Kato Hiroyuki, Kurosaki Rumiko, Oki Chie, Araki Tsutomu
Department of Neurology, Center for Clinical Medicine and Research, International University of Health and Welfare, 537-3 Iguchi, Nishinasuno, Tochigi 329-2763, Japan.
Brain Res. 2004 Dec 24;1030(1):66-73. doi: 10.1016/j.brainres.2004.09.046.
We examined the neuroprotective effects of a novel astrocyte-modulating agent, arundic acid (ONO-2506), in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of MPTP (20 mg/kg) at 2 h intervals. Dopamine content in the striatum was reduced to 21% of the normal control after 7 days. Treatment with arundic acid (30 mg/kg, i.p.) administered 1 min, 6 h, 24 h, 48 h, and 72 h after the last MPTP injection prevented the dopamine depletion (52% of the control, p<0.01). In addition, this treatment resulted in behavioral benefits. Behavioral testing showed that MPTP-injected mice exhibited motor deficits in the pole test and catalepsy test after 7 days, but arundic acid prevented the appearance of motor abnormalities in these tests. The MPTP-injected animals exhibited an 87% loss of tyrosine hydroxylase-containing dopaminergic neurons in the substantia nigra after 7 days, but the arundic acid-treated mice showed only a 56% reduction (p<0.01). GFAP-positive reactive astrocytes were accumulated in the striatum and substantia nigra 7 days after the MPTP injection, whereas arundic acid treatment induced an earlier appearance of reactive astrocytes by 3 days. The reactive astrocytes increased the production of S-100 protein, which is thought to promote neuronal damage, but arundic acid suppressed the expression of S-100. Thus, arundic acid protected dopaminergic neurons against MPTP neurotoxicity in mice and ameliorated neurological deficits. The results suggest that the neuroprotection is mediated through the modulation of astrocytic activation, including the inhibition of S-100 protein synthesis.
我们在帕金森病的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）小鼠模型中研究了一种新型星形胶质细胞调节剂阿润地酸（ONO-2506）的神经保护作用。雄性C57BL/6小鼠每隔2小时接受4次腹腔注射MPTP（20mg/kg）。7天后，纹状体中的多巴胺含量降至正常对照的21%。在最后一次MPTP注射后1分钟、6小时、24小时、48小时和72小时腹腔注射阿润地酸（30mg/kg）可防止多巴胺耗竭（为对照的52%，p<0.01）。此外，这种治疗还带来了行为改善。行为测试表明，注射MPTP的小鼠在7天后在转棒试验和僵住试验中表现出运动缺陷，但阿润地酸可防止这些试验中运动异常的出现。注射MPTP的动物在7天后黑质中含酪氨酸羟化酶的多巴胺能神经元损失了87%，但经阿润地酸治疗的小鼠仅减少了56%（p<0.01）。MPTP注射7天后，GFAP阳性反应性星形胶质细胞在纹状体和黑质中积聚，而阿润地酸治疗使反应性星形胶质细胞提前3天出现。反应性星形胶质细胞增加了S-100蛋白的产生，而S-100蛋白被认为会促进神经元损伤，但阿润地酸抑制了S-100的表达。因此，阿润地酸保护多巴胺能神经元免受MPTP对小鼠的神经毒性，并改善神经功能缺损。结果表明，神经保护作用是通过调节星形胶质细胞的激活介导的，包括抑制S-100蛋白的合成。
