Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson’s disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation  

作　　者：Yang Li Qiao Yin Qi Li An-ran Huo Ting-ting Shen Jia-qian Cao Chun-feng Liu Tong Liu Wei-feng Luo Qi-fei Cong 

机构地区：[1]Department of Neurology and Clinical Research Center of Neurological Disease,The Second Affiliated Hospital of Soochow University,Suzhou 215004,China [2]Department of Neurology,Huzhou Central Hospital,The Affiliated Huzhou Hospital,Zhejiang University School of Medicine,Huzhou 313000,China [3]Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases,Soochow University,Suzhou 215123,China [4]Institute of Pain Medicine and Special Environmental Medicine,Nantong University,Nantong 226019,China

出　　处：《Acta Pharmacologica Sinica》2023年第7期1322-1336,共15页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(32200778);Natural Science Foundation of Jiangsu Province(BK20220494);Suzhou Medical and Health Technology Innovation Project(SKY2022107);startup funding[NH21500221],[NH21500122];research funding by the Clinical Research Center of Neurological Disease in The Second Affliated Hospital of Soochow University[ND2022A04]to Qi fei Cong;the Suzhou Science and Technology Plan Key Technology Application Research Project[SS2019060];the National Natural Science Foundation of China[No.81671270];the Suzhou Clinical Research Center of Neurological Disease[SZZX201503];the Natural Science Foundation of Jiangsu Province of China[BK2011294]to Wei-feng Luo;the Priority Academic Program Development of Jiangsu Higher Education Institutes(PAPD)to Chun-feng Liu.

摘　　要：Depression is one of the common non-motor symptoms of Parkinson’s disease(PD).In the clinic,botulinum neurotoxin A(BoNT/A)has been used to treat depression.In this study,we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model.Mice were administered reserpine(3μg/mL in the drinking water)for 10 weeks.From the 10th week,BoNT/A(10 U·kg?1·d?1)was injected into the cheek for 3 consecutive days.We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta(SNpc)and striatum.BoNT/A treatment significantly ameliorated the depressive-like behaviors,but did not improve TH activity in SNpc of reserpine-treated mice.We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region.Furthermore,BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses,thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice.Moreover,BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-αand IL-1βin reserpine-treated mice.In addition,we showed that BoNT/A(0.1 U/mL)ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro.We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses.

关 键 词：Parkinson’s disease depression RESERPINE botulinum neurotoxin A microglia COMPLEMENT 

分 类 号：R285.5[医药卫生—中药学]