Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease
Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease
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DOI：
10.1523/jneurosci.22-05-01763.2002
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发表时间：
2002-03-01
影响因子：
5.3
通讯作者：
Przedborski, S
中科院分区：
文献类型：
--
作者：
Wu, DC;Jackson-Lewis, V;Przedborski, S
1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）损害黑质纹状体多巴胺能通路，如在帕金森病（PD）中所见，帕金森病是一种常见的神经退行性疾病，没有有效的保护性治疗。与胶质细胞在PD神经变性中的作用一致，在这里，我们表明米诺环素，一种批准的四环素衍生物，抑制小胶质细胞的激活，独立于其抗菌性能，减轻黑质纹状体多巴胺能神经元的死亡和MPTP产生的硝基酪氨酸的形成。此外，我们发现，米诺环素不仅可以防止MPTP诱导的小胶质细胞活化，而且还可以防止成熟白细胞介素-1 β的形成以及NADPH氧化酶和诱导型一氧化氮合酶（iNOS）的活化，这三种关键的小胶质细胞衍生的细胞毒性介质。以前，我们证明了iNOS的消融减弱MPTP诱导的神经毒性。现在，我们证明了iNOS不是MPTP诱导毒性中唯一与小胶质细胞相关的罪魁祸首，因为用米诺环素治疗的突变型iNOS缺陷小鼠比未用米诺环素治疗的iNOS缺陷小鼠对这种神经毒素更具抗性。这项研究表明，小胶质细胞相关的炎症事件在MPTP神经毒性过程中发挥了重要作用，并表明米诺环素可能是一种有价值的神经保护剂，用于治疗PD。
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages the nigrostriatal dopaminergic pathway as seen in Parkinson's disease (PD), a common neurodegenerative disorder with no effective protective treatment. Consistent with a role of glial cells in PD neurodegeneration, here we show that minocycline, an approved tetracycline derivative that inhibits microglial activation independently of its antimicrobial properties, mitigates both the demise of nigrostriatal dopaminergic neurons and the formation of nitrotyrosine produced by MPTP. In addition, we show that minocycline not only prevents MPTP-induced activation of microglia but also the formation of mature interleukin-1beta and the activation of NADPH-oxidase and inducible nitric oxide synthase (iNOS), three key microglial-derived cytotoxic mediators. Previously, we demonstrated that ablation of iNOS attenuates MPTP-induced neurotoxicity. Now, we demonstrate that iNOS is not the only microglial-related culprit implicated in MPTP-induced toxicity because mutant iNOS-deficient mice treated with minocycline are more resistant to this neurotoxin than iNOS-deficient mice not treated with minocycline. This study demonstrates that microglial-related inflammatory events play a significant role in the MPTP neurotoxic process and suggests that minocycline may be a valuable neuroprotective agent for the treatment of PD.