Platelet-activating factor receptor knockout mice are protected from MPTP-induced dopaminergic degeneration

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• 作者：Beom Keun Kim ; Eun-Joo Shin ; Hyoung-Chun Kim ; Yoon Hee Chung ; Duy-Khanh Dang ; Bae-Dong Jung ; Dae-Hun Park ; Myung Bok Wie ; Won-Ki Kim ; Takao Shimizu ; Toshitaka Nabeshima ; Ji Hoon Jeong
• 关键词：Platelet-activating factor receptor ; Parkinson&rsquo ; s disease ; Striatum ; Dopamine ; Nuclear factor kappa B ; Microglia ; Oxidative damage
• 刊名：Neurochemistry International
• 出版年：2013
• 出版时间：September, 2013
• 年：2013
• 卷：63
• 期：3
• 页码：121-132
• 全文大小：2401 K

文摘

Platelet-activating factor (PAF), a potent mediator of inflammatory and immune responses, plays various roles in neuronal functions. However, little is known about the role of PAF/platelet-activating factor receptor (PAF-R) in Parkinson¡¯s disease. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in significant increases in PAF species in the striatum of wild-type mice. These increases paralleled PAF-R gene expression in wild-type mice. Although nuclear factor kappa B (NF-¦ÊB) DNA-binding activity was increased significantly in MPTP-treated wild-type mice, this increase was not significant in PAF-R antagonist ginkgolide B (GB)-treated mice or PAF-R knockout (PAF-R^?/?) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-¦ÊB inhibitor, significantly ameliorated the dopaminergic deficits induced by MPTP in wild-type mice. MPTP treatment significantly increased oxidative damage, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglial cells, and microglial differentiation of the M1 type in the striatum of wild-type mice. Consistently, PDTC significantly attenuated MPTP-induced behavioral impairments in wild-type mice. However, dopaminergic deficits, oxidative damage, reactive microglial cells, and behavioral impairments induced by MPTP were not significantly observed in GB-treated mice or PAF-R^?/? mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R^?/? mice, indicating that NF-¦ÊB is a critical target for neurotoxic modulation of PAF-R. We propose for the first time that PAF/PAF-R can mediate dopaminergic degeneration via an NF-¦ÊB-dependent signaling process.