title: Platelet-activating factor receptor knockout mice are protected from MPTP-induced dopaminergic degeneration.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, Republic of Korea.
authors.forename: Beom Keun
authors.initials: BK
authors.lastname: Kim
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.forename: Duy-Khanh
authors.initials: DK
authors.lastname: Dang
authors.forename: Bae-Dong
authors.initials: BD
authors.lastname: Jung
authors.forename: Dae-Hun
authors.initials: DH
authors.lastname: Park
authors.forename: Myung Bok
authors.initials: MB
authors.lastname: Wie
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jeong
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Dopamine; Microglia; Nuclear factor kappa B; Oxidative damage; Parkinson’s disease; Platelet-activating factor receptor; Striatum