title: CB2 receptor activation prevents glial-derived neurotoxic mediator production, BBB leakage and peripheral immune cell infiltration and rescues dopamine neurons in the MPTP model of Parkinson's disease.
abstract: The cannabinoid (CB2) receptor type 2 has been proposed to prevent the degeneration of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. However, the mechanisms underlying CB2 receptor-mediated neuroprotection in MPTP mice have not been elucidated. The mechanisms underlying CB2 receptor-mediated neuroprotection of dopamine neurons in the substantia nigra (SN) were evaluated in the MPTP mouse model of Parkinson's disease (PD) by immunohistochemical staining (tyrosine hydroxylase, macrophage Ag complex-1, glial fibrillary acidic protein, myeloperoxidase (MPO), and CD3 and CD68), real-time PCR and a fluorescein isothiocyanate-labeled albumin assay. Treatment with the selective CB2 receptor agonist JWH-133 (10 μg kg(-1), intraperitoneal (i.p.)) prevented MPTP-induced degeneration of dopamine neurons in the SN and of their fibers in the striatum. This JWH-133-mediated neuroprotection was associated with the suppression of blood-brain barrier (BBB) damage, astroglial MPO expression, infiltration of peripheral immune cells and production of inducible nitric oxide synthase, proinflammatory cytokines and chemokines by activated microglia. The effects of JWH-133 were mimicked by the non-selective cannabinoid receptor WIN55,212 (10 μg kg(-1), i.p.). The observed neuroprotection and inhibition of glial-mediated neurotoxic events were reversed upon treatment with the selective CB2 receptor antagonist AM630, confirming the involvement of the CB2 receptor. Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Young C
authors.initials: YC
authors.lastname: Chung
authors.affiliation: Korea Institute of Toxicology, Daejon, Korea.
authors.forename: Won-Ho
authors.initials: WH
authors.lastname: Shin
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Jeong Y
authors.initials: JY
authors.lastname: Baek
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Eun J
authors.initials: EJ
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul, Korea.
authors.forename: Hyung H
authors.initials: HH
authors.lastname: Baik
authors.affiliation: School of Life Sciences, BK21 Plus KNU Creative Bio Research Group, Kyungpook National University, Daejon, Korea.
authors.forename: Sang R
authors.initials: SR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Signaling Disorder Research Center, College of Medicine, Chungbuk National University, Cheongju, Korea.
authors.forename: So-Yoon
authors.initials: SY
authors.lastname: Won
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, Age-Related and Brain Diseases Research Center, School of Medicine, Kyung Hee University, Seoul, Korea.
authors.forename: Byung K
authors.initials: BK
authors.lastname: Jin
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology / Q000473:pathology*; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000276:immunology / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D000066829:Neuroprotection; D010302:Parkinson Disease, Secondary / Q000276:immunology / Q000473:pathology*; D043885:Receptor, Cannabinoid, CB2 / Q000276:immunology*; D013378:Substantia Nigra / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D043885:Receptor, Cannabinoid, CB2; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine