Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre for Advanced Study, Panjab University, Chandigarh-160014, India.
Eur J Pharmacol. 2012 Jan 15;674(2-3):265-74. doi: 10.1016/j.ejphar.2011.11.030. Epub 2011 Nov 28.
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.
亨廷顿病是一种进行性神经退行性疾病，会逐渐降低患者的记忆、认知技能和正常运动能力。3-硝基丙酸的系统给药会在啮齿动物和非人类灵长类动物中引起选择性纹状体损伤。因此，本研究旨在阐明加巴喷丁、拉莫三嗪及其与 GABA 能调节剂相互作用对 3-硝基丙酸诱导的神经毒性的比较机制特征。连续 14 天给予系统 3-硝基丙酸（10mg/kg）显著降低了体重、运动活性、握力、氧化防御（LPO、亚硝酸盐、SOD 和过氧化氢酶）以及纹状体中线粒体复合酶（I、II、IV 和 MTT 测定）的活性。3-硝基丙酸处理还增加了纹状体中的 TNF-α 水平。与 3-硝基丙酸处理组相比，加巴喷丁（50 和 100mg/kg）和拉莫三嗪（10、20 和 40mg/kg）治疗显著恢复了行为、氧化防御和线粒体复合酶活性以及促炎标志物（TNF-α）。与单独使用加巴喷丁（50mg/kg）或拉莫三嗪（20mg/kg）相比，系统给予小剂量皮可托品（1mg/kg）预处理可显著减弱其保护作用。此外，GABA（50mg/kg）和/或 muscimol（0.05mg/kg）预处理加巴喷丁（50mg/kg）和拉莫三嗪（20mg/kg）的亚有效剂量显著增强了它们的保护作用，与单独使用相比具有统计学意义。本研究结果表明，GABA 能机制参与了加巴喷丁和拉莫三嗪对 3-硝基丙酸诱导的神经毒性的保护作用。
