A neuroprotective agent, T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy]propyl} azetidin-3-ol maleate), prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice
A neuroprotective agent, T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy]propyl} azetidin-3-ol maleate), prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in mice
复制标题
DOI：
10.1016/j.neuropharm.2008.05.032
复制
发表时间：
2008-10-01
影响因子：
4.7
通讯作者：
Matsuda, Toshio
中科院分区：
文献类型：
--
作者：
Kawasaki, Toshiyuki;Ago, Yukio;Matsuda, Toshio
T-817MA (1-{3-[2-(1-苯并噻吩-5-基)乙氧基]丙基]氮杂丁-3-醇马来酸酯)是阿尔茨海默病的候选治疗剂，可抑制氧化应激和一氧化氮诱导的神经毒性，并充当神经营养因子。本研究探讨了 T-817MA 对 C57BL/6J 小鼠中 1-甲基-4苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的多巴胺能神经毒性的影响。 MPTP 治疗（10 mg/kg，s.c. x 4，间隔 2 小时）损害了转棒性能，而 T-817MA 改善了这种缺陷。 MPTP 治疗还降低了黑质 (SNc) 和纹状体中的多巴胺水平和酪氨酸羟化酶免疫染色。用 T-817MA（T-817 为 10 和 30 mg/kg，口服）预处理可减弱多巴胺水平和酪氨酸羟化酶免疫反应性的降低，但不影响 1-甲基-4-苯基吡啶鎓离子（MPTP 的活性代谢物）的脑水平。 SNc 中的保护作用几乎是完全的，但纹状体中的保护作用仅是部分的。 MPTP仅增加中脑中脂质过氧化产物硫代巴比妥酸反应物质的水平，该物质可被T-817MA阻断。 MPTP 引起 SNc 和纹状体中的小胶质细胞活化，但 T-817MA 不影响小胶质细胞的活化。这些结果表明，T-817MA 通过阻断 SNc 中的脂质过氧化来防止 MPTP 诱导的神经毒性，并暗示该化合物可能可用于治疗与氧化应激相关的神经退行性疾病，例如帕金森病。 (c) 2008 Elsevier Ltd. 保留所有权利。
T-817MA (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl] azetidin-3-ol maleate) is a candidate therapeutic agent for Alzheimer's disease that inhibits oxidative stress and nitric oxide-induced neurotoxicity and acts as a neurotrophic factor. The present study examines the effect of T-817MA on 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity in C57BL/6J mice. MPTP treatment (10 mg/kg, s.c. x 4 at 2-h intervals) impaired rotarod performance, and T-817MA improved this deficit. MPTP treatment also decreased dopamine levels and tyrosine hydroxylase immunostaining in the substantia nigra (SNc) and striatum. Pretreatment with T-817MA (10 and 30 mg/kg as T-817, p.o.) attenuated these decreases in dopamine levels and tyrosine hydroxylase immunoreactivity, but did not affect brain levels of 1-methyl-4-phenylpyridinium ion, an active metabolite of MPTP. The protective effect was almost complete in the SNc, but only partial in the striatum. MPTP increased levels of the lipid peroxidation product, thiobarbituric acid reactive substance, only in the midbrain, which could be blocked by T-817MA. MPTP caused microglial activation both in the SNc and striatum, but T-817MA did not affect the activation of microglia. These results suggest that T-817MA protects against MPTP-induced neurotoxicity by blocking lipid peroxidation in the SNc, and imply that this compound may be useful for treating neurodegenerative disorders related to oxidative stress, such as Parkinson's disease. (c) 2008 Elsevier Ltd. All rights reserved.