Neuroprotective Effects of Fluoxetine Derivative 4-[3-Oxo-3-(2-trifluoromethyl-phenyl)-propyl]-morpholinium Chloride (OTPM) as a Potent Modulator of Motor Deficits and Neuroinflammatory Pathways in LPS-Induced BV-2 Microglial Cells and MPTP-Induced Parkinsonian Models.
Neuroprotective Effects of Fluoxetine Derivative 4-[3-Oxo-3-(2-trifluoromethyl-phenyl)-propyl]-morpholinium Chloride (OTPM) as a Potent Modulator of Motor Deficits and Neuroinflammatory Pathways in LPS-Induced BV-2 Microglial Cells and MPTP-Induced Parkinsonian Models.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Chungju, KR · Author affiliation
Department of Applied Life Sciences, BK21 Program, Graduate School, Konkuk University, Chungju 27478, Republic of Korea.Location evidence
Suwon, KR · Author affiliation
Molecular Science and Technology Research Center, Ajou University, Suwon 16499, Republic of Korea.Location evidence
Ahmedabad, IN · Author affiliation
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad 382355, India.Location evidence
Indianapolis, US · Author affiliation
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.Location evidence
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Original abstract
Background/Objectives: Parkinson's disease (PD) is the second most common neurodegenerative disease (NDD), marked by the progressive loss of dopaminergic neurons in the substantia nigra that causes motor dysfunction. Growing evidence indicates that neuroinflammation plays a crucial role in the onset and progression of PD, though the exact mechanisms are still unclear. In this study, we examined the anti-inflammatory and neuroprotective effects of 4-[3-oxo-3-(2-trifluoromethyl-phenyl)-propyl]-morpholinium chloride (OTPM), a fluoxetine derivative and selective serotonin reuptake inhibitor, in both lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and an MPTP-induced mouse model of PD. Methods: C57BL/6 mice were orally administered OTPM (10 mg/kg b.w.) for 7 days and intraperitoneally injected with MPTP (20 mg/kg b.w.) for one day, with four injections at 2 h intervals. Bradykinesia was assessed using the Y-maze and Pole tests. Protein and mRNA levels were examined in vitro and in vivo using Western blotting and RT-PCR. Immunofluorescence was used to assess microglial and astrocyte activation. Results: In vitro, OTPM significantly decreased nitric oxide (NO) production (p < 0.001) and suppressed the protein and mRNA expression of iNOS (p < 0.001), COX-2 (p < 0.001), and pro-inflammatory cytokines, including IL-β (p < 0.001), IL-6 (p < 0.001), and TNF-α (p < 0.01), in LPS-activated BV-2 microglia. Further mechanistic studies showed that OTPM inhibited NF-κB phosphorylation and blocked its nuclear translocation, thereby reducing inflammatory signaling. In vivo, treatment with OTPM (10 mg/kg for 7 days) significantly reduced the MPTP-induced activation of microglia (MAC-1) and astroglia (GFAP) in the brain and improved behavioral deficits associated with PD, as assessed in the Y-maze and pole tests. Conclusions: Overall, these results reveal that OTPM has strong anti-neuroinflammatory and neuroprotective properties, suggesting its potential as a new therapeutic candidate for PD and other disorders associated with neuroinflammation.