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

Young C. Chung, Sang R. Kim, Ju Young Park, Eun S. Chung, Keun W. Park, So Y. Won, Eugene Bok, Minyoung Jin, Eun S. Park, Sung Hwa Yoon, Hyuk Wan Ko, Yoon Seong Kim, Byung K. Jin

Research output: Contribution to journalArticle

96 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)963-974
Number of pages12
JournalNeuropharmacology
Volume60
Issue number6
DOIs
Publication statusPublished - 2011 May 1

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Fluoxetine
Dopaminergic Neurons
Microglia
Parkinson Disease
Oxidative Stress
Anti-Inflammatory Agents
1-Methyl-4-phenylpyridinium
Neurons
Corpus Striatum
Reactive Nitrogen Species
NADPH Oxidase
Parkinsonian Disorders
Nitric Oxide Synthase Type II
Coculture Techniques
Neuroglia
Antidepressive Agents
Reactive Oxygen Species
Dopamine
Theoretical Models

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Chung, Y. C., Kim, S. R., Park, J. Y., Chung, E. S., Park, K. W., Won, S. Y., ... Jin, B. K. (2011). Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology, 60(6), 963-974. https://doi.org/10.1016/j.neuropharm.2011.01.043
Chung, Young C. ; Kim, Sang R. ; Park, Ju Young ; Chung, Eun S. ; Park, Keun W. ; Won, So Y. ; Bok, Eugene ; Jin, Minyoung ; Park, Eun S. ; Yoon, Sung Hwa ; Ko, Hyuk Wan ; Kim, Yoon Seong ; Jin, Byung K. / Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. In: Neuropharmacology. 2011 ; Vol. 60, No. 6. pp. 963-974.
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Chung, YC, Kim, SR, Park, JY, Chung, ES, Park, KW, Won, SY, Bok, E, Jin, M, Park, ES, Yoon, SH, Ko, HW, Kim, YS & Jin, BK 2011, 'Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation', Neuropharmacology, vol. 60, no. 6, pp. 963-974. https://doi.org/10.1016/j.neuropharm.2011.01.043

Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. / Chung, Young C.; Kim, Sang R.; Park, Ju Young; Chung, Eun S.; Park, Keun W.; Won, So Y.; Bok, Eugene; Jin, Minyoung; Park, Eun S.; Yoon, Sung Hwa; Ko, Hyuk Wan; Kim, Yoon Seong; Jin, Byung K.

In: Neuropharmacology, Vol. 60, No. 6, 01.05.2011, p. 963-974.

Research output: Contribution to journalArticle

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AU - Chung, Young C.

AU - Kim, Sang R.

AU - Park, Ju Young

AU - Chung, Eun S.

AU - Park, Keun W.

AU - Won, So Y.

AU - Bok, Eugene

AU - Jin, Minyoung

AU - Park, Eun S.

AU - Yoon, Sung Hwa

AU - Ko, Hyuk Wan

AU - Kim, Yoon Seong

AU - Jin, Byung K.

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N2 - 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.

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