Desloratadine alleviates ALS-like pathology in hSOD1^(G93A)mice via targeting 5HTR2A on activated spinal astrocytes  

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

机构地区：[1]Jiangsu Key Laboratory of Drug Target and Drug for Degenerative Diseases,School of Medicine&Holistic Medicine,Nanjing University of Chinese Medicine,Nanjing,210023,China [2]School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing,210023,China

出　　处：《Acta Pharmacologica Sinica》2024年第5期926-944,共19页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82273930);the National Natural Science Foundation for Young Scientists of China(82304468,82304494,82204486);Major Program of the Natural Science Foundation of the Jiangsu Higher Education Institutions of China(23KJA350002);the Natural Science Foundation for Young Scientists of Nanjing University of Chinese Medicine(XPT82204486);Natural Science Foundation of Jiangsu Province(BK20200570).

摘　　要：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 5HTR2A 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 5HTR2A 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 5HTR2A/cAMP/AMPK/NF-κB/NLRP3 pathway in the spinal cord of hSOD1^(G93A)mice.In summary,5HTR_(2A)antagonism shows promise as a therapeutic stra

关 键 词：amyotrophic lateral sclerosis serotonin receptor 2A DESLORATADINE hSOD1^(G93A)mice spinal astrocytes NLRP3 inflammasome activation 

分 类 号：R749.61[医药卫生—神经病学与精神病学]