Fluoxetine shows neuroprotective effects against LPS-induced neuroinflammation via the Notch signaling pathway
International Immunopharmacology(2022)
Abstract
Aim: To determine the neuroprotective effects of fluoxetine on depression-like and motor behaviors in rats treated with lipopolysaccharide (LPS) and the mechanisms involved. Methods: A rat model of depression in Parkinson's disease (dPD) was established by administering LPS (0.5 mg/ kg, i.p.) for 4 days. The sucrose preference test (SPT), open field test (OFT), and rotarod test evaluated depression-like and motor behaviors. White matter fiber integrity and intrinsic activity in the brain were assessed using magnetic resonance imaging. For pathological and molecular expression detection, hematoxylin-eosin staining, immunohistochemistry, Luminex technology, western blotting, and quantitative real-time PCR were used. Results: Fluoxetine increased the sucrose preference in the SPT, the horizontal and center distances in the OFT, and the standing time in the rotarod test. Fluoxetine also improved intrinsic activities and white matter fiber damage in the brain, increased c-Fos expression, reduced Iba-1 expression in the prefrontal cortex, hippocampus, and substantia nigra, and increased TH expression in the substantia nigra. Fluoxetine reduced the concentration of inflammatory cytokines (IL-1 alpha, IL-6, TNF-alpha, and IFN-gamma). The gene and protein expression of Notch1, Jagged1, Hes1, and Hes5 were significantly lower than the LPS group after treatment with fluoxetine. Conclusion: Fluoxetine plays neuroprotective effects in relieving LPS-induced depression-like and motor behaviors. The underlying mechanisms may be related to inhibiting microglial activation, regulating the Notch signaling pathway, and inhibiting the inflammatory response.
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Key words
Parkinson?s disease,Depression,Fluoxetine,LPS,Neuroinflammation,Notch signaling pathway
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