{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:56:22Z","timestamp":1787507782179,"version":"build-2736575974"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Parkinson\u2019s 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>BV2 microglial cells were exposed to 50\u00a0nM Rot in the presence or absence of 0.5\u00a0\u03bcM 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).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      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, PPAR\u03b1, and glutathione-associated pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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\u2019s disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1895046","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T07:44:37Z","timestamp":1784533477000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological modulation of p75 neurotrophin receptor in microglial cells improves resilience to rotenone cytotoxicity"],"prefix":"10.3389","volume":"17","author":[{"given":"Alessio","family":"Valenza","sequence":"first","affiliation":[{"name":"Department of Science, University Roma Tre","place":["Rome, Italy"]},{"name":"LIFE Institute for Research and Health Care - Santa Lucia IRCCS","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Pensabene","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Territory, University of Molise","place":["Pesche, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Rendina","sequence":"additional","affiliation":[{"name":"Department of Science, University Roma Tre","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Muzzi","sequence":"additional","affiliation":[{"name":"Department of Science, University Roma Tre","place":["Rome, Italy"]},{"name":"Department of Biosciences and Territory, University of Molise","place":["Pesche, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Fracassi","sequence":"additional","affiliation":[{"name":"Mitchell Center for Neurodegenerative Diseases, Department of Neurology, University of Texas Medical Branch, UTMB","place":["Galveston, TX, United States"]},{"name":"Moody Brain Health Institute, UTMB","place":["Galveston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Moreno","sequence":"additional","affiliation":[{"name":"Department of Science, University Roma Tre","place":["Rome, Italy"]},{"name":"LIFE Institute for Research and Health Care - Santa Lucia IRCCS","place":["Rome, Italy"]},{"name":"Graduate School of Biomedical Sciences, UTMB","place":["Galveston, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Segatto","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Territory, University of Molise","place":["Pesche, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e18368","DOI":"10.1111\/jcmm.18368","article-title":"BDNF\/TrkB activators in Parkinson\u2019s disease: a new therapeutic strategy","volume":"28","author":"Ali","year":"","journal-title":"J. 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