{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:21:43Z","timestamp":1791584503615,"version":"4.3.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T00:00:00Z","timestamp":1714694400000},"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. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the demise of motor neurons has been linked to excitotoxicity caused by excessive calcium influx via N-methyl-D-aspartate receptors (NMDARs), suggesting that uncompetitive NMDAR antagonism could be a strategy to attenuate motor neuron degeneration. REL-1017, the dextro-isomer of racemic methadone, is a low-affinity uncompetitive NMDAR antagonist. Importantly, in humans REL-1017 has shown excellent tolerability in clinical trials for major depression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here, we tested if REL-1017 improves the disease phenotypes in the G93A SOD1 mouse, a well-established model of familial ALS, by examining survival and motor functions, as well as the expression of genes and proteins involved in neuroplasticity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found a sex-dependent effect of REL-1017 in G93A SOD1 mice. A delay of ALS symptom onset, assessed as 10%-decrease of body weight (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01 vs. control untreated mice) and an extension of lifespan (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.001 vs. control untreated mice) was observed in male G93A SOD1 mice. Female G93A SOD1 mice treated with REL-1017 showed an improvement of muscle strength (<jats:italic>p<\/jats:italic>\u2009&amp;lt;\u20090.01 vs. control untreated mice). Both males and females treated with REL-1017 showed a decrease in hind limb clasping. Sex-dependent effects of REL-1017 were also detected in molecular markers of neuronal plasticity (PSD95 and SYN1) in the spinal cord and in the GluN1 NMDAR subunit in quadricep muscles.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, this study provides preclinical<jats:italic>in vivo<\/jats:italic>evidence supporting the clinical evaluation of REL-1017 in ALS.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2024.1384829","type":"journal-article","created":{"date-parts":[[2024,5,3]],"date-time":"2024-05-03T15:49:18Z","timestamp":1714751358000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice"],"prefix":"10.3389","volume":"15","author":[{"given":"Martina","family":"Colognesi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atea","family":"Shkodra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Gabbia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hibiki","family":"Kawamata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo L.","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Manfredi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"De Martin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1159\/000516752","article-title":"Estimated prevalence and incidence of amyotrophic lateral sclerosis and SOD1 and C9orf72 genetic variants","volume":"55","author":"Brown","year":"2021","journal-title":"Neuroepidemiology"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"433","DOI":"10.3390\/ph15040433","article-title":"Neuronal hyperexcitability and free radical toxicity in amyotrophic lateral sclerosis: established and future targets","volume":"15","author":"Shibuya","year":"2022","journal-title":"Pharmaceuticals"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"90","DOI":"10.3389\/fncel.2020.00090","article-title":"Going the extra (synaptic) mile: excitotoxicity as the road toward neurodegenerative diseases","volume":"14","author":"Armada-Moreira","year":"2020","journal-title":"Front Cell Neurosci"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1007\/s12640-020-00302-0","article-title":"Is exposure to BMAA a risk factor for neurodegenerative diseases? 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