AUTHOR=Colognesi Martina , Shkodra Atea , Gabbia Daniela , Kawamata Hibiki , Manfredi Paolo L. , Manfredi Giovanni , De Martin Sara 

TITLE=Sex-dependent effects of the uncompetitive N-methyl-D-aspartate receptor antagonist REL-1017 in G93A-SOD1 amyotrophic lateral sclerosis mice

JOURNAL=Frontiers in Neurology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1384829

DOI=10.3389/fneur.2024.1384829

ISSN=1664-2295

ABSTRACT=<sec id="sec500"><title>Introduction</title><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.</p></sec><sec id="sec501"><title>Methods</title><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.</p></sec><sec id="sec502"><title>Results</title><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 (<italic>p</italic> &lt; 0.01 vs. control untreated mice) and an extension of lifespan (<italic>p</italic> &lt; 0.001 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 (<italic>p</italic> &lt; 0.01 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.</p></sec><sec id="sec503"><title>Conclusion</title><p>In conclusion, this study provides preclinical <italic>in vivo</italic> evidence supporting the clinical evaluation of REL-1017 in ALS.</p></sec>