Nature: Anxiolytics in the Lap of Nature

Article ID: WMC002140 2046-1690

Corresponding Author: Dr. Zulfiqar Ali Bhat, Sr. Asst. Professor, Department of Pharmaceutical sciences, University of Kashmir, Hazaratbal, Srinagar, J&K-190006, India, 190006 - India

Submitting Author: Mr. Dinesh Kumar, Major Project Fellow, Department of Pharmaceutical sciences, University of Kashmir, Hazaratbal, 190006 - India

Article ID: WMC002140 Article Type: Review articles Submitted on:01-Sep-2011, 06:54:52 PM GMT Published on: 02-Sep-2011, 04:41:24 PM GMT Article URL: http://www.webmedcentral.com/article_view/2140 Subject Categories:PHARMACEUTICAL SCIENCES Keywords:Anxiety, Anxiolytics, Traditional medicines, Neurotransmitters How to cite the article:Kumar D , Bhat Z , Kumar V , Shah M . Nature: Anxiolytics in the Lap of Nature . WebmedCentral PHARMACEUTICAL SCIENCES 2011;2(9):WMC002140 Competing Interests: None

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Nature: Anxiolytics in the Lap of Nature

Author(s): Kumar D , Bhat Z , Kumar V , Shah M

Abstract from 13.6 to 28.8% in Western countries. Individuals aged between 10 and 25 years are at highest risk for developing an anxiety condition. These conditions are among the most common mental diseases, and their Background prevalence and disease course are reasonably well A large number of populations depend on traditional documented. On the other hand, WHO launched its practitioners, who in turn are dependent on medicinal first-ever comprehensive traditional medicine strategy plants, to meet their primary health care needs. Today in 2002 with the objective of recognizing traditional "traditional medicine," characterized by the use of medicine in the treatment of public health problems [1]. herbs and other natural products, still remains a Anxiety is a feeling of uneasiness, uncertainty or fear, regular component of health care in the world. in response to a real or imagined danger. The body Aims responds to anxiety by releasing a number of "stress" To explore the natural and traditional medicines in hormones, like adrenaline and cortisol, which have an relation to anxieolytics effect on almost every organ in the body. Mild forms of Method anxiety caused by emotional conflict or life stress are Electronic literature searches were conducted using common and unproblematic. Anxiety disorders are a the following databases: AMED, Cinahl, Embase, group of conditions in which the feelings of anxiety are Elsevier, Medline, PsychInfo, PubMed (all from not associated with a real or appropriate threat, or are inception to August 2004), Google scholar and many much more intense and long lasting than they should important text books. The terms used for the electronic be. People feel frightened and distressed for no searches were limited to important receptors and apparent reason. This condition can paralyze the neurotransmitters present in brain which help to individual into inactivity or withdrawal, and can modulate anxiety, plants with neurological bioactivity dramatically reduce productivity and significantly and bioactive compounds with respective receptors diminish a person's quality of life. Anxiety disorders and mechanism of action along with few chemical are common - nearly 25% of people will experience structures involved in the treatment of anxiety. anxiety disorders at some time in their lives. Physical Results symptoms of anxiety disorders are due to released Systematic review were located with the above search stress hormones. These may increase blood pressure, strategy cause heart palpitations, chest pain, rapid breathing or Discussion and conclusion breathlessness, sweating, increased muscle tension or The review covered all aspects of traditional medicines irritability. Intestinal blood flow decreases, resulting in and revealed that a detailed study is required to nausea or diarrhoea. There is often a decreased sex explore the plants and their uses to treat serious drive. Children may also have a fear of being away complication of central nervous system. Nature and from the family, a refusal to go to school, a fear of tradition both is wonder agent of God for the treatment strangers, a fear of falling asleep or have recurrent of diseases. The review will pave a way for new drug nightmares. Specific anxiety disorders each have their search. own particular pattern of symptoms and additional Keywords: Anxiety, Anxiolytics, Traditional medicines, behavioural characteristics Figure 1. Neurotransmitters. Depression and Anxiety Introduction The simultaneous occurrence of depression and anxiety is very common. Figures show that between There is a high prevalence of mental and neurological 60% and 90% of people with depression also have disorders worldwide; these account for 13% of total symptoms of anxiety. The combination is well disability adjusted life years (DALYs) lost due to all recognized and can significantly increase the disability diseases and injuries in the world. WHO estimates that and disruption of normal function suffered by the 450 million persons suffer from mental illness. Anxiety patient. The anxiety associated with depression can is widespread, with lifetime prevalence rates ranging take many forms including panic attacks, obsessive

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compulsive disorder, post-traumatic stress disorder, neurotransmitters. Neurotransmitters can excite or social anxiety disorder or a generalized anxiety inhibit neurons (nerve cells). Some common disorder. Fortunately medication is available which can neurotransmitters are acetylcholine, norepinephrine, effectively relieve both depression and anxiety. dopamine, serotonin and gamma aminobutyric acid Anxiety is different type like Panic Disorder, Phobias, (GABA). Acetylcholine and norepinephrine are Post-Traumatic Stress Disorder (PTSD), excitatory neurotransmitters while dopamine, serotonin, Obsessive-Compulsive Disorder (OCD), Generalised and GABA are inhibitory. Each neurotransmitter can Anxiety Disorder (GAD). directly or indirectly influence neurons in a specific Anxiety disorders in a modern society have relatively portion of the brain, thereby affecting behaviour. high prevalence affecting between10 and 30% of the Cholecystokinin (CCK) is a neurotransmitter in the general population with considerable financial brain closely related to anxiety. resources. Excessive anxiety can debilitate and 4.2 Mechanism of impulse transmission damage the quality of life. In the clinical treatment of Neurotransmitters are chemicals that transmit anxiety benzodiazepines, GABAAreceptor agonist and messages from one nerve cell (neuron) to another. buspirone, 5-HT1A receptor agonist, are mainly The nerve impulse travels from the first nerve cell prescribed as first choice treatment. Chronic through the axon—a single smooth body arising from administration of benzodiazepines, however result in the nerve cell— to the axon terminal and the synaptic physical dependence such as sedation, myelo knobs. Each synaptic knob communicates with a relaxation, ataxia, amnesia and pharmacological dendrite or cell body of another neuron, and the dependence. More over buspirone also results in synaptic knobs contain neurovesicles that store and dizziness, headache, nervousness, paresthesia, release neurotransmitters. The synapse lies between diarrhea, excitation and sweating as adverse. the synaptic knob and the next cell. For the impulse to Therefore, research has been conducted to identify continue traveling across the synapse to reach the safer, more specific medications possessing anxiolytic next cell, the synaptic knobs release the effect without the complications. In past few years, neurotransmitter into that space, and the next nerve several herbal medicines have been used for the cell is stimulated to pick up the impulse and continue it. management of anxiety in the world [2]. Any changes in its normal function may cause CNS disorders Figure 2. Methods The mechanism of action and localization of neurotransmitters in the brain has provided valuable information concerning the cause of many mental Electronic literature searches were conducted using disorders, including clinical depression and chemical the following databases: AMED, Cinahl, Embase, dependency, and in researching medications that Elsevier, Medline, PsychInfo, PubMed (all from allow normal flow and movement of neurotransmitter inception to August 2004), Google scholar and many molecules. important text books. The terms used for the electronic 4.3 Noradrenaline; Dysregulation of norepinephrine in searches were limited to important receptors and depression and adaptation with treatment: neurotransmitters present in brain which help to Noradrenaline is one of the neurotransmitter in the modulate anxiety, plants with neurological bioactivity brain and its proper regulation helps to normalize the and bioactive compounds with respective receptors brain. Any change in regulation leads to disturbances and mechanism of action along with few chemical in the brain system and leads to psychological structures involved in the treatment of anxiety. diseases. In the 1960s, based on over a decade of accumulating Results data, a consensus was forming that catecholamines, specifically norepinephrine (NE), played a crucial role in affective disorders. “Some, if not all, depressions Systematic review was located with the above search are associated with an absolute or relative deficiency strategy. Nature and tradition in relation to anxieolytics of catecholamines, particularly norepinephrine, at 4.1 Neurotransmiter involve in the CNS disorder functionally important adrenergic receptor sites in the especially in anxiety brain. Elation conversely may be associated with an There are approximately 50 neurotransmitters excess of such amines” Figure 4. identified. There are billions of nerve cells located in 4.4 Role of Norepinephrine in Mood Disorders: the brain, which do not directly touch each other. Norepinephrine is highly involved in mood disorders Nerve cells communicate messages by secreting Figure 3 and 4.

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4.4.1 Receptor in the brain responsible for show analgesic activities through opioid receptors. anxiety/antianxiety Three kinds of opioid receptors are known: µ, delta Benzodizepine Receptors: and k receptors. In general, opioids were reported to BDZ-Rs; The specific antagonist of the BDZ-R, RO impair learning and memory and they are also play 15-1788, blocks the anxiolytic effects while the role in anxiety and antianxiety. agonists or partial agonists Potentiate the anxiolytic Adenosine A1 receptors: effects e.g: Flavonoids. Adenosine functions as a neuromodulator in the Drawback of benzodiazepines:BDZs is often central nervous system (CNS), acting through associated with tolerance development and withdrawal cell-surface receptors. Adenosine receptors were symptoms, which poses a risk of relapse upon recognised on the basis of the ability of caffeine to act discontinuation. as an antagonist at A1 and A2 receptors. At the Serotonin receptors (5-hydroxytriptamine): moment, four adenosine receptor subtypes (A1, A2A, 5-hydroxytryptamine1A (5-HT1A); 5-HT1Areceptors A2B and A3) have been cloned and characterised are located at the presynaptic and postsynaptic sites. from several mammalian species, including humans The somatodendritic autoreceptor, when activated by and mice, and they all belong to the G-protein coupled systemic stimulation, is believed to exert anxiolytic-like receptor (GPCR) family. In addition, many studies effects and to reduce 5- HT release both in the cell using selective adenosine receptor agonists and body and in the terminal regions of the serotonergic antagonists have demonstrated that adenosine A1 neurons. The other 5-HT1A receptor is localized receptors, localised in brain areas essential for motor postsynaptically to the serotonergic neurons in the control such as the striatum, the cerebellum and the hippocampus, septum, amygdala, and cortex, where it motor cortex, are the primary site where adenosine increases signal transfer, which leads to an inhibition modulates the incoordination induced by ethanol. of the firing activity. Thus (5-HT1A) receptor is viewed Adenosine A1 receptor agonist shows an as a relevant target for the treatment of psychiatric anxiolytic-like profile or receptors modulate disorders, notably anxiety and depression. anxiolytic-like actions of ethanol. 5-HT3 receptor: Dopaminergic Receptor: (D2) receptors; They have 5-HT3 receptor antagonism contributes the anxiolytic played role in psychological diseases and may have effect.Selective 5-HT reuptake inhibitors the role in anxiety. (SSRIs).y-aminobutyric acid receptor (GABA): GABAA Somodendritic autoreceptors: receptor; GABA is a major inhibitory transmitter in the GAC treatment on behavioural perturbations in anxiety central nervous system. The γ-aminobutyric acid type models may involve the somodendritic autoreceptors A (GABAA) receptor, the chloride ion channel complex of raphae nuclei, leading to decreased central and the central benzodiazepine receptors located on serotonergic and augmented catecholaminergic the neuronal membranes within this complex have function. Our fndings reflect the positive attributes of been suggested to play an important role in the ginkgolic acid conjugates in the actions of Ginkgo regulation of the stress and anxiety states. GABAA biloba [20]. receptors possess binding sites for several drugs, Adrenergic receptors: These receptors also play a key such as anxiolytics, anticonvulsants, general role in the nervous system. They might be a co anesthetics, barbiturates, ethanol, and neurosteroids, receptor for the anxiety. which are known to elicit at least some of their CCK receptor: Cholecystokinin (CCK) was first pharmacological effects via the GABAA receptors. identified (initially characterized as a 33-amino-acid GABAA-benzodiazepine receptorHistamine receptor long peptide) in the gastrointestinal tract and later it (H-receptor): was found to be one of the most widely distributed Histamine receptor plays an important role in anxiety peptides in the brain where it acts as a and other CNS disorder With reference to H1, H2, H3 neurotransmitter. receptors. H1, H2, H3 receptors: Opioid receptors: Brain histamine localizes in both histamine neurons Endogenous opioid peptides such as enkephalins, and non-neuronal mast cells, with the mast cells dynorphins and endomorphins, and their receptors storing approxi-mately 50% of whole brain histamine have been found in the peripheral and central nervous levels. Histaminergic neurons project to almost all systems. Various bioactive peptides are known to be regions of the mammalian brain from the derived from enzymatic digests of food proteins. tuberomammillary nucleus of the posterior Among them, several bioactive peptides derived from hypothalamic region. Clinically effective anxiolytic food proteins such as bovine casein and wheat gluten drugs, diazepam, benzodiazepines and buspirone,

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serotonin (5-HT1A) agonists have been found to background of each country. Herbal medicines are decrease turnover rate of brain histamine in mice and assuming greater importance in the primary health rats. These findings suggest that histaminergic system care of individuals and communities in many in the brain plays an important role in the regulation of developed as well as developing countries and there anxiety. Furthermore, Imaizumi and Onodera have has been an increase in international trade in herbal demonstrated that anxiety-like behavioral activity is medicines. India has 45000 diverse plant species induced or enhanced by the combined administration spread over 16 different agro-climatic zones, 10 of thioperamide, a neuronal histamine releaser having vegetation zones, 25 biotic provinces and 426 habitats inhibitory effect of histamine H3autoreceptors, with of specific spices. Besides, India has up to 18,000 zolanitidine, a histamine H2 receptor antagonist. In flowering plants, 2500 algae, 23,000 fungi, 1600 types addition it has also demonstrated that anxiety like of lichen and 1,800 varieties of bryophytes. Of this behavioral activity is also induced by co-injection of vast quantum around 15,000 to 20,000 are of non-neuronal selective mast cell histamine releaser, medicinal value, but out of this only, 7,000 to 7,500 Compound 48/80, with a histamine H2receptor plants are used by traditional medicine systems in antagonist, cimetidine. These neuronal and India.The use of natural products with therapeutic non-neuronal histaminergics induced experimental properties is as ancient as human civilization and, for anxiety models in mice are useful for assessing the a long time, mineral, plant and animal products were effect of any drug on brain histaminergic system in a the main sources of drugs. The Industrial Revolution state of anxiety. and the development of organic chemistry resulted in Role of histaminergic system in anxiety: Role of a preference for synthetic products for histaminergic system in anxiety showed in Table 1. pharmacological treatment. The reasons for this were CCK receptor subtypes: that pure compounds were easily obtained, structural CCK1 and CCK2: High densities of CCK-binding sites modifications to produce potentially more active and in several areas including the cerebral cortex, striatum, safer drugs could be easily performed and the olfactory bulb and tubercle, and certain amygdaloid economic power of the pharmaceutical companies nuclei. Moderate levels were observed in the was increasing. Furthermore, throughout the hippocampus, claustrum, substantia nigra, superior development of human culture, the use of natural colliculus, periaqueductal gray matter, and pontine products has had magical-religious significance and nuclei. Low densities were reported in several thalamic different points of view regarding the concepts of and hypothalamic nuclei and in the spinal cord. With health and disease existed within each culture. the advent of specific radioligands that could Obviously, this approach was against the new modus differentiate between the two types of CCK receptors, Vivendi of the industrialized western societies, in it has become apparent that the distributions of CCK1 which drugs from natural resources were considered and CCK2/gastrin receptors within the CNS are either an option for poorly educated or low income overlapping and yet distinct. CCK2 receptors are the people or simply as religious superstition of no predominant subtype in the CNS, with CCK1 receptors pharmacological value. However, even if we only restricted to some discrete nuclei. The widespread consider the impact of the discovery of the penicillin, distribution of CCK2 receptors in the CNS is consistent obtained from micro-organisms, on the development of with the diverse functions attributed to neural CCK, anti-infection therapy, the importance of natural including the regulation of feeding (satiety), the control products is clearly enormous. About 25% of the drugs of learning and memory, behavioral expression of prescribed worldwide come from plants, 121 such anxiety, mediation of pain, cardiovascular regulation, active compounds being in current use. Of the 252 neuroendocrine control, osmotic stress, drugs considered as basic and essential by the World neuropsychiatric disorders (such as panic attacks) and Health Organization (WHO), 11% are exclusively of modulation of dependence and withdrawal processes plant origin and a significant number are synthetic as well as functions controlled by the dopaminergic, drugs obtained from natural precursors. Examples of serotonergic, and opioid systems. important drugs obtained from plants are digoxin from 4.5 Tradition and nature helps to treat diseases Digitalis spp., quinine and quinidine from Cinchona During the last decade, there has been a growing spp., vincristrine and vinblastine from Catharanthus interest in traditional and alternative systems of roseus, atropine from Atropa belladonna and morphine medicine in many developed countries. Medicinal and codeine from Papaver somniferum. It is estimated plants are the oldest known health-care products. that 60% of anti-tumour and anti-infectious drugs Their importance is still growing although it varies already on the market or under clinical trial are of depending on the ethnological, medical and historical natural origin. The vast majority of these cannot yet be

Webmedcentral > Review articles Page 5 of 25 WMC002140 Downloaded from http://www.webmedcentral.com on 28-Dec-2011, 09:19:10 AM synthesized economically and are still obtained from Discussion and Conclusion wild or cultivated plants. Natural compounds can be lead compounds, allowing the design and rational planning of new drugs, biomimetic synthesis During the past decade, the indigenous or traditional development and the discovery of new therapeutic system of medicine has gained importance in the field properties not yet attributed to known compounds [24]. of medicine. In most of the developing countries, a In addition, compounds such as muscarine, large number of populations depend on traditional physostigmine, cannabinoids, yohimbine, forskolin, practitioners, who in turn are dependent on medicinal colchicines and phorbol esters, all obtained from plants, to meet their primary health care needs. plants, are important tools used in pharmacological, Although modern medicines are available, herbal physiological and biochemical studies. medicines have retained their image for historical and Plants have been used by human beings since cultural reasons. As the usage of these herbal immemorial times to cure diseases and to promote medicines has increased, issues and the motto relief from ailments There were times when they were regarding their quality, safety, and efficacy in the most important sources of medicines for people industrialized and developing countries have cropped However, beginning in the late 1940s, this old form of up [64]. therapeutics began to lose its importance, being more The search for new molecules that act on the central and more replaced by synthetic remedies The lessons nervous system (CNS) and that can be used for from millennia were forgotten and were considered therapeutic purposes started with several studies in ‘‘unscientific.’’ Many species of plants possessing the 19th century. In fact, the first drugs used to treat activity on the central nervous system (CNS) In fact, pathologic conditions of the CNS were based on they cover the whole spectrum of central activity such natural resources, specifically on plants. However, as psychoanaleptic, psycholeptic and psychodysleptic studies targeting plants with this type of bioactivity effects, and several of these plants are currently used represent only a very small percentage of those in therapeutics to treat human ailments. Mind-altering investigations. In a review of the existing literature, it drugs, especially plants, have always fascinated appears that plants with molecules that produce this human beings Surrounded by mystic superstitions, kind of activity are increasingly attractive targets for magic thoughts and religious rituals, they have always the development of new drugs [20]. Flavonoids have occupied man’s attention Among the plants used by recently increased in importance because they have humans, those able to alter the conscience and the been identified as a new type of ligand with in vivo sensorium have drawn special consideration In fact, anxiolytic properties. Different plant species utilized in due to their astonishing effects, the psychodysleptic traditional medicine have been submitted to drugs (hallucinogenic drugs) have occupied much of neuropharmacological evaluation (among others, the the researchers’ time, directed most of their thoughts EPM) in which sedative effects have been and efforts towards attempts to understand their demonstrated [65]. The flavones chrysin and apigenin, mechanism of action and hence, to understand human obtained from medicinal plants, have shown an behavior, thoughts, humor, sensations etc. anxiolytic effect in rodents exposed to behavioral tests. 4.6 Traditional medicines previously evaluated for their Apparently, these compounds modulate the claims as anxiolytics: gama-aminobutyric acid (GABA)ergic system to Plants has been evaluated for the treatment of anxiety produce the biological effect [66-67]. Many studies showed in Table 2 along with their parts used, have examined the use of native plants for more traditional claims related to anxiety, constituents specific, lower cost treatments with fewer harmful isolated from respective plants. effects. The review covered all aspects of traditional 4.7 Plant drugs and isolated compounds as anxiolytics medicines and revealed that a detailed study is Plant drugs as extract and their single molecules/ required to explore the plants and their uses to treat compounds helps to reduce anxiety has been showed serious complication of central nervous system. in Table 3 along with their capacity for receptor site Medicines are hiding in the lap of nature and tradition and mechanism of action [2, 6, 16, 17, 20, 28--32, always helps to shine the medicines for the treatment 61-63]. of human illness. Nature and tradition both is really a 4.8 Chemical structure of natural isolates responsible wonder agent of God for the treatment of diseases. for treatment of anxiety: This review helps to understand the anxiety or central The structure of natural isolatesshowed in Figure 5,6 nervous system disorders along with treatment by and 7 which have the potential to treat anxiety and natural medicines. This review also stimulates the showed anxieolytic effects.

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young researchers and students to search out the 5-HT1A autoreceptor sensitivity in the rat dorsal raphe novel drug from the lap of nature and tradition. nucleus—in vitro electrophysiological evidence. Fundam Clin Pharmacol., 11, 206–14. Acknowledgments 11. KAZAWA H., YAMANE, F., BLIER, P., & DIKSIC, M., 1999. Effects of acute and chronic administration of the serotonin1A agonist buspirone on serotonin Dinesh Kumar, ZA Bhat, and MY Shah would like to synthesis in the rat brain. J Neurochem., 72, 2022–31. thank the Department of Pharmaceutical Sciences, 12. FILE, S. E., 1996. Recent developments in anxiety, University of Kashmir, Srinagar-190006 (India) and stress, and depression. Pharmacol Biochem Behav., UGC - Delhi for their interest and help with this 54, 3–12. manuscript. 13. EGUCHI, J., INOMATA, Y., & SAITO, K., 2001. The anxiolytic-like effect of MCI-225, a selective NA References reuptake inhibitor with 5-HT3 receptor antagonism. Pharmacology, Biochemistry and Behavior 2001; 68: 677-683. 1. HERRERA-RUIZA, M., ROMAN-RAMOSB, R., 14. SH.ORT, K. R., & MAIER, S. F., 1993 Stressor ZAMILPAA, A., TORTORIELLO, J., & controllability, social interaction, and benzodiazepine JIMENEZ-FERRER, J. E., 2008. Flavonoids from Tilia systems. Pharmacol Biochem Behav., 45, 827–35. americana with anxiolytic activity in plus-maze test. 15. JOHNSON, M. R., MARAZZITI, D., Journal of Ethnopharmacology, 118, 312–317. BRAWMAN-MINTZER, O., EMMANUEL, N. P., WARE, 2. KUMAR, R., MURUGANANTHAN, G., M. R., & MORTON, W. A., 1998. Abnormal peripheral NANDAKUMAR, K., & TALWAR, S., 2010. Isolation of benzodiazepine receptor density associated with anxiolytic principle from ethanolic root extract of generalized social phobia. Biol Psychiatry, 43, Cardiospermum halicacabum. Phytomedicine: In press. 306–309. 3. WANG, H., WONG, P. T. –H., SPIESS, J., & ZHU, 16. YU, H., LEE, S., & JANG, C., 2007. Involvement of Y. Z., 2005. Cholecystokinin-2 (CCK2) 5-HT1A and GABAA receptors in the anxiolytic-like receptor-mediated anxiety-like behaviors in rats. effects of Cinnamomum cassia in mice. Pharmacology, Neuroscience and Biobehavioral Reviews 29, Biochemistry and Behavior, 87, 164–170. 1361–1373. 17. YUZURIHARA, M., IKARASHI, Y., ISHIGE, A., 4. JERALD, T. A. K. & Lieberman, J. A., 1997. SASAKI, H., & MARUYAMA, Y., 2000. Anxiolytic-like Psychiatry. 1st ed. Philadelphia: W. B. Saunders effect of saiboku-to, an oriental herbal medicine, on Company. histaminergics-induced anxiety in mice. Pharmacology, 5. RESSLER, K. J., & NEMEROFF, C. B., 1999. Role Biochemistry and Behavior, 67, 489-495. of Norepinephrine in the Pathophysiology and 18. HIRATA, H., SONODA, S., AGUI, S., YOSHIDA, Treatment of Mood Disorders. Biol Psychiatry, 46, M., OHINATA, K., & YOSHIKAWA M., 1998. 1219–1233. Rubiscolin-6, a delta opioid peptide derived from 6. SALGUEIRO, J. B., ARDENGHI, P., DIAS, M., spinach Rubisco, has anxiolytic effect via activating FERREIRA, M. B. C., IZQUIERDO, I & MEDINA, J. H., sigma1 and dopamine D1 receptors. Peptides, 28, 1997. Anxiolytic natural and synthetic flavonoid ligands 1998 – 2003. of the central benzodiazepine receptor have no effect 19. PREDIGER, R. D. S., BATISTA, L. C., & on memory tasks in rats. Pharmacology Biochemistry TAKAHASHI, R. N., 2004. Adenosine A1 receptors and Behavior, 5(4), 887–891. modulate the anxiolytic-like effect of ethanol in the 7. LADER, M., 1995. Clinical pharmacology of elevated plus-maze in mice. European Journal of anxiolytic drugs: past, present and future. Adv Pharmacology, 499, 147– 154. Biochem Psychopharmacol., 48, 135–52. 20. GOMES, N. G. M., CAMPOS, M. GA., ORFAO, J. 8. BALLENGER, J. C., 2001. Treatment of anxiety M. C., & RIBEIRO, C. A. F., 2009. Plants with disorders to remission. J Clin Psychiatry, 62(12), 5–9. neurobiological activity as potential targets for drug 9. BLIER, P., LISTA, A., & DE, M. C., 1993. discovery. Progress in Neuro-Psychopharmacology & Differential properties of pre- and postsynaptic 5- Biological Psychiatry, 33, 1372–1389. hydroxytryptamine1A receptors in the dorsal raphe 21. SHETH, P. P., 2005. Global opportunities and and hippocampus: II. Effect of pertussis and cholera challenges for medicinal uses of ayurveda, herbal toxins. J Pharmacol Exp Ther., 265, 16–23. products, neutraceuticals and alternatives. Health 10. LAARIS, N., LE, P. E., HAMON, M., & LANFUMEY, Administrator, 74-75. L., 1997. Stress-induced alterations of somatodendritic 22. DE PASQUALE, A., 1984. Pharmacognosy: the

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Illustrations

Illustration 1

Figure 4: Dysregulation of norepinephrine in depression and adaptation with treatment.

Illustration 2

Figure 2: Mechanism of impulse transmission

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Illustration 3

Figure 1: Symptoms of anxiety

Illustration 4

Figure 3. Regulation and function of the norepinephrine modulatory system.

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Illustration 5

Figure 5: Structure of chrysin, apigenin, Sinapic acid, Sanjoinine A

Illustration 6

Figure 6: Flavonols, Flavanones, Flavanoid glycoside (1-12) showed anxiolytic activity

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Illustration 7

Figure 7: Structure of Trideca-7, 9, 1-,trienoic acid and Cardiospermin

Illustration 8

Table 1: Histaminergic system in anxiety

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Illustration 9

Table 2: Traditional medicines as anxiolytics

Biological source Part used Traditional uses related to anxiety Compounds having anxiolytic activity Ficus religiosa Linn. Roots, stem, Nervous disorders, nervine tonic, epilepsy, unconsciousness, and (Moraceae) barks drug addiction (bhang and opium) Uncaria rhynchophylla Stem Anti-hypertensive, anti-epileptic, and neuroprotective activities (Rubiaceae) Tilia americana var. Anxiolytic-like effect Quercetin, kaempferol, Mexicana (Tiliaceae) flavonoids Rubus brasiliensis Martius Leaf Nervous breakdown treatment (Rosaceae) Zizyphi Spinosi Semen Seed Analgesic, tranquilizer and anticonvulsant anxiolyticlike Sanjoinine A (ZSS), the dried seed of effect Zizyphus jujuba Mill var. spinosa (Rhamnaceae),

WebmedcentralMagnolia obovata > Review articles Thrombotic stroke, headache and anxiety Honokiol, magnolol,Page 14 of 25 obovatol Valeriana Officinalis L. Roots Tranquilizer insomnia, anxiety and sleep inducer Sphaeranthus indicus Linn Flower Epileptic, hypotensive, peripheral vasodilatory and convulsions, WMC002140 Downloaded from http://www.webmedcentral.com on 28-Dec-2011, 09:19:10 AM

Asteraceae mental illnesses and hemicranias Turnera aphrodisiaca Ward Anxiety neurosis, and as an aphrodisiac Apigenin (Turneraceae) Spondias mombin L. leaves Psychiatric disorders (Anacardiacaea) Casimiroa pringlei (S. Leaves Watson) Engl. (Rutaceae) Casimiroa edulis Llave and Bark, leaves Induce sleep and as an anxiolytic Lex. Matricaria recutita L Sedative and anticonvulsant properties Passiflora incarnata L. Flower Anxiolytic and sedative properties Piper methysticum Forst Anxiolytic and sedative properties Valeriana officinalis L. Anxiolytic and sedative properties, insomnia Euphorbia hirta L. Whole herb Anxiolytic and sedative properties (Euphorbiaceae) Lavandula angustifolia Linalyl acetate and linalool are considered to have sedative and local Linalool anesthetic effects Cecropia glazioui Sneth leaves Antihypertensive, cardiotonic, and antiasthmatic (Moraceae) Butea frondosa leaves Rejuvenato and stress treatment (Leguminosae)

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Bacopa monniera Whole herb Cognitive functions of the brain Azadirachta indica Leaves Cognitive functions of the brain

Withania somnifera Roots and Cognitive functions of the brain Whole plant Ocimum sanctum Whole plant Cognitive functions of the brain Annona muricata Leaves Anticonvulsant activity, tranquilizing and sedative properties (Annonaceae) Annona Cherimolia Tranquilizing and sedative properties (Annonaceae) A. glabra (Annonaceae) tranquilizing and sedative properties A. Montana (Annonaceae) tranquilizing and sedative properties Annona diversifolia Leaves Anticonvulsant activity (Annonaceae) Salvia reuterana Boiss. Arial part of Anti-anxiety herbal drugs (Labiatae) the plant Portulaca oleracea L. Anxiolytic agent (Portulacaceae) Kaempferia parviflora Rhizomes Impotent symptoms and promote longevity Zingiberaceae

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Elaeocarpus sphaericus Fruits Sedative, hypnotic, transquillizing, antiepileptic, and (Elaeocarpaceae) antihypotensive properties Citrus paradisi var. starruby Fruits Mood enhancer, anxiety Essential oils Citrus paradisi Fruits Mood enhancer, anxiety Essential oils CitrusLimon Fruits Mood enhancer, anxiety Essential oils Citrus bergamia Fruits Mood enhancer, anxiety Essential oils Citrus Aurantifolia Fruits Mood enhancer, anxiety Essential oils Citrus nobilis Fruits Mood enhancer, anxiety Essential oils Citrus aurantium Fruits Mood enhancer, anxiety Essential oils Passiflora incarnata whole plants Sedative, anxiolytic and antispasmodic purpose L.(Passifloraceae) Echium amoenum L. Flower Anxiolytic (Boraginaceae) Tilia americana var. Aerial parts Relieve sleeplessness, headache, and nervous excitement Flavonoids mexicana (Tiliaceae) Alstonia scholaris leaves Mental illnesses Linn.R.Br., (Apocynaceae) Ginkgo biloba Linn. leaves Cerebrovascular insu¦ciency, cardiovascular malfunction and Ginkgolicacid (Ginkgoaceae) bronchitis conjugates Clerodendrum philippinum Flower Treatment of neuropsychological schauer, (Verbenaceae) diseases Webmedcentral > Review articles Page 17 of 25 WMC002140 Downloaded from http://www.webmedcentral.com on 28-Dec-2011, 09:19:10 AM

Angelica sinensis Whole plant Sedative and antianxiety activities Essential oil (Umbelliferaceae) Aniba riparia (Nees) Mez, Fruit Sedative and antianxiety activities (Lauraceae) Aethusa cynapium L. Aerial parts Convulsions, mental tension, sleep disorders, Trideca-7,9,11- (Umbelliferae/Apiaceae) delirium trienoic acid Cardiospermum Roots Curing diseases related to the nervous system Cardiospermin halicacabum Nardostachys jatamansi Roots Nervous system (Valerianaceae) Bacopa monnieri L. Anxiety, poor cognition and a lack of concentration (Scrophulariaceae) Centella asiatica (Apiaceae) Nervine tonic in various brain diseases, In parts of India it is given with milk to improve memory against dementia and aging.

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Illustration 10

Table 3: Plant drugs and isolated compounds as anxiolytics

Plant extracts/drugs Natural isolates or Binding Receptor/ compete/ Mode of action compounds Mimick Action receptor Chrysin BDZ-Rs Partial agonists [5,7-dihdroxyflavone] Apigenen BDZ-Rs Partial agonists

[5,7,41trihydroxyflavone]

50% EtOH extract of Somatodendritic WAY100635, a somatodendritic 5-HT1A antagonist, Cinnamomum cassia autoreceptors (5-HT1A) enhances serotonergic system activity via complete (stem barks) blockade of the somatodendritic autoreceptors and possesses anxiogenic activity.The anxiolytic-like effect of C. cassia was significantly blocked by WAY100635 at 0.3 and 1.0 mg/kg and the above mentioned that the

action of extract is due to 5-HT1A receptor.

50% EtOH extract of GABAA receptors GABAA receptors are potentially inhibited by Webmedcentral > Review articles Page 19 of 25 Cinnamomum cassia picrotoxin bicuculline and SR95531 (compitative (stem barks) antagonist) and the anxiolytic-like effect of C. cassia was significantly blocked by (+)-bicuculline at 0.1, 0.3, WMC002140 Downloaded from http://www.webmedcentral.com on 28-Dec-2011, 09:19:10 AM

and 1.0 mg/kg. Cinnamic acid of ------phenylpropanoid compounds p-Coumaric acid, caffeic ------acid, and ferulic acid of cinnamic acid derivatives

U n c a r i a 5-HT1A 5-HT1A receptor activation. rhynchophylla aqueous extract Quercetin and kaempferol ______cinnamic acid, p-coumaric acid, caffeic acid and ferulic acid

sinapic acid GABAA receptor, Agonist of GABAA receptor Magnolol and Honokiol Histaminergic system Saiboku-to Histaminergic system By acting on H-receptor Sanjoinine A GABA receptor Sanjoinine A may exert its anxiolytic effect by increasing GABA synthesis via GAD65/67 activation and increasing receptors for benzodiazepine or GABA Webmedcentral > Review articles Page 20 of 25 WMC002140 Downloaded from http://www.webmedcentral.com on 28-Dec-2011, 09:19:10 AM

by influencing GABA receptor subunit compositions.

Hexanic fraction of GABAA-benzodiazepine By acting as an agonist on GABAA-benzodiazepine Rubus brasiliensis receptor complex receptor complex.

Obovatol GABAA/benzodiazepine Anxiolytic effect mediated by GABA-benzodiazepine receptor complex receptors-activated Cl-channel opening. Trideca-7,9,11- Antianxiety activity was confirmed using the trienoic acid mCPP-induced hypolocomotion test. Cardiospermin valerenic acid GABAA-minergic system Valerenic acid interacts with the GABAA-ergic system, a mechanism of action similar to benzodiazepine drugs.

Ginkgolic acid conjugates 5-HT1, receptor, dopamine Indian Ginkgo biloba extracts (unpuriÞed) containing (GAC) (6-alkylsalicylates, GAC have been found to decrease the serotonin 5-HT , D2 receptor 1 namely n-tridecyl-, receptor binding activity in the frontal cortex and n-pentadecyl-, dopamine D2 receptor binding activity in corpus n-heptadecyl-, striatum. n-pentadecenyl- and n-heptadecenylsalicylates)

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Reviews Review 1

Review Title: Nature: Anxiolytics in the Lap of Nature

Posted by Mr. Girish K Gupta on 06 Oct 2011 10:43:55 AM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Partly 3 Is this a new and original contribution? No 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase Yes the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? No 10 Are the references adequate and are they all necessary? No 11 Are the keywords and abstract or summary informative? Yes

Rating: 6 Comment: The work apppeard to be quite intresting and worth publishing. 1) lot of spelling and grammatical mistakes should be revised. 2) more interpretaions or discussion should be suggested. 3) references should be uniform and correct.

Competing interests: none Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: 2yrs

Publications in the same or a related area of science: No How to cite: Gupta G.Nature: Anxiolytics in the Lap of Nature [Review of the article 'Nature: Anxiolytics in the Lap of Nature ' by ].WebmedCentral 1970;2(10):REVIEW_REF_NUM993

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Review 2

Review Title: accepted

Posted by Dr. Mohamed Ashour on 03 Sep 2011 09:23:25 AM GMT

1 Is the subject of the article within the scope of the subject category? Yes 2 Are the interpretations / conclusions sound and justified by the data? Partly 3 Is this a new and original contribution? No 4 Does this paper exemplify an awareness of other research on the topic? Yes 5 Are structure and length satisfactory? Yes 6 Can you suggest brief additions or amendments or an introductory statement that will increase Yes the value of this paper for an international audience? 7 Can you suggest any reductions in the paper, or deletions of parts? No 8 Is the quality of the diction satisfactory? Yes 9 Are the illustrations and tables necessary and acceptable? No 10 Are the references adequate and are they all necessary? Yes 11 Are the keywords and abstract or summary informative? Yes

Rating: 5 Comment: more discussion and explannation are needed to correlate the activity and different classes of natural products other than flavonoids

Competing interests: no Invited by the author to make a review on this article? : No Experience and credentials in the specific area of science: i havd published 3 original papers, one review article and one book chapter in that field

Publications in the same or a related area of science: Yes References: Genus Bupleurum: a review of its phytochemistry, pharmacology and modes of action How to cite: Ashour M.accepted[Review of the article 'Nature: Anxiolytics in the Lap of Nature ' by ].WebmedCentral 1970;2(9):REVIEW_REF_NUM919

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