Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation

    Authors

    Y. C. Chung; S. R. Kim; J. Y. Park; E. S. Chung; K. W. Park; S. Y. Won; E. Bok; M. Jin; E. S. Park; S. H. Yoon; H. W. Ko; Y. S. Kim;B. K. Jin

    Comments

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    Abbreviated Journal Title

    Neuropharmacology

    Keywords

    Parkinson's disease; Fluoxetine; Microglial activation; Oxidative; stress; Neuroinflammation; NITRIC-OXIDE SYNTHASE; PARKINSONS-DISEASE; NADPH OXIDASE; IN-VIVO; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; MOUSE MODEL; CELL-DEATH; TNF-ALPHA; MICE; Neurosciences; Pharmacology & Pharmacy

    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-methy1-4-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. (C) 2011 Elsevier Ltd. All rights reserved.

    Journal Title

    Neuropharmacology

    Volume

    60

    Issue/Number

    6

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    963

    Last Page

    974

    WOS Identifier

    WOS:000289133200017

    ISSN

    0028-3908

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