Colognesi Martina, Shkodra Atea, Gabbia Daniela, Kawamata Hibiki, Manfredi Paolo L, Manfredi Giovanni, De Martin Sara
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.
Front Neurol. 2024 May 3;15:1384829. doi: 10.3389/fneur.2024.1384829. eCollection 2024.
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.
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.
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 ( < 0.01 vs. control untreated mice) and an extension of lifespan ( < 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 ( < 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.
In conclusion, this study provides preclinical evidence supporting the clinical evaluation of REL-1017 in ALS.
肌萎缩侧索硬化症（ALS）是一种由运动神经元死亡引起的致命性神经退行性疾病，其发病机制与通过N-甲基-D-天冬氨酸受体（NMDARs）过度钙内流导致的兴奋性毒性有关，这表明非竞争性NMDAR拮抗作用可能是减轻运动神经元变性的一种策略。消旋美沙酮的右旋异构体REL-1017是一种低亲和力的非竞争性NMDAR拮抗剂。重要的是，在人类中，REL-1017在重度抑郁症的临床试验中表现出了极佳的耐受性。
在此，我们通过检查生存和运动功能以及参与神经可塑性的基因和蛋白质表达，测试了REL-1017是否能改善G93A SOD1小鼠（一种成熟的家族性ALS模型）的疾病表型。
我们在G93A SOD1小鼠中发现了REL-1017的性别依赖性效应。在雄性G93A SOD1小鼠中观察到ALS症状发作延迟，以体重下降10%来评估（与未治疗的对照小鼠相比，P<0.01），并且寿命延长（与未治疗的对照小鼠相比，P<0.001）。用REL-1017治疗的雌性G93A SOD1小鼠肌肉力量有所改善（与未治疗的对照小鼠相比，P<0.01）。用REL-1017治疗的雄性和雌性小鼠后肢紧握反射均减少。在脊髓中神经元可塑性的分子标志物（PSD95和SYN1）以及股四头肌中的GluN1 NMDAR亚基中也检测到了REL-1017的性别依赖性效应。
总之，本研究提供了临床前证据，支持对REL-1017在ALS中的临床评估。
