Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with progressive loss of motor neurons in the spinal cord, cerebral cortex and brain stem. ALS is characterized by gradual muscle atrophy and dyskinesia. The limited knowledge on the pathology of ALS has impeded the development of therapeutics for the disease. Previous studies have shown that autophagy and astrocyte-mediated neuroinflammation are involved in the pathogenesis of ALS, while 5HTR_2A participates in the early stage of astrocyte activation, and 5HTR_2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR_2A antagonist, in human SOD1^G93A (hSOD1^G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1^G93A mice were administered DLT (20 mg·kg⁻¹·d⁻¹, i.g.) from the age of 8 weeks for 10 weeks or until death. ALS onset time and lifespan were determined using rotarod and righting reflex tests, respectively. We found that astrocyte activation accompanying with serotonin receptor 2 A (5HTR_2A) upregulation in the spinal cord was tightly associated with ALS-like pathology, which was effectively attenuated by DLT administration. We showed that DLT administration significantly delayed ALS symptom onset time, prolonged lifespan and ameliorated movement disorders, gastrocnemius injury and spinal motor neuronal loss in hSOD1^G93A mice. Spinal cord-specific knockdown of 5HTR_2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1^G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR_2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR_2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR_2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1^G93A mice. In summary, 5HTR_2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease.

肌萎缩侧索硬化症 (ALS) 是一种致命的神经退行性疾病，会导致脊髓、大脑皮层和脑干中的运动神经元逐渐丧失。 ALS 的特点是逐渐的肌肉萎缩和运动障碍。对 ALS 病理学的了解有限，阻碍了该疾病治疗方法的开发。既往研究表明自噬和星形胶质细胞介导的神经炎症参与ALS的发病机制，而5HTR _2A参与星形胶质细胞活化的早期阶段，5HTR _2A拮抗作用可能抑制星形胶质细胞活化。在这项研究中，我们评估了地氯雷他定 (DLT)（一种选择性 5HTR _2A拮抗剂）对人 SOD1 ^G93A (hSOD1 ^G93A ) ALS 模型小鼠的治疗效果，并阐明了其潜在机制。 HSOD1 ^G93A小鼠从8周龄起接受DLT（20mg·kg ^-1 ·d ^-1 ，ig），持续10周或直至死亡。 ALS 的发作时间和寿命分别通过旋转棒和翻正反射测试来确定。我们发现，脊髓中伴随血清素受体 2 A (5HTR _2A ) 上调的星形胶质细胞活化与 ALS 样病理密切相关，而 DLT 给药可有效减弱这种病理。我们发现，DLT 给药可显着延迟 hSOD1 ^G93A小鼠的 ALS 症状发作时间、延长寿命并改善运动障碍、腓肠肌损伤和脊髓运动神经元损失。 通过鞘内注射腺相关病毒 9 (AAV9)-si -5Htr2a脊髓特异性敲除 5HTR _2A也可改善 hSOD1 ^G93A小鼠的 ALS 病理，并阻断 DLT 给药的治疗效果。此外，我们证明DLT给药通过5HTR _2A /cAMP/AMPK途径促进自噬以降低突变hSOD1水平，通过5HTR _2A /cAMP/AMPK/Nrf2-HO-1/NQO-1途径抑制氧化应激，并通过抑制星形胶质细胞神经炎症hSOD1 ^G93A小鼠脊髓中的 5HTR _2A /cAMP/AMPK/NF-κB/NLRP3 通路。总之，5HTR _2A拮抗作用显示出作为 ALS 治疗策略的前景，凸显了 DLT 在治疗该疾病中的潜力。