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

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

doi:10.1038/s41401-023-01058-x

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

Acta Pharmacol Sin. 2023 Jul;44(7):1322-1336. doi: 10.1038/s41401-023-01058-x. Epub 2023 Feb 10.

Authors

Yang Li^#^{1

2}, Qiao Yin^#¹, Qi Li³, An-Ran Huo³, Ting-Ting Shen¹, Jia-Qian Cao¹, Chun-Feng Liu^{1

3}, Tong Liu⁴, Wei-Feng Luo⁵, Qi-Fei Cong^{6

7}

Affiliations

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.
⁵ Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. lwfwxx@126.com.
⁶ Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China. qfcong@suda.edu.cn.
⁷ Institute of Neuroscience and Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, China. qfcong@suda.edu.cn.

^# Contributed equally.

Abstract

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 (3 μg/mL in the drinking water) for 10 weeks. From the 10^th 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-α and IL-1β in 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. BoNT/A ameliorates depressive-like behavior, and reverses synapse loss mediated by classical complement pathway-initiated microglia engulfment as well as alleviates microglia-mediated proinflammatory response in the reserpine-induced Parkinson's disease mouse model.

Keywords: Parkinson’s disease; botulinum neurotoxin A; complement; depression; microglia; reserpine.

MeSH terms

Animals
Botulinum Toxins, Type A* / metabolism
Botulinum Toxins, Type A* / pharmacology
Disease Models, Animal
Hippocampus / metabolism
Mice
Mice, Inbred C57BL
Microglia / metabolism
Neuroinflammatory Diseases
Parkinson Disease* / drug therapy
Parkinson Disease* / metabolism
Reserpine / metabolism
Reserpine / pharmacology

Substances

Botulinum Toxins, Type A
Reserpine