Kuang Xi, Du Jun-Rong, Liu Yan-Xin, Zhang Guang-Yi, Peng Hai-Yan
Department of Pharmacology, Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University West China School of Pharmacy, Chengdu, PR China 610041.
Pharmacol Biochem Behav. 2008 Jan;88(3):213-21. doi: 10.1016/j.pbb.2007.08.006. Epub 2007 Aug 24.
Previous studies have demonstrated that Z-Ligustilide (LIG), a characterized phthalide constituent present in numerous medical Umbelliferae plants, has significant neuroprotective effects in transient forebrain ischemia and permanent cerebral focal ischemia. The present study further investigated the effect of LIG on chronic cerebral hypoperfusion. Male Wistar rats were subjected to permanent ligation of both common carotid arteries (2VO). On Days 8-12 postsurgery, rat cognition was assessed in the Morris water maze. Rats with significantly impaired acquisition of spatial information were randomly allocated to three groups and orally administered LIG (10 or 40 mg/kg/day) or volume-matched vehicle on Days 13-40 post-2VO surgery. The sham-operated group served as controls. After long-term treatment with LIG, the impaired animals' behavioral, biochemical, and histopathological features were examined. Compared to the sham-operated group, significant cognitive impairment was observed in the vehicle-treated group 40 days after 2VO. Shortened mean escape latency was detected in the Morris water maze in rats treated with LIG (p<0.01 vs. vehicle-treated group) during the same trial days. Chronic 2VO-induced pathological changes included neuronal loss and an increase of glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes in the hippocampus. These effects were prevented with LIG treatment (p<0.01 vs. vehicle-treated group). LIG also significantly reduced malondialdehyde levels and increased superoxide dismutase activity in ischemic brain tissue (p<0.05 and p<0.01 vs. vehicle-treated group). In addition, LIG significantly increased choline acetyltransferase activity and inhibited acetylcholinesterase activity in ischemic brain tissues (p<0.05 and p<0.01 vs. vehicle-treated group). The present data demonstrate that LIG significantly prevented chronically hypoperfused cognitive deficits and brain damage at least partly through an antioxidant effect and improved cholinergic activity. The present findings suggest that LIG may have therapeutic potential in treating vascular dementia and cerebrovascular insufficiency.
先前的研究表明，Z-藁本内酯（LIG）是众多药用伞形科植物中一种具有特征性的苯酞类成分，在短暂性前脑缺血和永久性脑局部缺血中具有显著的神经保护作用。本研究进一步探讨了LIG对慢性脑灌注不足的影响。雄性Wistar大鼠接受双侧颈总动脉永久性结扎（2VO）。在术后第8 - 12天，通过莫里斯水迷宫评估大鼠的认知能力。空间信息获取能力显著受损的大鼠在2VO手术后第13 - 40天被随机分为三组，分别口服LIG（10或40 mg/kg/天）或等体积的溶剂，假手术组作为对照。长期给予LIG治疗后，检测受损动物的行为、生化和组织病理学特征。与假手术组相比，2VO术后40天，溶剂治疗组出现显著的认知障碍。在同一试验天数内，LIG治疗的大鼠在莫里斯水迷宫中的平均逃避潜伏期缩短（与溶剂治疗组相比，p<0.01）。慢性2VO诱导的病理变化包括海马神经元丢失和胶质纤维酸性蛋白（GFAP）免疫反应性星形胶质细胞增多。LIG治疗可预防这些效应（与溶剂治疗组相比，p<0.01）。LIG还显著降低了缺血脑组织中的丙二醛水平并提高了超氧化物歧化酶活性（与溶剂治疗组相比，p<0.05和p<0.01）。此外，LIG显著提高了缺血脑组织中的胆碱乙酰转移酶活性并抑制了乙酰胆碱酯酶活性（与溶剂治疗组相比，p<0.05和p<0.01）。目前的数据表明，LIG至少部分通过抗氧化作用和改善胆碱能活性显著预防了慢性灌注不足引起的认知缺陷和脑损伤。目前的研究结果表明，LIG在治疗血管性痴呆和脑血管功能不全方面可能具有治疗潜力。
