Fluoxetine protects neurons against microglial activation-mediated neurotoxicity
Open accessAbstract
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.
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Fluoxetine has a neuroprotective effect through an anti-inflammatory action against microglia activation, reducing production of IL1beta, IL6, and TNF-alfa.
“Fluoxetine, in turn, has been demonstrated to have a neuroprotective effect through an antinflammatory action against microglia activation, as it reduces the production of IL1beta and IL6 as well as of TNF-alfa (Liu et al., 2011;Zhang et al., 2012).”
From Depression and adult neurogenesis: Positive effects of the antidepressant fluoxetine and of physical exercise (2018) · cites this paper as Zhang et al., 2012
Results §3.2 reports that fluoxetine reduced LPS-induced release of IL-1β and TNF-α, and the Discussion attributes its neuroprotection to inhibition of microglial activation and inflammatory factors. The paper does not report reduced IL-6 production; its methods list assays for IL-1β and TNF-α, but not IL-6. (LLM, conf=0.90)
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- Authors
- Zhang, F., Zhou, H., Wilson, B. C., Shi, J.-S., Hong, J.-S., & Gao, H.-M.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Gao, Hui-Ming
- Venue
- Parkinsonism & Related Disorders
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 18
- Pages
- S213-S217
- ISSN
- 1353-8020 (ISSN-L)
- PMC
- PMC3608679
- OpenAlex
- W2062917074
- Cited by
- 123
- References
- 23
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 8 · 2023: 5 · 2022: 8 · 2021: 12 · 2020: 3 · 2019: 5 · 2018: 11 · 2017: 11 · 2016: 14 · 2015: 14 · 2014: 10 · 2013: 7 · 2012: 6
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Parkinsonism & Related Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Environmental Health Sciences (ZIAES090082)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- fluoxetine, neuroprotection
- MeSH terms
- Animals, Cells, Cultured, Female, Fluoxetine, Neurons, Parkinson Disease, Pregnancy, Rats, Inbred F344, NF-kappa B, Reactive Oxygen Species, Microglia, Neuroprotective Agents, Neurotoxicity Syndromes, Rats
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