Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University, Chandigarh, India.
Br J Pharmacol. 2011 Sep;164(2b):644-54. doi: 10.1111/j.1476-5381.2011.01418.x.
Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by a degeneration of striatal neurons. The possible role of COX and lipoxygenase (LOX) pathways has been well-documented in the pathology of several neurodegenerative disorders including HD. Licofelone is a competitive inhibitor of COX-1- and COX-2 and 5-LOX isoenzymes. Therefore, the present study was designed to investigate possible neuroinflammatory and apoptotic mechanisms in the neuroprotective effect of licofelone against 3-nitropropionic acid (3-NP)-induced HD-like symptoms in rats.
Rats were administered 3-NP (10 mg·kg⁻¹ day⁻¹, i.p.) for 14 days. Licofelone (2.5, 5 and 10 mg·kg⁻¹, p.o.) was given once a day, 1 h before 3-NP treatment for 14 days. Body weight and behavioural parameters (locomotor and rotarod activity) were assessed on the 1st, 5th, 10th and 15th day post-3-NP administration. Malondialdehyde, nitrite concentration, endogenous antioxidant enzymes (superoxide dismutase and catalase levels), mitochondrial enzyme complexes, pro-inflammatory compounds (TNF-α, IL-6, NF-κB), PGs (PGE₂ and PGF(2α)) and caspase-3 activity were measured on day 15 in the striatum.
Systemic 3-NP treatment significantly reduced body weight, locomotor activity, oxidative defence, mitochondrial enzyme complex activities and increased TNF-α, IL-6, caspase-3 activity, NF-κB and PGE₂ and PGF(2α) levels in the striatum. Licofelone (2.5, 5 and 10 mg·kg⁻¹) significantly attenuated the impairment in behavioural, biochemical and mitochondrial, pro-inflammatory and pro-apoptotic markers as compared with vehicle-treated group.
The results demonstrate the involvement of pro-inflammatory compounds and the apoptotic cascade in the neuroprotective effect of licofelone against 3-NP-induced neurotoxicity.
亨廷顿病（HD）是一种进行性神经退行性疾病，其特征在于纹状体神经元的退化。环加氧酶（COX）和脂氧合酶（LOX）途径的可能作用在包括 HD 在内的几种神经退行性疾病的病理学中已有很好的记载。依托考昔是 COX-1 和 COX-2 以及 5-LOX 同工酶的竞争性抑制剂。因此，本研究旨在探讨依托考昔对 3-硝基丙酸（3-NP）诱导的大鼠类似 HD 症状的神经保护作用的可能神经炎症和细胞凋亡机制。
大鼠腹腔注射 3-NP（10mg·kg⁻¹·天⁻¹）14 天。依托考昔（2.5、5 和 10mg·kg⁻¹，po）每天一次，在 3-NP 处理前 1 小时给予，共 14 天。在 3-NP 给药后第 1、5、10 和 15 天评估体重和行为参数（运动和转棒活动）。在纹状体中，于第 15 天测量丙二醛、亚硝酸盐浓度、内源性抗氧化酶（超氧化物歧化酶和过氧化氢酶水平）、线粒体酶复合物、促炎化合物（TNF-α、IL-6、NF-κB）、PGs（PGE₂和 PGF（2α））和 caspase-3 活性。
系统 3-NP 处理显著降低了体重、运动活性、氧化防御、线粒体酶复合物活性，并增加了 TNF-α、IL-6、caspase-3 活性、NF-κB 和 PGE₂和 PGF（2α）水平在纹状体中。与载体处理组相比，依托考昔（2.5、5 和 10mg·kg⁻¹）显著减弱了行为、生化和线粒体、促炎和促凋亡标志物的损伤。
结果表明，促炎化合物和凋亡级联在依托考昔对 3-NP 诱导的神经毒性的神经保护作用中起作用。
