Matrix Metalloproteinase-9 Triggers the Gap Junction Impairment and Somatosensory Neuronal Dysfunction in Septic Encephalopathy
Matrix Metalloproteinase-9 Triggers the Gap Junction Impairment and Somatosensory Neuronal Dysfunction in Septic Encephalopathy
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DOI：
10.4172/2167-0501.1000108
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发表时间：
2013
影响因子：
5.8
通讯作者：
Huan Wang;Y. Imamura;N. Matsumoto;Nao Yoshikawa;Junichiro Nakagawa;K. Yamakawa;Tomoki Yamada;Yuki Murakami;S. Mitani;Takashi Jin;H. Ogura;T. Shimazu;A. Seiyama
中科院分区：
文献类型：
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作者：
Huan Wang;Y. Imamura;N. Matsumoto;Nao Yoshikawa;Junichiro Nakagawa;K. Yamakawa;Tomoki Yamada;Yuki Murakami;S. Mitani;Takashi Jin;H. Ogura;T. Shimazu;A. Seiyama
虽然脓毒性脑病导致的是毁灭性的神经系统症状，包括感觉功能障碍，认知障碍和意识障碍，潜在的底物和它们的作用引起的突触功能障碍仍然不清楚。在这项研究中，我们成功地表征了感觉功能障碍的免疫组织化学，免疫印迹和电生理。在盲肠结扎和穿刺或腹膜内注射脂多糖（1 mg）后20小时检查脓毒性脑病的小鼠模型。我们发现，基质金属蛋白酶-9活性酶（MMP-9）对躯体感觉皮层、丘脑和前额叶皮层的影响与脓毒性脑病的感觉功能有关。起初，活性MMP-9被上调。第二，构成血脑屏障的紧密连接蛋白occludin和间隙连接的跨膜蛋白connexin-43均被破坏，它们是活性MMP-9的有效底物。第三，皮层和丘脑神经元的诱发局部场电位在感觉神经元刺激时受阻。相反，基质金属蛋白酶抑制剂GM 6001显著保护闭合蛋白、连接蛋白-43的减少和神经元活动的消退。总之，MMP-9是保护连接蛋白减少和脓毒性脑病感觉功能障碍的有效治疗的先决条件。
Although septic encephalopathy leads to be the devastating neurological symptoms including sensory dysfunction, cognitive impairment and unconsciousness, potent substrates and their effects inducing the synaptic dysfunction remain obscure. In this study, we successfully characterized the sensory dysfunction with immunohistochemistry, immunoblotting and electrophysiology. A mouse model of septic encephalopathy was examined at 20 hrs after cecal ligation and puncture or intraperitoneal injection of lipopolysaccharide (1 mg). We found several effects of active enzyme of matrix metalloproteinases-9 (active MMP-9) on the somatosensory cortex, thalamus and prefrontal cortex related to the sensory functions in septic encephalopathy. At first, active MMP-9 was up-regulated. Second, both of the occludin, tight junction protein composing blood brain barrier, and the connexin-43, transmembrane protein of gap junction, which were potent substrate of active MMP-9, were disrupted. Third, the evoked local field potentials in cortical and thalamic neurons were impeded during sensory neuronal stimulation. Conversely, matrix metalloproteinase inhibitor GM6001 significantly protected the reduction of occludin, connexin-43 and the regression of neuronal activities. In conclusion, MMP-9 is a prerequisite candidate for protection of the junction proteins reduction and for the potent therapeutics in the sensory dysfunction in septic encephalopathy.