title: Possible GABAergic mechanism in the neuroprotective effect of gabapentin and lamotrigine against 3-nitropropionic acid induced neurotoxicity.
abstract: Huntington's disease is a progressive neurodegenerative disorder that gradually reduces memory, cognitive skills and normal movements of affected individuals. Systemic administration of 3-Nitropropionic acid induces selective striatal lesions in rodents and non-human primates. Therefore, the present study has been designed to elucidate the comparative mechanistic profile of gabapentin, lamotrigine and their interactions with GABAergic modulators against 3-Nitropropionic acid induced neurotoxicity. Systemic 3-Nitropropionic acid (10 mg/kg) administration for 14 days significantly reduced body weight, locomotor activity, grip strength, oxidative defense (LPO, nitrite, SOD and catalase) and impaired mitochondrial complex enzyme (I, II, IV and MTT assay) activities in the striatum. 3-Nitropropionic acid treatment also increased TNF-α level in the striatum. Gabapentin (50 and 100 mg/kg) and lamotrigine (10, 20 and 40 mg/kg) treatments significantly restored behavioural, oxidative defense and mitochondrial complex enzyme activities and proinflammatory markers (TNF-α) as compared to 3-Nitropropionic acid treated group. Systemic picrotoxin (1 mg/kg) pretreatment with sub effective dose of gabapentin (50 mg/kg) or lamotrigine (20mg/kg) significantly attenuated their protective effect. Further, GABA (50 mg/kg) and/or muscimol (0.05 mg/kg) pretreatment with sub effective dose gabapentin (50 mg/kg) and lamotrigine (20 mg/kg) significantly potentiated their protective effects which were significant as compared to their effect alone. The results of the present study suggest that a GABAergic mechanism is involved in the protective effect of gabapentin and lamotrigine against 3-Nitropropionic acid induced neurotoxicity.
authors.affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre for Advanced Study, Panjab University, Chandigarh-160014, India.
authors.forename: Puneet
authors.initials: P
authors.lastname: Kumar
authors.forename: Harikesh
authors.initials: H
authors.lastname: Kalonia
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D059330:GABAergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000077206:Gabapentin; D006816:Huntington Disease / Q000473:pathology; D000077213:Lamotrigine; D015227:Lipid Peroxidation / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D009573:Nitrites / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D013482:Superoxide Dismutase / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009573:Nitrites; D009574:Nitro Compounds; D011422:Propionates; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D002374:Catalase; D013482:Superoxide Dismutase; C015392:3-nitropropionic acid; D000077213:Lamotrigine