Lin Chih-Li, Zheng Ting-Lin, Tsou Sing-Hua, Chang Hung-Ming, Tseng Li-Ho, Yu Ching-Han, Hung Ching-Sui, Ho Ying-Jui
Institute of Medicine, Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC.
Department of Psychology, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung 40201, Taiwan, ROC.
Behav Brain Res. 2022 Oct 28;435:114035. doi: 10.1016/j.bbr.2022.114035. Epub 2022 Aug 2.
Dementia with Lewy bodies (DLB), a highly prevalent neurodegenerative disorder, causes motor and cognitive deficits. The main pathophysiologies of DLB are glutamate excitotoxicity and accumulation of Lewy bodies comprising α-synuclein (α-syn) and β-amyloid (Aβ). Amitriptyline (AMI) promotes expression of glutamate transporter-1 and glutamate reuptake. In this study, we measured the effects of AMI on behavioral and neuronal function in a DLB rat model. We used rivastigmine (RIVA) as a positive control. To establish the DLB rat model, male Wistar rats were stereotaxically injected with recombinant adenoassociated viral vector with the SNCA gene (10 μg/10 μL) and Aβ (5 μg/2.5 μL) into the left ventricle and prefrontal cortex, respectively. AMI (10 mg/kg/day, i.p.), RIVA (2 mg/kg/day, i.p.), or saline was injected intraperitoneally after surgery. From the 29th day, behavioral tests were performed to evaluate the motor and cognitive functions of the rats. Immunohistochemical staining was used to assess neuronal changes. We measured the α-syn level, number of newborn cells, and neuronal density in the hippocampus and in the nigrostriatal dopaminergic system. The DLB group exhibited deficit in object recognition. Both the AMI and RIVA treatments reversed these deficits. Histologically, the DLB rats exhibited cell loss in the substantia nigra pars compacta and in the hippocampal CA1 area. AMI reduced this cell loss, but RIVA did not. In addition, the DLB rats exhibited a lower number of newborn cells and higher α-syn levels in the dentate gyrus (DG). AMI did not affect α-syn accumulation but recovered neurogenesis in the DG of the rats, whereas RIVA reversed the α-syn accumulation but did not affect neurogenesis in the rats. We suggest that AMI may have potential for use in the treatment of DLB.
路易体痴呆（DLB）是一种高度流行的神经退行性疾病，会导致运动和认知缺陷。DLB的主要病理生理学机制是谷氨酸兴奋性毒性以及由α-突触核蛋白（α-syn）和β-淀粉样蛋白（Aβ）组成的路易体的积累。阿米替林（AMI）可促进谷氨酸转运体-1的表达和谷氨酸的再摄取。在本研究中，我们测量了AMI对DLB大鼠模型行为和神经元功能的影响。我们使用 rivastigmine（RIVA）作为阳性对照。为建立DLB大鼠模型，将雄性Wistar大鼠分别立体定向注射携带SNCA基因（10μg/10μL）的重组腺相关病毒载体和Aβ（5μg/2.5μL）至左心室和前额叶皮层。术后腹腔注射AMI（10mg/kg/天，腹腔注射）、RIVA（2mg/kg/天，腹腔注射）或生理盐水。从第29天开始，进行行为测试以评估大鼠的运动和认知功能。采用免疫组织化学染色评估神经元变化。我们测量了海马体和黑质纹状体多巴胺能系统中的α-syn水平、新生细胞数量和神经元密度。DLB组在物体识别方面表现出缺陷。AMI和RIVA治疗均逆转了这些缺陷。组织学上，DLB大鼠在黑质致密部和海马CA1区出现细胞丢失。AMI减少了这种细胞丢失，但RIVA没有。此外，DLB大鼠齿状回（DG）中的新生细胞数量较少，α-syn水平较高。AMI不影响α-syn的积累，但可恢复大鼠DG中的神经发生，而RIVA可逆转α-syn的积累，但不影响大鼠的神经发生。我们认为AMI可能具有用于治疗DLB的潜力。
