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パーキンソン病(PD)黒質線条体ドパミン(DA)神経の選択的細胞死の原因は不明であったが,少しずつ変性機序が明らかにされつつある。われわれはPD脳(線条体)と脳室・脊椎脳脊髄液にTNF-α,IL-1β,IL-2,IL-4,IL-6,EGF,TGF-α,TGF-β1などのサイトカイン類が増加することを見出し,PD脳内の神経細胞死に炎症反応や免疫反応およびアポトーシスが重要な役割を担うことを提唱してきた(サイトカイン仮説)。PDモデル動物においても,MPTP-PDマウスの線条体にIL-1βの増加,また6-OHDA半側PDラットの傷害側黒質線条体にTNF-αの増加を見出し,PD脳内で観察された結果を再現できた。また,神経栄養因子であるBDNFとNGFが,PD脳およびMPTP-PDマウスで減少することを見出した。TNF-αやIL-1βなどの炎症性サイトカインの増加とBDNFやNGFの減少は神経およびその支持細胞(グリア細胞)にアポトーシスを誘導する原因となりうる。
Parkinson's disease (PD) is an aging-related neurodegenerative disorder with motor disturbances and is characterized by selective neuronal cell death of the nigrostriatal dopamine (DA) neurons by unknown causes. Sporadic PD is thought to be caused by the combined effects of the genes related to the risk factors and some environmental factors such as neurotoxins. We found for the first time that the levels of cytokines related to inflammatory or immune responses such as TNF-α, IL-1β, IL-2, IL-4, IL-6, EGF, TGF-a and TGF-β1 are increased in the brain (striatum) and in ventricular and spinal cerebrospinal fluid in PD. We also found increased IL-1β levels in the striatum of MPTP-treated PD mice, and increased TNF-α levels in the lesioned side of the substantia nigra and striatum of 6-0HDA-treated hemiparkinsonian rats. We also found that neurotrophins of NGF superfamily, BDNF and NGF, were drastically decreased in the substantia nigra, striatum, and putamen in PD. These increases in the levels of proinflammatory cytokines such as TNF-α or IL-1β, or the decreased levels of apoptosis-related neurotrophins such as BDNF may induce apoptosis.
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