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Pharmacological modulation of p75 neurotrophin receptor in microglial cells improves resilience to rotenone cytotoxicity
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DOI：10.3389/fphar.2026.1895046.png)
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Abstract
En 中文
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.
Keywords:
oxidative stress
microglia
neuroinflammation
Parkinson’s disease
rotenone
p75NTR
LM11A-31
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