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

Introduction: Parkinson'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. Methods: BV2 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). Results: Rot 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 Conclusion: Our 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.