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EVALUATION OF ANTIEPILEPTIC AND NOOTROPIC EFFECTS OF GALLIC ACID IN RATS. M. Pharm Dissertation Protocol Submitted to Rajiv Gandhi University of Health Sciences, Karnataka Bangalore – 560 041 By Mr. SHAIK IMRAN B.Pharm Under the Guidance of Dr. Kalyani Divakar M.Pharm, Ph.D. Professor and Head, Department of Pharmacology Acharya & B.M.Reddy College of Pharmacy, Soldevanahalli, Chikkabanavara (Post), Hesaraghatta Main Road, Bangalore – 560 090. 2012-2013 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION 1. Name of the candidate & Address Shaik Imran 8-6-74 Thummala Gadda Khammam(507001) Andhra Pradesh 2. Name of the Institution Acharya & B.M. Reddy College Of Pharmacy Soldevanahalli, Hesaraghatta main Road, Chikkabanavara Post, Bangalore-560090. Phone No: 080 65650815 Fax No: 080 28393541 3. Course of the study & subject M.Pharm (Pharmacology) 4. Date of admission 16/08/2011 5. Title of the Topic Evaluation of antiepileptic and nootropic effects of gallic acid in rats 6. Brief resume of intended work 6.1 Introduction and need of the work 6.2 Review of Literature 6.3 Aim of the study Enclosure I Enclosure II Enclosure III 7. Materials & Methods 7.1 Source of data 7.2 Methods of collection of data 7.3 Does the study require investigation on animals? a. If yes give details 7.4 Has ethical clearance been obtained from your institution in case of 7.3 Enclosure IV Enclosure V Yes. The above study requires investigation on Albino Wistar Rats (either sex) for anti-epileptic and nootropic activities. Enclosed 8. List of references Enclosure VI 9. Signature of the candidate 10. Remarks of the guide RECOMMENDED 11. 11.1. Name & Designation of Guide Dr. Kalyani Divakar, M.Pharm., Ph.D. Professor & Head, Dept. of Pharmacology, Acharya & B.M. Reddy College of Pharmacy. 11.2. Signature of Guide 11.3. Name & Designation of Co-guide Mr. Uday Raj Sharma. M.Pharm Assistant professor Acharya & B.M. Reddy College of Pharmacy. 11.4. Signature of Co-guide 11.5. Name & Signature of HOD Dr. Kalyani Divakar, M.Pharm., Ph.D. Professor & Head, Dept. of Pharmacology, Acharya & B.M. Reddy College of Pharmacy. 12 12.1. Remarks of the Principal 12.2. Name & Signature of Principal Dr.Divakar Goli M.Pharm., Ph.D. Professor & Head, Dept. of Pharmacology, Acharya & B.M. Reddy College of Pharmacy. Chikkabanavara (Post), Bangalore-560090 ENCLOSURE - I 6. BRIEF RESUME OF INTENDED WORK 6.1 NEED OF THE WORK: Epilepsy is a common and diverse set of chronic neurological disorders characterised by seizures1. Epilepsy results from abnormal, excessive (or) hyper synchronous neuronal activity in brain2. Epilepsy is usually controlled but cannot be cured with medication. However over 30% of people with epilepsy do not have seizures controlled even with best available medicines3, 4, 5. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries. Epilepsy is more likely to occur in young children (or) people over the age of 65 years. It can occur at any time6, 7. According to WHO, about 450 million people in the entire world have suffered from mental, neurological, (or) behavioural problems at some time in their life6, 8. This chronic disorder involves alteration in the voltage – dependent ion channels reduction in inhibitory i.e. GABA mediated decrease (or) increase in excitatory i.e. glutamate mediated inputs9. Nootropic:Nootropic also referred as smart drugs. These are mainly used in the treatment of memory and intelligence enhancement10, 11. Memory is the ability of an individual to record sensory stimuli, events, information, etc. to retain them at over a short or long period of time to recall at latter when it needed12. Poor memory, lower retention and slow recall are common problems in today’s stress full and competitive world. Age, stress, emotion may lead to memory loss13, 14, 15, 16. Cognitive disorders are common in patients who are under the treatment of epilepsy. Nootropic agents are used to correct observed cognitive defects17. Nootropics are thought to work by altering the availability of the brain’s supply of neurochemicals (neurotransmitters, enzymes, & hormones), by improving brain’s oxygen supply, or stimulating nerve growth12, 18, 19. The most common cause of dementia is a progressive neurodegenerative disorder associated with loss of neurons in distinct brain areas. The central cholinergic pathway plays a prominent role in learning and memory processes20. Central acting anti muscaranic drugs impair learning and memory in both animals and human beings21 22. The nootropic drugs belong to the class of psychotropic agents with selective facilitator effect on intellectual performance, learning memory23. Gallic acid is also known as gallate. Its IUPAC name is 3, 4, 5 – trihydroxybenzoic acid. Gallic acid is used as starting material in synthesis of psychotic alkaloid mescaline24, 25. Gallic acid has anti fungal and anti viral property26. It has an antioxidant property which helps to protect human cells against oxidative damage. Gallic acid was found to be cytotoxic against cancer cells without harming healthy cells. Also used to treat albuminuria and diabetes25, 26, 27. Based on the literature survey we found that Amla, Tulasi, Ocimum sanctum, Galla rhois are using in treatment of epilepsy however gallic acid is the one of the chemical constituent in treatment of epilepsy. However gallic acid alone having anti epileptic property, and till now no one scientifically evaluated, Hence the parent study is planned to find out antiepileptic and nootropic activities of synthetic gallic acid. ENCLOSURE – II 6.2 REVIEW OF LITERATURE: Gallic acid is a trihydroxybenzoic acid, a type of phenolic acid, a type of organic acid, also known as 3, 4, 5-trihydroxybenzoic acid. The chemical formula is C6H2(OH)3COOH, [C7H6O5]. Gallic acid is found both free and as part of tannins. Therapeutic uses25, 26, 27, 28 1. Anti-fungal 2. Anti-viral 3. Strong antioxidant 4. Cytotoxic agent for cancer cells 5. Astringent in cases of internal haemorrhage 6. Used to treat albuminuria and diabetes. 7. As ointment to treat psoriasis and external haemorrhoids contain gallic acid 8. Also used as a standard for determining the phenol content of various analytes by the Folin-Ciocalteau assay; results are reported in gallic acid equivalents Reported Pharmacological actions. 1. S. Tavassoli and Z. Emam Djomeh shows Antimicrobial Activity of Methanol Extract of Rosemary (Rosmarinus officinalis L.) and they concluded that rosemary extract were a stronger inhibitory effect on the bacteria. Minimum inhibitory concentration values for both bacteria Leuconostoc mesenteroides and Lactobacillus delbruekiiranged between 1. 5 mg/ml and 1.75 mg/ml29. 2. Hari Om Saxena, Uzma Faridi, Suchita Srivastava, Kumar J. K, Darokar M. P, Suaib et.al. Proved that Gallic acid-based indanone derivatives as anticancer agents. In conclusion, gallic acid-based indanone derivatives showed potent anticancer activity against hormone-dependent breast cancer, oral and liver cancer cell lines. As one of the potent molecules was found non-toxic to human erythrocytes, this compound may further be optimised to better anticancer leads with no or low toxicities to normal cells30. ENCLOSURE – III 6.3 AIM OF THE STUDY AIM: To evaluate antiepileptic and nootropic effects of Gallic acid in rats. ENCLOSURE – IV 7. MATERIALS AND METHODS MATERIALS: Chemical: Gallic acid, PTZ, Diazepam, Lithium carbonate, Scopolamine (SigmaAldrich, Bangalore), all other chemicals to be used in this project are of highly analytical grade. Dose: Gallic acid (dose-I)-15mg/kg, Gallic acid (dose-II)-30mg/kg, PTZ-40mg/kg Diazepam-2.0mg/kg, Lithium carbonate-190mg/kg, Scopolamine-1.4mg/kg. Animals: All experiments and protocols proposed in present study will be carried out according to the guidelines of CPCSEA, New Delhi and approved by the Institutional Animal Ethical Committee (IAEC) of Acharya & B. M. Reddy college of Pharmacy, Bangalore. Albino Wistar rats of either sex (150-200gm) will be housed in group of 6 animals per cage and maintained under standard laboratory conditions ( 12-h light/dark cycle, 24hrs) and provided free access to palleted PRANAV AGRO Pvt. Ltd. diet and purified drinking water ad libitium. 7.1 SOURCE OF DATA: The source of data will be obtained from, Laboratory based studies. Literature survey, CD ROM. National & International Journals. Text books. Internet. The sources of data are from experiments on animals which involves the following: To evaluate the antiepileptic and nootropic effects of Gallic acid in animals (Albino Wistar rats). ENCLOSURE – V 7.2 METHOD OF COLLECTION OF DATA 1. Pharmacological studies: To evaluate the antiepileptic and nootropic effects of Gallic acid in animals (albino Wistar rats). I. Healthy Albino Wistar rats (Either sex), weighing between 150-200g will be selected. II. Rats will be randomly divided for two models for epilepsy, one for nootropic with four groups each consisting of Six animals Antiepileptic activity Method (a):- MES model Group 1: vehicle control Group 2: Standard (diazepam) Group 3: Gallic acid (dose I) Group 4: Gallic acid (dose II) All rats will be stimulated with MES simultaneously to produce convulsions. Group-I will be treated with vehicle, group-II with standard drug (diazepam) and group-III & IV with gallic acid of different doses. Each group undergoes pre-treatment for 7 days. Report will be noted by the observation of behavioural studies. Method (b):- PTZ model Group 1: vehicle control Group 2: Standard (diazepam) Group 3: Gallic acid (dose I) Group 4: Gallic acid (dose II) All rats will be treated with PTZ simultaneously to produce convulsions. Group-I will be treated with vehicle, group-II with standard drug (diazepam) and group-III & IV with gallic acid of different doses. Each group undergoes pre-treatment for 7 days. Report will be noted by the observation of behavioural studies. Nootropic Activity Method: - Scopolamine model Group 1: vehicle control Group 2: Standard (lithium carbonate) Group 3: Gallic acid (dose I) Group 4: Gallic acid (dose II) All rats will be treated with scopolamine simultaneously to produce amnesia. Group-I will be treated with vehicle, group-II with standard drug (lithium carbonate) and group-III & IV with gallic acid of different doses. Each group undergoes four trails per day for 7 days. Report will be noted by the observation of behavioural studies. 2. Behavioural studies: A. Antiepilepsy31 a. The number of animals protected from hind limb tonic extension seizure (HLTE). B. Nootropic a. Memory deficit activity32. b. Elevated plus maze model32. c. Passive avoidance activity33. 3. Statistical analysis The data will be expressed as mean ± S.D and will be analyzed using one way ANOVA and Student t-test. The Value of p<0.05 will be considered significant. ENCLOSURE – VI 8. LIST OF REFERENCES: 1. Mizrahi E, Tassinari C, van Emde Boas W, Engel J. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia, 2001; 42:1212-18. 2. World health organization epilepsy (sic), epidemiology and prognosis (online). 2001. (cited2009nov 22). Available from URL: http://www.who.int/mediacenter/factsheets/fs165/en/. 3. The National Society for Epilepsy. What is Epilepsy? 2009. [cited 2009 Nov19] Available from: URL:http://www.epilepsynse.org.uk/AboutEpilepsy/Whatisepilepsy 4. Singal PK. Role of free radicals in catecholamine-induced cardiomyopathy. Can J Physiol Pharmacol 1982; 60: 1390-97 5. Debnath S, Kannadasan M,Ghosh S, Ghosh NS, Chakrborthy R,Sen S. Antiepileptic activity of the hydro alcoholic extract of Erythrina fuscalour bark against the animal models of MES, PTX and PTZ induced epileptic seizure models. Int J Chem 2010; 1 (2):6-10. 6. http://en.wikipedia.org/wiki/Epilepsy. [cited 2009 Nov 19] 7. Enge J. Surgery for seizures. NEJM [online] 1996; 334:647–52. [cited 2009Nov 19] Available from: URL: http://content.nejm.org/cgi/content/extract/334/10/647 8. Dorland’s Medical Dictionary. Archived from the original on 2008-01-30 9. 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Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease & experimental cholinergic denervation. Science 1985.228: 115-17. 16. Whitehouse O. J. Neuronal loss & neurotransmitter receptor alterations in Alzheimer’s disease. In Alzheimer’s & Parkinsonism disease: Strategies for research & development. Plenum New York, 1986, 85-94. 17. Vermeulen J, Aldenkamp AP. Cognitive side-effects of chronic anti-epileptic drug treatment: a review of 25 years of research. Epilepsy Research 1995; 22: 65–95. 18. Girish S Achliya, Barabde U, Wadodkar S, Dorle A. Effect of Bramhi Ghrita, a polyherbal formulation on learning and memory paradigms in experimental animals, Indian Journal of Pharmacology, 2004;36; 3: 159-62. 19. Kulkarni S K, Ashish Dhir, Withania somnifera: An Indian ginseng, Progress in NeuroPsychopharmacology and Biological Psychiatry, 2008; 32; 5(1) 1093-1105 20. Nabeshima T. Behavioral aspects of cholinergic transmission: role of basal forebrain cholinergic system in learning and memory. Progress in Brain Research 98, 1993: 405– 11. 21. Sitaram N, Weingartner H, Gillin JC. Human serial learning. Enhancement with arecholine and choline and impairment with scopolamine. Science;1978; 201, 247–76. 22. Higashida A, Ogawa N. Differences in the acquisition process and the effect of scopolamine on radial maze performance in the strains of rats. Pharmacology Biochemistry and Behavior 1987; 27: 483–89. 23. Giurgea C. The nootropic approach to the pharmacology of the integrative action of the brain. Conditioned Reflex; 1973; 8: 108-15. 24. Reynolds LD, Wilson NG, Scribes and Scholars 3rd Ed. Oxford: 1991.193–94. 25. Tsao, Makepeasce. A New Synthesis of Mescaline. Journal of the American Chemical Society; 195173 (11): 5495–96. 26. Phytochemicals.info 27. Fiuza S M. Phenolic acid derivatives with potential anticancer properties––structure– acids. Activity relationship study. Part 1: Methyl, propyl and octyl esters of caffeic and Gallic 026; Elsevier; 2004. 28. Andrew Waterhouse, UC Davis. Folin-Ciocalteau Micro Method for Total Phenol in Wine. 29. S. Tavassoli and Z. Emam Djomeh Total Phenols, Antioxidant Potential and Antimicrobial Activity of Methanol Extract of Rosemary (Rosmarinus officinalis L.); 2011; 7 (4): 337-41. 30. Hari Om Saxena, Uzma Faridi, Suchita Srivastava, Kumar J K, Darokar M P, Suaib Luqman et.al. Gallic acid-based indanone derivatives as anticancer agents. Journal of Ethno pharmacology. elsevier.com; 2008; 18: 3914–18. 31. Jiban Debnath, Uday Raj Sharma, Bimlesh Kumar, Nitesh Singh Chauhan. Anticonvulsant activity of ehanolic extracts of fruits of Terminalia chebula on experimental animals. International Journal of Drug Development & Research; 2010: 2(4). 32. Bhupendra Chauhan, Amrendra Kumar Chaudhary. Memory enhancing activity of methanolic extract of Pterocarpus Marsupium Roxb. Phytopharmacology 2012, 2(1) 7280. 33. Das A, Shanker G, Nath C, Pal R, Singh S, Singh HA. Pharmacol. Biochem. 2002; 73(4): 893-900.