Mousavi Majd Alireza, Ebrahim Tabar Forough, Afghani Arghavan, Ashrafpour Sahand, Dehghan Samaneh, Gol Mohammad, Ashrafpour Manouchehr, Pourabdolhossein Fereshteh
Student Research Committee, Babol University of Medical Sciences, Babol, Iran; Neuroscience Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
Physiology Departments, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran.
Behav Brain Res. 2018 Jan 15;336:111-121. doi: 10.1016/j.bbr.2017.08.046. Epub 2017 Sep 1.
Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05μg/2μl/animal) or muscimol (0.1, 0.2μg/2μl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy.
认知障碍和记忆缺陷是多发性硬化症患者的常见特征。MS中记忆障碍的机制尚不清楚，但神经影像学研究表明海马脱髓鞘与之有关。在此，我们在海马脱髓鞘局部模型中研究GABA A受体对空间记忆的作用。通过向雄性Wistar大鼠双侧海马CA1区注射1%溶血磷脂酰胆碱（LPC）诱导脱髓鞘。在LPC注射5天后，治疗组每天经脑室注射荷包牡丹碱（0.025、0.05μg/2μl/动物）或蝇蕈醇（0.1、0.2μg/2μl/动物）。使用莫里斯水迷宫评估大鼠的学习和记忆。我们分别使用Luxol固蓝染色和qPCR评估脱髓鞘范围和髓鞘碱性蛋白（MBP）表达水平。进行CD45免疫组织化学（IHC）和苏木精-伊红（H&E）染色以评估炎性细胞浸润。行为学研究表明，海马注射LPC会损害学习和记忆功能。两种剂量的荷包牡丹碱治疗的动物改善了空间学习和记忆功能；然而，蝇蕈醇治疗无效。组织学和MBP表达研究证实LPC组的脱髓鞘最为严重。荷包牡丹碱治疗显著减少了脱髓鞘范围并增加了MBP表达水平。H&E和IHC结果表明，荷包牡丹碱减少了损伤部位的炎性细胞浸润。在LPC诱导的海马脱髓鞘模型中，荷包牡丹碱改善了学习和记忆并减少了脱髓鞘范围。我们得出结论，海马脱髓鞘背景下GABA能稳态的破坏可能与记忆障碍有关，这对病理生理学和治疗都有影响。
