南京中医药大学Xu Shen等研究人员合作发现，地氯雷他定通过靶向活化脊髓星形胶质细胞上的5HTR_2A减轻hSOD1^G93A小鼠的ALS样病理变化。这一研究成果于2024年1月29日在线发表在国际学术期刊《中国药理学报》上。

研究人员表示，肌萎缩性脊髓侧索硬化症（ALS）是一种致命的神经退行性疾病，脊髓、大脑皮层和脑干的运动神经元会逐渐丧失。ALS的特征是肌肉逐渐萎缩和运动障碍。由于对ALS的病理的了解有限，阻碍了该病治疗药物的开发。以往的研究表明，自噬和星形胶质细胞介导的神经炎症参与了ALS的发病机制，而5HTR_2A参与了星形胶质细胞活化的早期阶段，5HTR_2A 拮抗可抑制星形胶质细胞的活化。

研究人员评估了选择性5HTR_2A拮抗剂地氯雷他定（DLT）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周龄起开始注射DLT（20 mg kg^-1d^-1，静脉注射），持续10周或直至死亡。ALS发病时间和寿命分别通过旋转杆和翻正反射测试来确定。研究人员发现，伴随着脊髓中5-羟色胺受体_2A（5HTR_2A）上调的星形胶质细胞激活与类似ALS的病理变化密切相关，而服用DLT能有效减轻这种病理变化。研究结果表明，服用DLT能明显延缓ALS症状的发作时间，延长寿命，并改善hSOD1^G93A小鼠的运动障碍、腓肠肌损伤和脊髓运动神经元缺失。通过鞘内注射腺相关病毒9（AAV9）-si-5Htr2a，脊髓特异性敲除5HTR_2A，也能改善hSOD1^G93A小鼠的ALS病理变化，并阻断DLT给药的治疗效果。

此外，研究人员还证明了服用 DLT 可通过5HTR_2A/cAMP/AMPK通路促进自噬以降低突变体hSOD1的水平，通过5HTR_2A/cAMP/AMPK/Nrf2-HO-1/NQO-1通路抑制氧化应激，以及通过5HTR_2A/cAMP/AMPK/NF-κB/NLRP3通路抑制hSOD1^G93A小鼠脊髓中星形胶质细胞的神经炎症。总之，5HTR_2A拮抗剂有望成为ALS的治疗策略，这凸显了DLT在治疗该疾病方面的潜力。

附：英文原文

Title: Desloratadine alleviates ALS-like pathology in hSOD1G93A mice via targeting 5HTR2A on activated spinal astrocytes

Author: Lu, Jian, He, An-xu, Jin, Zhuo-ying, Zhang, Meng, Li, Zhong-xin, Zhou, Fan, Ma, Lin, Jin, Hong-ming, Wang, Jia-ying, Shen, Xu

Issue&Volume: 2024-01-29

Abstract: 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 5HTR2A participates in the early stage of astrocyte activation, and 5HTR2A antagonism may suppress astrocyte activation. In this study, we evaluated the therapeutic effects of desloratadine (DLT), a selective 5HTR2A antagonist, in human SOD1G93A (hSOD1G93A) ALS model mice, and elucidated the underlying mechanisms. HSOD1G93A mice were administered DLT (20mg·kg1·d1, 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 2A (5HTR2A) 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 hSOD1G93A mice. Spinal cord-specific knockdown of 5HTR2A by intrathecal injection of adeno-associated virus9 (AAV9)-si-5Htr2a also ameliorated ALS pathology in hSOD1G93A mice, and occluded the therapeutic effects of DLT administration. Furthermore, we demonstrated that DLT administration promoted autophagy to reduce mutant hSOD1 levels through 5HTR2A/cAMP/AMPK pathway, suppressed oxidative stress through 5HTR2A/cAMP/AMPK/Nrf2-HO-1/NQO-1 pathway, and inhibited astrocyte neuroinflammation through 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1G93A mice. In summary, 5HTR2A antagonism shows promise as a therapeutic strategy for ALS, highlighting the potential of DLT in the treatment of the disease.

DOI: 10.1038/s41401-023-01223-2

Source: https://www.nature.com/articles/s41401-023-01223-2