Pharmacological modulation of p75 neurotrophin receptor in microglial cells improves resilience to rotenone cytotoxicity.

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IntroductionParkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by dopaminergic neuronal loss, mitochondrial dysfunction, oxidative stress, and chronic neuroinflammation. Microglial activation plays a primary role in disease progression, by amplifying inflammatory response and redox imbalance. The low-affinity neurotrophin receptor p75NTR has recently emerged as a potential therapeutic target in neurodegenerative disorders, due to its involvement in cell survival, apoptosis, and inflammatory signaling. In the present study, we investigated whether pharmacological modulation of p75NTR by LM11A-31 could protect microglial cells against Rotenone (Rot)-induced toxicity, a widely used tool to mimic PD.MethodsBV2 microglial cells were exposed to 50 nM Rot in the presence or absence of 0.5 μM LM11A-31. Cell viability, apoptotic signaling, oxidative stress, inflammatory response, and cytoskeletal organization were evaluated using immunofluorescence, Western blotting, TUNEL assay, and Scanning Electron Microscopy (SEM).ResultsRot exposure significantly increased p75NTR expression and induced marked microglial dysfunction, characterized by activation of apoptosis, oxidative stress, and inflammatory phenotype. LM11A-31 treatment improved cell survival and reduced apoptotic features, as shown by decreased TUNEL+ cells and cleaved caspase-3 immunoreactivity. In parallel, LM11A-31 restored microglial morphology and cytoskeletal integrity, also reducing ultrastructural alterations induced by Rot. Moreover, p75NTR modulation significantly blunted microglial activation markers, including Iba1 and CD68. LM11A-31 also reduced oxidative stress by limiting NOX-related signaling and lipid peroxidation, while partially restoring antioxidant defenses through modulation of Nrf2, PPARα, and glutathione-associated pathways.ConclusionOur findings demonstrate that pharmacological modulation of p75NTR by LM11A-31 protects microglial cells against Rot-induced cytotoxicity and inflammatory activation. These protective effects involve the rescue of redox balance, suppression of pro-inflammatory signaling, preservation of cytoarchitecture, also resulting in increased cell survival. Overall, targeting p75NTR may represent a promising therapeutic strategy to counteract microglial dysfunction and neuroinflammatory processes associated with Parkinson's disease.

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