Role of Herbal Drugs on Neurotransmitters for Treating Various CNS Disorders: a Review

Indian Journal of Traditional Knowledge Vol. 17(1), January 2018, pp. 113-121

Role of herbal drugs on neurotransmitters for treating various CNS disorders: A review

Tarkeshwar Dubey, Garima Sahu, Swati Kumari, Bhooshan Singh Yadav & Alakh N Sahu* Department of Pharmaceutical Engineering & Technology, IIT (BHU), Varanasi- 221 005, UP, India E-mail: [email protected]

Received 12 January 2017, revised 14 February 2017

Neurotransmitters are chemical messengers in the human body and are associated with several CNS disorders. Plant drugs can be used as agonist/antagonist/modulator to neurotransmitters to treat CNS disorders like Alzheimer’s disease, Parkinson’s disease etc. The current review comprises the role of various neurotransmitters in CNS diseases and plants to treat them. This review compiles most of the scientific research related to the role of neurotransmitters and potential plants to treat various CNS disorders. Authors hope that researchers will utilize this current knowledge to explore and establish the potential herbal drugs to treat CNS disorders. This review has been compiled using references from major databases such as Chemical Abstracts, Medicinal and Aromatic Plants Abstracts, ScienceDirect, SciFinder, Google Scholar, Scopus, PubMed, Springer Link, and books, without limiting the dates of publication. General web searches were also carried out using Google and Yahoo search engines by applying some related search terms (e.g., Neurotransmitters, herbal drugs, pathophysiology and CNS disorders). The articles related to agriculture, ecology, and synthetic works and those using languages other than English or Persian have been excluded. Neurotransmitters play an important role in the pathophysiology of various CNS disorders. Plants can be used as potential drugs to treat various CNS disorders as confirmed by various pharmacological studies illustrated in this review. This review discusses the current knowledge of neurotransmitters, their role in CNS disorders and herbal drugs that can be used to treat these diseases.

Keywords: Plant drugs, Phytotherapy, Phytoconstituents, Bioactive, Acetylcholine, GABA, Glutamate, Serotonin, Catecholamines IPC Int. Cl.8: A61K 36/00, A01D 8/46, A01D 8/00, A61K 38/00, A61K 48/00, A61K 45/06, A61K 31/00

Neurotransmitters are chemicals that travel across the create balance are called inhibitory. Inhibitory synapse and allow communication between neurons neurotransmitters balance mood and get easily throughout our brain and body1. depleted when the excitatory neurotransmitters are The general properties of neurotransmitters are as overactive. follows: 1. They are synthesized in the presynaptic neuron Inhibitory neurotransmitters and localized to vesicles in the presynaptic 1. Serotonin is an inhibitory neurotransmitter3. neuron. Adequate amounts of serotonin are necessary for 2. They are released from the presynaptic neuron a stable mood and to balance any excessive under physiological conditions and rapidly excitatory (stimulation) neurotransmitter in the removed from the synaptic cleft by uptake or brain4. Serotonin also regulates many other degradation. processes such as carbohydrate cravings, sleep 3. They bind to the receptor present on the post- cycle, pain control, and appropriate digestion3. synaptic neuron to elicit a biological response. Decreased serotonin levels also affect functioning There are two types of neurotransmitters: inhibitory of body’s immune system. and excitatory2. Excitatory neurotransmitters are 2. GABA is another inhibitory neurotransmitter exciting the brain and also, they are what stimulate when GABA is out of range (high or low levels) it the brain. Those that calm the brain and help is likely that an excitatory neurotransmitter is 2,5 —————— firing too often in the brain . GABA will be sent *Corresponding author out to attempt to balance this stimulating firing. 114 INDIAN J TRADIT KNOWLE, VOL. 17, NO. 1, JANUARY 2018

Excitatory neurotransmitters activity and hence can be used in the treatment of 1. Acetylcholine is very widely distributed excitatory several CNS disorders because the currently available neurotransmitter that triggers muscle contraction synthetic drugs show a profound adverse reaction due and stimulates the excretion of a certain hormone. In to which the treatment strategies for various CNS the CNS, it is involved in wakefulness, disorders is limited. attentiveness, learning and memory6, anger, Current review covers the role of different aggression, sexuality and thirst among other things. neurotransmitters in various CNS disorders and the 2. Dopamine is an excitatory neurotransmitter plants acting on those neurotransmitters to treat CNS involved in controlling movement and posture. It disorders. also modulates mood and plays a central role in positive reinforcement and dependency. When dopamine is either elevated or low, we can have issues such as not remembering where to put our keys, forgetting what a paragraph said when we just finished reading it or simply daydreaming and not being able to stay on task7. 3. Norepinephrine helps to make epinephrine. This neurotransmitter can cause anxiety as well as some mood dampening effects at elevated excretion levels, low levels of neurotransmitter cause low energy, decreased focus and sleep cycle problems2. 4. Epinephrine is an excitatory neurotransmitter8. This neurotransmitter will often be elevated when ADHD-like symptoms are present. Long-term stress or insomnia can cause epinephrine levels to be depleted. Epinephrine also regulates heart rate and blood pressure. Apart from above, neurotransmitters can also be classified by their chemical nature as per their basic ring and arrangement of the side chain present (Fig. 1). Fig. 1 — Chemical nature of neurotransmitters [small neurotransmitters- acetylcholine, amino acids (GABA, glutamate, The brain uses neurotransmitters to tell the heart to aspartate, glycine), catecholamines (dopamine, epinephrine, beat, lungs to breathe, stomach to digest. They can norepinephrine), indolamine (5-HT), imidazolamine (histamine), also affect mood, sleep, concentration, weight and can purine (ATP)]. cause adverse symptoms or any other pathological condition when they are out of balance. The main function of neurotransmitters is to relay the information from one nerve cell to another nerve cell to produce a quick response toward any external or internal stimuli (Fig. 2). In contrast to CNS disorders, neurotransmitters have a positive pathophysiological role in the development of diseases including dementia, anxiety, neurodegenerative disorders, epilepsy, stroke as well as Parkinson’s disease, Alzheimer’s disease and Huntington’s disease and mood disorders. Various studies involving different kind of neurotransmitters revealed that herbal drugs can affect the normal physiology pertained by a particular neurotransmitter Fig. 2 — Schematic representation of neurotransmission across because of their agonistic, antagonistic or modulator the neurons DUBEY et al.: ROLE OF HERBAL DRUGS ON NEUROTRANSMITTERS FOR TREATING VARIOUS CNS DISORDERS 115

Role of neurotransmitters Gamma-Aminobutyric Acid (GABA) Acetylcholine GABA is the neurotransmitter associated with All the muscarinic receptors (M1-M5) are located in depressive disorders, and several studies revealed that different parts of the brain and hence are very widely there is a significant decrease in the GABA levels in involved in various neurodegenerative disorders such as various types of depressive disorders including panic 11 Parkinson’s disease and Alzheimer’s disease9. In the disorders and unipolar disorders (Flow diagram B) . case of Alzheimer’s disease M1 and M2 receptor agonists Premenstrual dysphoric disorder (PMDD) has also have been proved to be an effective medication in the been found to be associated with the reduced GABA management of this disease. Muscarinic receptors are levels during the follicular phase. Several pieces of also involved in schizophrenia, especially M2 and M4 evidence have been found showing that many receptors. Agonists of these receptors have been found antidepressant drugs increase the level of GABA in to be effective in the treatment of schizophrenia. M4 the cortical region as well as some specific agents that antagonists have been found to be effective as target GABA receptors play an important role in the 11 antiparkinsonian agent revealed by several animal treatment of several depressive disorders . 9 studies . Except for memantine, all other FDA approved Glutamate the medication for symptomatic treatment of Glutamate is an excitatory neurotransmitter and if Alzheimer’s disease are acetylcholine esterase inhibitors the glutaminergic system becomes overactive can lead but the efficacy is limited to first two years of treatment, to Parkinson’s disease as demonstrated in several and also they possess several adverse effects that limit studies (Flow diagram C). their action as an effective drug for the treatment of Glutamate receptors can be divided into two groups 9,10 Alzheimer’s disease . according to the mechanism by which their activation The postulated mechanism by which acetylcholine gives rise to a postsynaptic current. Ionotropic is involved in CNS disorders may be understood by glutamate receptors form the ion channel pore that (Flow diagram A). activates when glutamate binds to the receptor.

Flow diagram A

Flow diagram B

Flow diagram C 116 INDIAN J TRADIT KNOWLE, VOL. 17, NO. 1, JANUARY 2018

Flow diagram D

Ionotropic receptors tend to be quicker in relaying α1-Adrenoceptors and blockade of these receptors information. Metabotropic glutamate receptors may lead to depressive conditions. Antagonists of indirectly activate ion channels on the plasma α2-Adrenoceptor also possess antidepressant activity. membrane through a signaling cascade that involves It is also suggested that β-adrenoceptor agonists can G proteins. Metabotropic receptors are associated also act like antidepressants14. Dopamine acts through 11 with a more prolonged stimulus . Several antagonists dopaminergic receptors and several agonists of D2/D3 of NMDA have been used for symptomatic treatment receptors show antidepressant activity14. of Parkinson’s disease. Other than this glutaminergic Table 1 summarizes the involvement of different system is also involved in the development of several neurotransmitters in various CNS disorders. disorders like schizophrenia, epilepsy, anxiety, Plants active on neurotransmitters Alzheimer’s disease, dementia, depression, tolerance, sensitization12. Another study also revealed that the Acetylcholine NMDA blockers also play an important role as mood Amanita muscaria (L.) Lam. stabilizers and used as antidepressants11. It is a fungus that belongs to the family 16 Amanitaceae . It is native to Siberia and North Serotonin America commonly known as Amanita, fly agaric. It is Serotonin is a monoaminergic neurotransmitter cholinergic receptor agonist more potent than which is involved in the pathophysiology of several acetylcholine17. Main chemical constituent responsible mental disorders, especially schizophrenia. One study for its cholinergic effect is muscarine. Muscarine salt shows that different antagonists of serotonin can has all the activity similar to acetylcholine as it causes cause mental disorders in laboratory animals contraction of the horse ureter and carotid artery chain suggesting that this may be due to decreased levels of in vitro and slows down the isolated auricles of the serotonin13. Several serotonergic receptors have been guinea-pig and rabbit, and the frog heart17. It also found to be involved in depression and other mental causes a reduction in blood pressure, although in vitro disorders, but only 5-HT1A is clinically evaluated it produces either constriction or dilatation of the (Flow diagram D). blood vessels of the rabbit ear17.

Besides this, other receptors like 5-HT1B, 5-HT5 Pilocarpus jaborandi Holmes and 5-HT6 are also involved in depressive conditions It bears the common name Indian hemp belonging but lack clinical evidence. 5-HT7 receptor antagonists to the family Rutaceae. It is commonly found in 14 have shown improvements in depressive states . 5- Tropical America and West Indies. Its major HT1A is more extensively found to be involved in constituent pilocarpine is a potent agonist for various psychiatric disorders like depression, anxiety muscarinic (postganglionic) receptor stimulation and and schizophrenia and hence can be an important nicotinic (ganglionic) receptor stimulation. 15 target for treatment of these diseases . Pilocarpine has also been used in the treatment of xerostomia or dry mouth and shown a better efficacy Catecholamines than placebo-controlled models18. The complete review of the catecholamines is out of scope of this article, however, we have highlighted Areca catechu L. some keypoints which are important to understand It is commonly known as betel nut, areca nut or the effects of herbal drugs targeting these supari (Hindi) and is a plant of family Arecaceae. neurotransmitters. Catecholamines include adrenaline, Mainly seeds of this plant are used. Arecoline, the noradrenaline, and dopamine. Adrenaline and main chemical constituent stimulates both muscarinic noradrenaline act through adrenoreceptors, i.e., and nicotinic receptors (in ANS and CNS)19. Several α-Adrenoceptors and β-adrenoceptors. Evidence show studies have been done to establish its activity like it that antidepressant drugs increase the level of causes contraction of guinea pig ileum, smooth DUBEY et al.: ROLE OF HERBAL DRUGS ON NEUROTRANSMITTERS FOR TREATING VARIOUS CNS DISORDERS 117

Table 1 — Involvement of different neurotransmitters in various CNS disorders Neurotransmitters Associated diseases Acetylcholine is a very widely distributed excitatory Alzheimer’s disease is associated with a lack of acetylcholine in neurotransmitter that triggers muscle contraction and stimulates certain region of brain. the excretion of certain hormones. It is involved in wakefulness, attentiveness, anger, aggression, sexuality, and thirst, among other things. Dopamine is a neurotransmitter involved in controlling The loss of dopamine in certain parts of the brain causes the muscle movement and posture. It also modulates mood and plays a central rigidity typical Parkinson disease. role in positive reinforcement and dependency. GABA (gamma-aminobutyric acid) inhibitory neurotransmitter Some drugs that increase the level of GABA in the brain are used to that is very widely distributed in the neurons of the cortex. GABA treat epilepsy and to calm the trembling of people suffering from contributes to motor control, vision, and many other cortical Huntington’s disease. functions. It also regulates anxiety. Glutamate is a major excitatory neurotransmitter that is Alzheimer disease whose first symptoms including memory associated with learning and memory. malfunctions. Norepinephrine Norepinephrine plays a role in mood disorders such as manic Important for attentiveness, emotions, sleeping, dreaming, and depression. learning. Norepinephrine is also released as a hormone into the blood, where it causes blood vessels to contract and heart rate to increase. Serotonin Depression, suicide, impulsive behavior, and aggressiveness all Regulating body temperature, sleep, mood, appetite, and pain. appear to involve certain imbalances in serotonin. muscle contraction19. It also increases the learning and hyoscyamine has two forms, i.e., (+) –hyoscyamine memory in Alzheimer’s dementia through muscarinic and (-) hyoscyamine. (+) hyoscyamine is non- receptor type 1 and has vasodilator as well as competitive whereas (-) hyoscyamine is a competitive antithrombotic effect19. antagonist of acetylcholine23,24. Hyoscyamine is used

Physostigma venenosum Balf. as sedative in premedication in anesthesia and The common names for this plant are Calabar, possesses other several effects which are likely to be involved in the treatment of various CNS disorders24. ordeal, or esere bean. It belongs to the family Fabaceae (pea or bean family). Its main constituent Gamma-Aminobutyric Acid (GABA) physostigmine, Inhibits acetylcholinesterase in Dicentra cucullaria (L.) Bernh. postganglionic nerves & myoneural nerve endings It is a North American plant commonly known as 20 (somatic motor neurons) . It increases the Dutchman's breeches. It belongs to the family acetylcholine level peripherally as well as centrally in Papaveraceae. Bicuculline, a phthalide isoquinoline 20 a dose-dependent manner . Physostigmine is more alkaloid is the main constituent of this plant. It potent than other cholinesterase inhibitor drugs in the competitively inhibits the GABAA receptor treatment of memory loss in aging primate models20. 25,26 activation . Quaternary salts are more appropriate Atropa belladonna L. to use than the tertiary salts as Quaternary salts are It is commonly known as belladonna herb more water soluble than tertiary salts 25. Bicuculline belonging to the family Solanaceae. Leaves are rich also possesses anticholinesterase activity25. in its principle active constituent atropine. Atropine is Anamirta cocculus (L.) Wight & Arn. a competitive antagonist for the muscarinic It is commonly known as Indian berry, fish berry, acetylcholine receptor types M1, M2, M3, M4 and 21 or Levant nut belonging to the family M5 . With atropine molecular acetylcholine/receptor Menispermaceae. It is mainly found in Philippines, reaction is modified and conductance is also East India, Malaysia, and New Guinea. The major lowered22. chemical constituent Picrotoxin is an equimolar Hyoscyamus niger L. mixture of picrotoxinin and picrotin. Picrotoxinin is It is commonly known as henbane and belongs to more potent and a noncompetitive GABAA receptor the family Solanaceae. The main chemical constituent antagonist, while the activity that picrotin has is 50 118 INDIAN J TRADIT KNOWLE, VOL. 17, NO. 1, JANUARY 2018

times less than picrotoxinin. Other than GABAA herbaceous plant from mint family having the gentle picrotoxinin also antagonizes GABAC, glycine fragrance of lemon. It contains citronellal, linalyl (moderate), and 5HT3 (weak) receptors. Both acetate, caryophyllene, geraniol, rosmarinic acid and picrotoxinine and picrotin are equally potent in eugenol. Essential oil is used in aromatherapy, blocking the glycine receptor25. contains eugenol that calms muscles. Extract of lemon balm contains rosmarinic acid, Ginkgo biloba L. inhibits GABA transaminase, enhances GABAergic It is a Chinese plant commonly known as activity in the brain and provides calming effect on maidenhair tree. It belongs to the family depression and also in anxiety. It also has a Ginkgoaceae. It mainly contains a sesquiterpenoid carminative, diaphoretic and hypotensive effect. lactone, i.e., bilobalide which has the structural The anxiolytic & antidepressant-like effect was similarity to picrotoxinin and thus it is also an discussed by performing some behavioral test on male antagonist of GABAA and GABAC receptors. & female wistar rat in elevated plus-maze (EPM), Although bilobalide is structurally similar to forced swimming (FS) and open field (OF) tests after Picrotoxinin, it shows a huge difference in vivo. oral route administration of leaf extract of Melissa Picrotoxinin is a convulsant while bilobalide is an officinalis30. anticonvulsant25. Rosa centifolia L. Amanita muscaria (L.) Lam. Its synonyms are Rose petals, Gulkand (Hindi), It is commonly known as fly agaric or fly amanita Shatapatri. It belongs to Family Rosaceae. It is a belonging to the family Amanitaceae. These beautifully fragrant flower plant, containing volatile mushroom are mainly found in France, and Romania oil, pectin, tannic acid, flavonoids, nicotinamide, fruit and its major component is muscarine. It is an agonist acids, salts and coloring matter. Rose hips, flower, of GABA receptors and widely used to study the and leaves are mainly used. It has a ionotropic GABA receptors. It is a more potent neuropharmacological effect. The Rosa centifolia 25 agonist of GABAC than GABAA receptor . contains flavonoid that possesses an effective anti- depressant and anxiolytic activity in numerous Lavandula angustifolia Mill. studies. It modulates GABAergic neurotransmission, Its synonyms are Lavender; Khas (Hindi) & it enhances the inhibitory tone of the nervous system, belongs to Family Lamiaceae. It has long traditional improves the symptoms like restlessness, disturbed use in the therapy of depressive disorder, contains sleep and calms depression and anxiety. It has other linalool and linalyl acetate. Mainly the leaves and uses also such as hepatoprotective, reproductive tonic, flower part are used. anti-inflammatory activity, and diaphoretic, as well as Lavender oil is used as herbal medicine, gives a carminative. The anxiolytic-like effect was observed relaxation while giving massage therapy. It modulates by using geller conflict Vogel anxiety model on mice 29 GABAergic neurotransmission on GABAA receptor by i.p route . that non-selectively reduces the influx of calcium, Piper methysticum G. Forst. enhances inhibitory tone and reduces depression. Synonyms are Kava, Ava pepper and Family is The herbal extract of lavender with imipramine has Piperaceae. Kava is a traditional south pacific a synergistic effect that plays more effective role in medicinal plant used for treating anxiety. It is the depression. People also use it in toothaches, joint most effective natural remedy for anxiety. Root is pains, to repel mosquitoes and other insects, flavoring 27 used mainly. It contains kavain, dihydrokavain, agent, etc. . methysticin and yangonin which potentiates Anxiolytic, depression & similar to this activity GABA receptor activity. Kavain and methysticin are was explained by performing behavioral tests like A– able to inhibit voltage-gated sodium channels and marble buying test, elevated plus maze, locomotor voltage-gated calcium channels29. activity, serotonin syndrome on adult male swiss 28,29 It has been reported that the consumption of albino mice (30-45 g) . alcohol is avoided while taking of Kava because Melissa officinalis L. it interacts poorly. It may be effective alternatives Its synonyms are Lemon balm, Balm mint & it to the drugs like benzodiazepines and tricyclic belongs to Family Lamiaceae. It is a calming anti- depressants for the treatment of anxiety. DUBEY et al.: ROLE OF HERBAL DRUGS ON NEUROTRANSMITTERS FOR TREATING VARIOUS CNS DISORDERS 119

Passiflora edulis Sims. The main chemical constituent theanine is an Its synonyms are Passion flower, Maypop, Apricot antagonist of NMDA receptor. Theanine prevents the vine, Jhumkalata (Hindi) and the Family is death of cultured rat cortical neurons induced by Passifloraceae. It is an American traditional medicine glutamic acid34. Although the binding capacity in all that has been used to overcome wakefulness and cases is markedly less than that of glutamic acid, restlessness. It contains flavonoids, indole alkaloids theanine has a higher affinity for the AMPA/kainate like harmane, harmine, and harmol. receptors than for NMDA receptors34. Passiflora incarnata modulates GABAnergic Catecholamines system including affinity to the GABAA and GABAB receptors and also effects on GABA uptake that Hypericum perforatum L. suppresses anxiety and gives relaxation to CNS. It bears the synonyms St John's wort (SJW), Choli Phulya (Hindi) & belongs to Family Hypericaceae. Valeriana officinalis L. It is a flowering herbaceous plant, contains hyperforin Its synonyms are valerian, Garden valerian, and hypericin having highly effective role in the tagar (Hindi/Sanskrit) belonging to the Family treatment of depression. Flowers, leaves, herb tops Valerianaceae. The roots of valerian are used for are used. It also contains flavonoids, tannins, volatile medicinal purposes. It contains volatile oil, flavanones, oils, etc. and alkaloids. The work of valerian is more effective The mechanism of the anti-depressant action by than benzodiazepines. The constituents of valerian SJW is that it inhibits the nonselective re-uptake of have an affinity to GABAA receptor and suppress the neurochemicals (Dopamine, Norepinephrine, serotonin, symptoms of anxiety. In place of hypnotic drugs, GABA, and Glutamate) that decreases neurochemical valerian is used as an alternative medicine for degradation, enhances binding to many receptors and 31 insomnia without producing side effects . suppresses depression and condition along with it such as sleepiness, anxiety, etc.27. Withania somnifera (L.) Dunal SJW is also used in anxiolytic, heart palpitations, Its synonyms are Ashwagandha, Indian ginseng, and symptoms of menopause. Anxiolytic activity Poison gooseberry, Winter cherry and the Family is of Hypericum was explained by performing open Solanaceae. It is a medicine that was classified in field test experiment on adult Charles Foster rats Ayurveda as 'Rasayana' that improves mental as well (180-200 g)35. as physical performance. Ashwagandha contains withanolides which can interfere with the GABA Crocus sativus L. neurotransmission and decreases neuronal activity Its synonyms are Saffron, Saffron crocus, Crocus, 27 that stabilizes the mood in patients . Kesar (Hindi), Kumkuma (Sanskrit) belonging to It helps to induce sleep, uplift mood, and has Family Iridaceae36. It is a Persian traditional calming effect on the brain, antioxidant property, anti- medicinal flowering herbaceous plant used for its 32 inflammatory property, etc. . anti-depressant activity, belongs to the iris family

Glutamate with a pleasant odor. Mainly its dried stigma and style tops are used. It contains crocin, crocetin, safranal, Tabernanthe iboga Baill. picrocrocin and flavonoids among which safranal is It is a plant of family Apocynaceae commonly the main constituent. known as iboga. This plant has the origin in Western It is proposed that the constituent crocin inhibits Central Africa. It mainly contains ibogaine which is the uptake of neurochemicals (Norepinephrine and an indole alkaloid. Ibogaine is mainly a non- Dopamine) that helps in improving mood and are competitive antagonist of NMDA receptor. A effective in treating mild to moderate depression37. It concentration-dependent block of NMDA-induced has also been proposed for increased serotonin level currents (ICse, 3.1 PM at -60 mV) was caused slowly in the brain38, the exact mechanism of action for this by ibogaine as demonstrated in whole-cell recordings 33 is unknown, but more specifically serotonin re-uptake from cultured rat hippocampal neurons . in synapses might be inhibited by crocin. By this Camellia sinensis (L.) Kuntze serotonin is stored in the brain longer. It is commonly known as green tea and is a native It is also used as a flavoring agent, spice, fragrance of China and India. It belongs to the family Theaceae. in perfume, dye for cloth, menstrual cramps, etc. 120 INDIAN J TRADIT KNOWLE, VOL. 17, NO. 1, JANUARY 2018

Rosmarinus officinalis L. this will also open areas in the field of phytotherapy Synonyms of this plants are Rosemary, Anthos, especially for medicinal plants used in long-term Rusmari (Sanskrit) belonging to the Family treatment of CNS disorders like AD, Parkinson’s Lamiaceae. It is an Indian traditional medicinal plant disease, depression, and dementia. belonging to mint family and has a pleasant aroma. It Further study of such plants will help to breach the contains rosmarinic acid, camphor, caffeic acid, anti- contemporary scientific studies with traditional and oxidants, ursolic acid39. Its essential oil, extracts and folklore claims and believes. Multitarget effects of herbal tea is used in the therapy of depressive disorders. plant bioactive are well established as in the case of The ursolic acid inhibits the uptake of neurochemicals Crassocephalum bauchiense and Annona cherimola (dopamine, serotonin, and noradrenaline) and suppresses Miller, and this review will help researchers to find out the condition of depression40. more such plants for the treatment of CNS diseases.

Drugs acting on multiple neurotransmitters Disclosure statement Crassocephalum bauchiense (Hutch.) Milne-Redh The authors report that there is no conflict of This plant belongs to the Family Compositeae. The interest. leaf of the Crassocephalum bauchiense is used for medicinal purposes. It contains alkaloids. This plant References acts by blocking dopamine D-2 receptors and active 1 Siegel GJ, et al., Basic Neurochemistry, 1999. 31 2 Webster R, Neurotransmitters, drugs and brain function, GABAergic systems . (John Wiley & Sons), 2001. 3 Jacobs BL & EC Azmitia, Structure and function of the brain Annona cherimola Mill. serotonin system, Physiol Rev, 72 (1) (1992) 165-229. Its synonyms are ilama, ilama zapote, zapote de 4 Young SN & M Leyton, The role of serotonin in human vieja, papausa, papauce or anona blanca, papause and it mood and social interaction: insight from altered tryptophan belongs to Family Annonaceae. The leaf of the Annona levels, Pharmacol Biochem Behavior, 71 (4) (2002) 857-865. 5 Macdonald RL & RW Olsen, GABAA receptor channels, cherimola Mill. is used for medicinal purposes. This Ann Rev Neuroscie, 17 (1) (1994) 569-602. plant act on GABAA/BZD; 5-HT1A receptors; 6 Blokland A, Acetylcholine: a neurotransmitter for learning increases DA and serotonin (5- HT) turnover31. and memory?, Brain Res Rev, 21 (3) (1995) 285-300. 7 Vallone D, R Picetti & E Borrelli, Structure and function of Conclusion dopamine receptors, Neurosci Biobehav Rev, 24 (1) (2000) Neurotransmitters are very widely distributed in the 125-132. 8 Sanzone M, Epinephrine, in Encyclopedia of Clinical human body and are involved in almost all activities. Neuropsychology, Springer, 2011, 965-967. They are mainly concentrated in the brain and are also 9 Langmead CJ, J Watson & C Reavill, Muscarinic involved in the pathophysiology of various CNS acetylcholine receptors as CNS drug targets, Pharmacol disorders like AD and Parkinson’s disease which Therapeut, 117 (2) (2008) 232-243. 10 Youdim MB & JJ Buccafusco, Multifunctional drugs for mainly include acetylcholine, dopamine, GABA, various CNS targets in the treatment of neurodegenerative glutamate, catecholamines, and serotonin. It has also disorders, Trends Pharmacol Sci, 26 (1) (2005) 27-35. been proved that these neurotransmitters and their 11 Krystal JH, et al., Glutamate and GABA systems as targets receptors can be regarded as an important molecular for novel antidepressant and mood-stabilizing treatments, target for treating CNS disorders. The use of Mole Psychiatr, 7 (2002) S71-S80. 12 Danysz W, et al., Glutamate in CNS disorders, Drug News agonist/antagonist of these receptors can control CNS Persp, 8 (1995) 261-261. disorders to a great extent either symptomatically or 13 Woolley DW & E Shaw, A biochemical and at the molecular level by potentiating or blocking pharmacological suggestion about certain mental disorders, the activity of these neurotransmitters. Chemical Proc Nat Acad Sci, 40 (4) (1954) 228-231. constituents isolated from various plants have been 14 Millan MJ, The role of monoamines in the actions of established and “novel” antidepressant agents: a critical the interesting tool of research for the researchers and review, European J Pharmacol, 500 (1) (2004) 371-384. are preferable over the synthetic drugs due to their 15 Celada P, A Bortolozzi & F Artigas, Serotonin 5-HT1A minimal adverse events. This review describes how receptors as targets for agents to treat psychiatric disorders: the plants have been established as the drug of choice rationale and current status of research, CNS drugs, 27 (9) for the treatment of various CNS disorders. This study (2013) 703-716. 16 Kosentka P, et al., Evolution of the toxins muscarine and also contains the various experimental studies and psilocybin in a family of mushroom-forming fungi, PloS one, results in the field of medicinal plants research, and 8 (5) (2013) e64646. DUBEY et al.: ROLE OF HERBAL DRUGS ON NEUROTRANSMITTERS FOR TREATING VARIOUS CNS DISORDERS 121

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