title: Impaired motor learning attributed to altered AMPA receptor function in the cerebellum of rats with temporal lobe epilepsy: ameliorating effects of Withania somnifera and withanolide A.
abstract: The aim of this study was to investigate the effect of Withania somnifera (WS) extract, withanolide A (WA), and carbamazepine (CBZ) on cerebellar AMPA receptor function in pilocarpine-induced temporal lobe epilepsy (TLE). In the present study, motor learning deficit was studied by rotarod test, grid walk test, and narrow beam test. Motor learning was significantly impaired in rats with epilepsy. The treatment with WS and WA significantly reversed the motor learning deficit in rats with epilepsy when compared with control rats. There was an increase in glutamate content and IP3 content observed in rats with epilepsy which was reversed in WS- and WA-treated rats with epilepsy. alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor dysfunction was analyzed using radiolabeled AMPA receptor binding assay, AMPA receptor mRNA expression, and immunohistochemistry using anti-AMPA receptor antibody. Our results suggest that there was a decrease in Bmax, mRNA expression, and AMPA receptor expression indicating AMPA receptor dysfunction, which is suggested to have contributed to the motor learning deficit observed in rats with epilepsy. Moreover, treatment with WS and WA resulted in physiological expression of AMPA receptors. There was also alteration in GAD and GLAST expression which supplemented the increase in extracellular glutamate. The treatment with WS and WA reversed the GAD and GLAST expression. These findings suggest that WS and WA regulate AMPA receptor function in the cerebellum of rats with TLE, which has therapeutic application in epilepsy.
authors.affiliation: Molecular Neurobiology and Cell Biology Unit, Centre for Neuroscience, Department of Biotechnology, Cochin University of Science and Technology, Cochin 682 022, Kerala, India.
authors.forename: Smijin
authors.initials: S
authors.lastname: Soman
authors.forename: T R
authors.initials: TR
authors.lastname: Anju
authors.forename: S
authors.initials: S
authors.lastname: Jayanarayanan
authors.forename: Sherin
authors.initials: S
authors.lastname: Antony
authors.forename: C S
authors.initials: CS
authors.lastname: Paulose
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002220:Carbamazepine / Q000627:therapeutic use; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000473:pathology / Q000628:therapy; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007859:Learning Disabilities / Q000209:etiology*; D016014:Linear Models; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D008517:Phytotherapy; D010862:Pilocarpine / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics; D032341:Withania; D054358:Withanolides / Q000627:therapeutic use*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000493:pharmacokinetics
chemical_list: C433551:3-rhamnopyranosyl(1-4)-glucopyranosyl-12-diacetoxy-20-hydroxywitha-5,24-dienolide; D000927:Anticonvulsants; D027341:Excitatory Amino Acid Transporter 1; D012333:RNA, Messenger; D018091:Receptors, AMPA; D054358:Withanolides; D010862:Pilocarpine; D014316:Tritium; D002220:Carbamazepine; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015544:Inositol 1,4,5-Trisphosphate; D005968:Glutamate Decarboxylase