Sugama Shuei, Takenouchi Takato, Kitani Hiroshi, Fujita Masayo, Hashimoto Makoto
Department of Physiology, Nippon Medical School, Tokyo, Japan.
J Neuroimmunol. 2009 Mar 31;208(1-2):104-14. doi: 10.1016/j.jneuroim.2009.01.016. Epub 2009 Feb 7.
The present study compared 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced microglial activation in 3 different groups, sham-operated (SHM) mice, adrenalectomized mice (ADX), and ADX mice administered with corticosterone (ADX + CORT), to investigate the roles of glucocorticoids on microglial activation and dopaminergic neurodegeneration. Acute MPTP treatment induced moderate tyrosine hydroxylase (TH)-immunoreactive neuronal loss in the substantia nigra (SN) of SHM mice; this neuronal loss was significantly enhanced in ADX mice, but eventually recovered following the administration of corticosterone. Consistent with neuronal findings, acute MPTP treatment induced microglial activation in the SN from 1-3 days post injection in SHM mice. Interestingly, microglial activation was further enhanced and occasionally showed a phagocytic morphology in ADX mice that showed no circulating corticosterone. Furthermore, the activated microglia was significantly suppressed by the administration of corticosterone to ADX mice. Moreover, a confocal microscopic study demonstrated that the expression of inducible nitric oxide synthase protein, exclusively colocalized with activated microglia in the SN in ADX mice, was substantially decreased by the administration of corticosterone. Thus, the present study, using in-vivo adrenalectomy for a dopaminergic neurodegeneration model, successfully demonstrated the neuroprotective effects of corticosterone by microglial inhibition.
本研究比较了1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的3个不同组小鼠的小胶质细胞激活情况，即假手术（SHM）小鼠、肾上腺切除小鼠（ADX）以及给予皮质酮的ADX小鼠（ADX + CORT），以研究糖皮质激素在小胶质细胞激活和多巴胺能神经变性中的作用。急性MPTP处理导致SHM小鼠黑质（SN）中中度酪氨酸羟化酶（TH）免疫反应性神经元丢失；这种神经元丢失在ADX小鼠中显著增强，但在给予皮质酮后最终恢复。与神经元研究结果一致，急性MPTP处理在SHM小鼠注射后1至3天诱导SN中小胶质细胞激活。有趣的是，在没有循环皮质酮的ADX小鼠中，小胶质细胞激活进一步增强，偶尔呈现吞噬形态。此外，给ADX小鼠给予皮质酮可显著抑制激活的小胶质细胞。此外，共聚焦显微镜研究表明，在ADX小鼠的SN中，诱导型一氧化氮合酶蛋白的表达仅与激活的小胶质细胞共定位，给予皮质酮后该蛋白表达大幅下降。因此，本研究通过对多巴胺能神经变性模型进行体内肾上腺切除，成功证明了皮质酮通过抑制小胶质细胞发挥神经保护作用。
