期刊
NEUROCHEMISTRY INTERNATIONAL
卷 63, 期 3, 页码 121-132出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2013.05.010
关键词
Platelet-activating factor receptor; Parkinson's disease; Striatum; Dopamine; Nuclear factor kappa B; Microglia; Oxidative damage
资金
- Brain Research Center from 21st Century Frontier Research Program [2012K001115]
- Ministry of Science and Technology, Republic of Korea
- Bio & Medical Technology Development Program through the National Research Foundation [20120006020]
- Ministry of Education, Science and Technology, Republic of Korea
- JSPS: joint research project under the Japan-Korea basic scientific cooperation program
- MHLW: Research on Regulatory Science of Pharmaceuticals and Medical Devices
- SRF
- BK 21 program
- [22248033]
- [22659213]
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 PAP 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-kappa B) 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 (PAP-R-/-) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-kappa B 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 PAP-R-/- mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R-/- mice, indicating that NF-kappa B 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-kappa B-dependent signaling process. (C) 2013 Elsevier Ltd. All rights reserved.
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