title: Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation.
abstract: Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic (DA) neurons. Mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) exhibit microglial activation-induced oxidative stress and inflammation, and nigrostriatal DA neuronal damage, and thus serve as an experimental model of PD. Here, we report that fluoxetine, one of the most commonly prescribed antidepressants, prevents MPTP-induced degeneration of nigrostriatal DA neurons and increases striatal dopamine levels with the partial motor recovery. This was accompanied by inhibiting transient expression of proinflammatory cytokines and inducible nitric oxide synthase; and attenuating microglial NADPH oxidase activation, reactive oxygen species/reactive nitrogen species production, and consequent oxidative damage. Interestingly, fluoxetine was found to protect DA neuronal damage from 1-methyl-4-phenyl-pyridinium (MPP(+)) neurotoxicity in co-cultures of mesencephalic neurons and microglia but not in neuron-enriched mesencephalic cultures devoid of microglia. The present in vivo and in vitro findings show that fluoxetine may possess anti-inflammatory properties and inhibit glial activation-mediated oxidative stress. Therefore, we carefully propose that neuroprotection of fluoxetine might be associated with its anti-inflammatory properties and could be employed as novel therapeutic agents for PD and other disorders associated with neuroinflammation and microglia-derived oxidative damage.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
authors.forename: Young C
authors.initials: YC
authors.lastname: Chung
authors.forename: Sang R
authors.initials: SR
authors.lastname: Kim
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Eun S
authors.initials: ES
authors.lastname: Chung
authors.forename: Keun W
authors.initials: KW
authors.lastname: Park
authors.forename: So Y
authors.initials: SY
authors.lastname: Won
authors.forename: Eugene
authors.initials: E
authors.lastname: Bok
authors.forename: Minyoung
authors.initials: M
authors.lastname: Jin
authors.forename: Eun S
authors.initials: ES
authors.lastname: Park
authors.forename: Sung-Hwa
authors.initials: SH
authors.lastname: Yoon
authors.forename: Hyuk W
authors.initials: HW
authors.lastname: Ko
authors.forename: Yoon-Seong
authors.initials: YS
authors.lastname: Kim
authors.forename: Byung K
authors.initials: BK
authors.lastname: Jin
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002452:Cell Count / Q000379:methods; D018920:Coculture Techniques / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D020267:MPTP Poisoning / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects*; D045442:Rotarod Performance Test / Q000379:methods; D013378:Substantia Nigra
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D005473:Fluoxetine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine