Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.
Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.
复制标题
DOI：
10.1016/j.expneurol.2012.01.008
复制
发表时间：
2012-04
影响因子：
5.3
通讯作者：
Masliah, Eliezer
中科院分区：
文献类型：
--
作者：
Ubhi, Kiren;Inglis, Chandra;Mante, Michael;Patrick, Christina;Adame, Anthony;Spencer, Brian;Rockenstein, Edward;May, Verena;Winkler, Juergen;Masliah, Eliezer
α-突触核蛋白病是指一组与年龄相关的神经系统疾病，包括帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA），这些疾病表现出α-突触核蛋白（α-syn）的异常积累。与PD和DLB中观察到的神经元α-syn积累相反，MSA的特征是广泛的少突胶质细胞α-syn积累。在少突胶质细胞特异性髓鞘碱性蛋白启动子（mbp1 -h α-syn tg小鼠）下表达人α-syn的转基因小鼠在MSA中观察到许多行为和神经病理改变。氟西汀是一种选择性5 -羟色胺再摄取抑制剂，已被证明在毒素诱导的PD模型中具有保护作用，但其在α-突触核蛋白病的体内转基因模型中的作用尚不清楚。在此背景下，本研究检测了氟西汀对MSA模型小鼠MBP1-hαsyn的影响。氟西汀可改善mbp1 -h - α - syn小鼠的运动缺陷，同时降低基底神经节、新皮层和海马的神经退行性病理。氟西汀也增加了MBP1-hαsyn小鼠的神经营养因子、神经胶质源性神经营养因子和脑源性神经营养因子的水平。氟西汀诱导的GDNF和BDNF蛋白水平的升高伴随着ERK信号通路的激活。氟西汀对髓磷脂和血清素标志物的影响也进行了检查。总的来说，这些结果表明氟西汀可能是MSA和其他神经退行性疾病的一种新的治疗干预手段。
The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.
登录
查看更多内容
影响因子：
5.3
作者：
Bianchi, Patrizia;Ciani, Elisabetta;Bartesaghi, Renata
通讯作者：
Bartesaghi, Renata
影响因子：
2.9
作者：
Chung, Eun S.;Chung, Young C.;Jin, Byung K.
通讯作者：
Jin, Byung K.
影响因子：
3.4
作者：
Allaman, Igor;Fiumelli, Hubert;Martin, Jean-Luc
通讯作者：
Martin, Jean-Luc
影响因子：
7.7
作者：
Kahle, PJ;Neumann, M;Haass, C
通讯作者：
Haass, C
影响因子：
2.6
作者：
Gonzalez-Pinto, Ana;Mosquera, Fernando;Matute, Carlos
通讯作者：
Matute, Carlos