Protection of dopaminergic neurons with a novel astrocyte modulating agent (R)-(-)-2-propyloctanoic acid (ONO-2506) in an MPTP-mouse model of Parkinson's disease

被引:31
作者
Kato, H
Araki, T
Imia, Y
Takahashi, A
Itoyama, Y
机构
[1] Tohoku Univ, Dept Neurol, Sch Med, Aoba Ku, Sendai, Miyagi 9808574, Japan
[2] Tohoku Univ, Grad Sch Med, Dept Neuroendovasc Therapy, Aoba Ku, Sendai, Miyagi 9808574, Japan
[3] Tohoku Univ, Grad Sch Pharmaceut Sci & Med, Dept Clin Pharmacol & Therapeut, Sendai, Miyagi 980, Japan
基金
日本学术振兴会;
关键词
MPTP; Parkinson's disease; dopamine; ONO-2506; neuroprotection; astrocytes; mice;
D O I
10.1016/S0022-510X(02)00411-2
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
We examined the neuroprotective effects of a novel astrocyte-modulating agent, (R)-( -)-2-propyloctanoic acid (ONO-2506), in a mouse model of Parkinson's disease. Male C57BL/6 mice received four intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (10 mg/kg) at 1-h intervals. Dopamine content in the striatum, measured with HPLC 3 days after MPTP injection, was reduced to 23% of control. But this dopamine depletion was dose-dependently prevented by repeated treatments with ONO-2506 (3, 10 and 30 mg/kg, i.p.) administered 1, 6, 24 and 48 h after MPTP injection (51% of control in 30 mg/kg group, p<0.01). ONO-2506 treatment (30 mg/kg) started after 6 h, followed by treatments at 24 and 48 la, also prevented the reduction of dopamine content (42% of control vs. 11% of control in the saline-treated group, p<0.01). We also performed immunohistochemistry for tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP). The MPTP injection resulted in a loss of TH-positive dopaminergic neurons (42% of control, p<0.01) in the substantia nigra after 7 days, but ONO-2506 treatment prevented this neuronal loss (70% of control, p<0.01). The MPTP injection led to reactive astrocytosis in the striatum after 7 days, but ONO-2506 induced earlier, moderate astrocytic activation after 3-7 days. These findings show that ONO-2506 protects dopaminergic neurons against MPTP neurotoxicity probably through facilitating astrocytic support for neuronal recovery from injury. Pharmacological modulation of astrocytes may offer a novel therapeutic strategy for Parkinson's disease. (C) 2003 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:9 / 15
页数:7
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