Department of Clinical Pharmacy, Kobe Gakuin University School of Pharmaceutical Sciences, 1-1-3 Minatojima, Chuo-ku, Kobe 650-8586, Japan.
J Pharmacol Exp Ther. 2011 Aug;338(2):701-10. doi: 10.1124/jpet.110.178079. Epub 2011 May 20.
Neural cell adhesion molecule (NCAM) is a membrane protein abundantly expressed in the central nervous system. Recently, it has been reported that dysfunction of NCAM is linked to human brain disorders. Furthermore, NCAM is one of the proteolysis targets of matrix metalloproteinase (MMP), whose activation is implicated in neuronal damage. The aim of this study was to elucidate the involvement of MMP-mediated proteolysis of NCAM in the development of ischemic neuronal damage. Male ddY and MMP-9 knockout (KO) C57BL/6J mice were subjected to 2 h of middle cerebral artery occlusion (MCAO). In MCAO model mice, development of infarction and behavioral abnormality were clearly observed on days 1 and 3 after MCAO. Protein levels of MMP-2 and MMP-9 were significantly increased on days 1 and 3 after MCAO. In addition, full-length NCAM (180 kDa) was significantly decreased, but its metabolite levels increased on day 1 by ischemic stress per se. NCAM small interfering RNA significantly increased the neuronal damage induced by MCAO. MMP inhibition or MMP-9 gene KO attenuated the infarction, behavioral abnormalities, and decrease of NCAM (180 kDa) observed after MCAO in mice. The present findings clearly suggest that MMP-2/MMP-9-mediated NCAM proteolysis is implicated in the exacerbation of ischemic neuronal damage.
神经细胞黏附分子（NCAM）是一种在中枢神经系统中大量表达的膜蛋白。最近有报道称，NCAM 的功能障碍与人类大脑紊乱有关。此外，NCAM 是基质金属蛋白酶（MMP）的蛋白水解靶标之一，其激活与神经元损伤有关。本研究旨在阐明 MMP 介导的 NCAM 蛋白水解在缺血性神经元损伤中的作用。雄性 ddY 和 MMP-9 基因敲除（KO）C57BL/6J 小鼠接受 2 小时大脑中动脉闭塞（MCAO）。在 MCAO 模型小鼠中，MCAO 后第 1 天和第 3 天明显观察到梗死和行为异常的发展。MCAO 后第 1 天和第 3 天 MMP-2 和 MMP-9 的蛋白水平显著增加。此外，全长 NCAM（180 kDa）水平显著降低，但缺血应激本身在第 1 天就增加了其代谢产物的水平。NCAM 小干扰 RNA 显著增加了 MCAO 诱导的神经元损伤。MMP 抑制或 MMP-9 基因 KO 减轻了 MCAO 后小鼠的梗死、行为异常和 NCAM（180 kDa）的减少。这些发现清楚地表明，MMP-2/MMP-9 介导的 NCAM 蛋白水解参与了缺血性神经元损伤的加重。
