title: Fluoxetine protects neurons against microglial activation-mediated neurotoxicity.
abstract: Neuroinflammation is closely associated with the pathogenesis of Parkinson's disease (PD) and other neurological disorders. Increasing evidence suggests that inhibition of microglia-mediated neuroinflammation might represent a promising therapeutic potential for PD and related disorders. Fluoxetine, a selective serotonin reuptake inhibitor, is commonly used for the treatment of major depression due to its tolerability and safety profiles. Recent studies have shown that fluoxetine affords robust neuroprotection in a series of neurological disease models. However, the mechanism underlying fluoxetine-mediated neuroprotection remains unclear. Here, by using rat primary midbrain neuronglia cultures, we report that both R and S enantiomers of fluoxetine attenuated chronic neurodegeneration induced by a common inflammogen lipopolysaccharide (LPS) and a neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)). Reconstituted cell culture studies further revealed that microglia were required for fluoxetine-mediated neuroprotection. Fluoxetine significantly inhibited LPS-induced activation of microglia and subsequent release of multiple pro-inflammatory and cytotoxic factors including tumor necrosis factor-α, interleukin-1β, nitric oxide, and reactive oxygen species. Furthermore, inhibition of microglial NF-κB signaling pathway participated in fluoxetine-mediated neuroprotection. Collectively, fluoxetine exerted neuroprotection against microglia-mediated neurotoxicity. Thus, fluoxetine might hold a potential to retard inflammation-mediated chronic neurodegenerative process of PD.
authors.affiliation: Neuropharmacology Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Belinda C
authors.initials: BC
authors.lastname: Wilson
authors.forename: Jing-Shan
authors.initials: JS
authors.lastname: Shi
authors.forename: Jau-Shyong
authors.initials: JS
authors.lastname: Hong
authors.forename: Hui-Ming
authors.initials: HM
authors.lastname: Gao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000517:prevention & control; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D005473:Fluoxetine