extracts of Clitoria ternatea on biochemical and behavioral parameters related to cognitive impairment was studied in vitro and in vivo. In vitro free radical scavenging and enzyme-inhibitory (cholinesterase, glycogen synthase kinase-3-β, rho kinase, prolyl endopeptidase, catechol-Omethyl transferase, and lipoxygenase) activities of aqueous and hydroalcoholic extracts of Clitoria ternatea plant were evaluated. Based on in vitro results, hydroalcoholic extract of Clitoria ternatea (100, 300, and 500mg/kg, p.o) was selected for evaluation in intracerebroventricularly injected streptozotocin (STZ)-induced cognitive impairment in male Wistar rats. Behavioral assessment was performed at baseline and on the 14th, 21st, and 28th days after STZ injection using elevated plus maze, passive avoidance, Morris water maze, and photoactometer. Oxidative stress parameters (malondialdehyde, reduced glutathione, nitric oxide levels, and superoxide dismutase activity), cholinesterase activity, and rho kinase (ROCK II) expression were studied in cerebral cortex and hippocampus of rats' brain at the end of the study. The hydroalcoholic extract possessed significantly more in vitro antioxidant and enzyme-inhibitory activities as compared to aqueous extract. The hydroalcoholic extract of Clitoria ternatea prevented STZ-induced cognitive impairment dose dependently, by reducing oxidative stress, cholinesterase activity, and ROCK II expression. The authors concluded that in vitro and in vivo results suggest the potential of hydroalcoholic extract of Clitoria ternatea for treatment of cognitive deficit in neurological disorders.^43-44

Anticonvulsant activity:

An imbalance between excitatory and inhibitory neurotransmitter caused seizures. The drugs which increase the GABA level in brain, may possess anticonvulsant activity in experimental model of seizures. The maximal electroshock (MES) is the validated model for screening of antiepileptic drugs in the generalized tonic-clonic seizure.⁴⁵The methanolic extract of aerial parts of CT has shown anticonvulsant activity at dose of 100mg/kg, p.o in both pentylenetetrazole (PTZ) and MES induced seizures in mice delaying the onset of convulsions and reducing the duration of tonic hind limb extension, respectively. These results suggest the potential of CT as an antiepileptic drug. However, in another experimental study, 230 and 460mg/kg, p.o of ethanolic extract of aerial part of CT was not effective against PTZ and MES induced seizures in rats.⁴⁶

Antidepressant activity:

The methanolic extract of CT at the doses of 100 and 400mg/kg, p.o has shown antidepressant effect in tail suspension test in mice.³⁶The extract of CT significantly decreased the duration of immobility at the doses of 100 and 400mg/kg. The decrease in the duration of immobility was more at dose of 400mg/kg of CT as compared to fluoxetine, 10mg/kg, i.p. In another study, anti-depressant effect of ethanolic extract of CT root was also reported at the dose of 150mg/kg and 300mg/kg. The results from previous study indicated that two compounds, (Z)-9, 17-octadecadienal and n-hexadecanoic acid isolated from root of CT can serve as potential lead molecules for developing novel selective MAO-A inhibitors which can give herbal remedy for the treatment of psychiatric disorders including depression and anxiety.⁴⁷

Anti-anxiety effect:

CT exhibited a weak anti-anxiety in the elevated plus maze and light/dark exploration test. The methanolic extract of CT has shown the dose (100-400mg/kg, p.o) dependant anti-anxiety effect in mice when administered 60 min before the test.³⁶ The oral administration of CT (100-400mg/kg) dose dependently increased the time spent in the open arm. In light/dark exploration test, higher doses of CT (100, 200 and 400mg/kg, p.o) increased the time spent in the lit box. The duration of time spent in dark box decreased in dose dependant manner.⁴⁸

In another study Perinatal maternal separation stress (PMSS) were introduced to the pups by separating them from their mothers for a period of 6 h/day for 30 days, during these period one group of pups were receiving Clitoria ternatea aqueous root extract (CTR): 100mg/kg b.w./day. Rats were sacrificed on day 30, 60, 90, 210 and 360. Brains were processed for MDA and protein thiol levels, and it was found that PMSS causes enhanced brain lipid peroxidation (MDA levels) and reduces endogenous antioxidants. Supplementation of CTR during PMSS in rats persistently attenuates brain oxidative stress through aging.⁴⁹

CONCLUSION:

The paper reviewed Clitoria ternatea Linn. as promising medicinal plant with wide range of neuro pharmacological activities which could be utilized in several medical applications especially for the treatment of various neurodegenerative disorders because of its effectiveness and safety.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of C.L. Baid Metha College of Pharmacy, Chennai for the facilities. This publication is a part of Ph.D Thesis of The Tamilnadu Dr. M.G.R. Medical University, Chennai, Tamilnadu , India.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 12.11.2019 Modified on 25.01.2020

Research J. Pharm. and Tech. 2020; 13(11):5497-5502.

DOI: 10.5958/0974-360X.2020.00960.9