Platelet-activating factor receptor knockout mice are protected from MPTP-induced dopaminergic degeneration |
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Authors: | 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 |
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Affiliation: | 1. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea;2. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Republic of Korea;3. Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea;4. School of Veterinary Medicine, Kangwon National University, Chunchon 200-701, Republic of Korea;5. Department of Oriental Medicine Materials, Dongshin University, Naju 520-714, Republic of Korea;6. Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, South Korea;g Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, Tokyo 113-0033, Japan;h Department of Regional Pharmaceutical Care & Science, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan |
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Abstract: | 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-κB) 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-κB 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-κB 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-κB-dependent signaling process. |
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Keywords: | Platelet-activating factor receptor Parkinson&rsquo s disease Striatum Dopamine Nuclear factor kappa B Microglia Oxidative damage |
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