Division of Pharmacology, Central Drug Research Institute, P.O. Box 173, Lucknow (U.P.) 226001, India.
Pharmacol Biochem Behav. 2011 Dec;100(2):311-9. doi: 10.1016/j.pbb.2011.08.019. Epub 2011 Aug 26.
Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction.
线粒体异常已在很大比例的神经退行性疾病中被发现。最近我们报道了脑室（ICV）内给予岗田酸（OKA）可导致大鼠记忆障碍。然而，线粒体功能是否参与 OKA 诱导的记忆障碍和神经元损伤尚未确定。通过脑室途径给予 OKA（200ng）。在 OKA 给药 13 天后，通过 Morris 水迷宫试验评估记忆功能。在第 16 天完成行为研究后，评估大鼠大脑皮质、海马、纹状体和小脑线粒体制剂中的线粒体膜电位、Ca（2+）和活性氧。同时研究大鼠脑区突触体制剂中的 ATP、线粒体活性、脂质过氧化和亚硝酸盐。研究了大鼠脑区凋亡因子 caspase-3 和 caspase-9 的活性和 mRNA 表达。通过组织病理学研究证实了神经元损伤。OKA 处理的大鼠表现出记忆障碍，包括线粒体制剂中 Ca（2+）和活性氧增加，线粒体膜电位、ATP 和线粒体活性降低。突触体制剂中的脂质过氧化和亚硝酸盐显著增加。用抗痴呆药物多奈哌齐（5mg/kg，po）和美金刚（10mg/kg，po）每天预防性治疗 13 天，可显著减轻 OKA 诱导的线粒体功能障碍、凋亡细胞死亡、记忆障碍和组织学变化。线粒体功能障碍似乎是 OKA 诱导记忆障碍和凋亡细胞死亡的关键因素。这项研究表明，临床上使用的抗痴呆药物可有效对抗 OKA 诱导的行为、细胞和组织学水平以及线粒体功能障碍的不良反应。
