title: Cannabinoids prevent lipopolysaccharide-induced neurodegeneration in the rat substantia nigra in vivo through inhibition of microglial activation and NADPH oxidase.
abstract: We investigated the effects of synthetic cannabinoids, WIN55,212-2 and HU210, on LPS-injected rat substantia nigra in vivo. Intranigral injection of LPS resulted in a significant loss of nigral dopaminergic (DA) neurons, as determined by Nissl staining and TH immunohistochemistry. LPS-induced neurotoxicity was accompanied by microglial activation, as demonstrated by OX-42 immunohistochemistry. In parallel, Western blot analysis, ELISA assay and hydroethidine histochemistry revealed activation of NADPH oxidase, as demonstrated by increased translocation of the cytosolic proteins p47(phox) and p67(phox), generation of reactive oxygen species (ROS) and increased level of proinflammatory cytokines (TNF-α and IL-1β), where degeneration of nigral DA neurons was evident. Interestingly, WIN55,212-2 and HU210 increased the survival of nigral DA neurons at 7days post-LPS treatment. Consistent with these results, cannabinoids inhibited activation of NADPH oxidase, ROS production and production of proinflammatory cytokines in the rat SN. The present data suggest that cannabinoids may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with microglial activation.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine Kyung Hee University, Seoul 130-701, Korea.
authors.forename: Eun Sook
authors.initials: ES
authors.lastname: Chung
authors.forename: Eugene
authors.initials: E
authors.lastname: Bok
authors.forename: Young Cheul
authors.initials: YC
authors.lastname: Chung
authors.forename: Hyung Hwan
authors.initials: HH
authors.lastname: Baik
authors.forename: Byung Kwan
authors.initials: BK
authors.lastname: Jin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000494:pharmacology*; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009281:Naphthalenes / Q000494:pharmacology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D000975:Antioxidants; D048588:Benzoxazines; D002186:Cannabinoids; D008070:Lipopolysaccharides; D009025:Morpholines; D009281:Naphthalenes; D017382:Reactive Oxygen Species; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D019255:NADPH Oxidases; C062018:HU 211