TY - JOUR T1 - Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.110.178079 SP - jpet.110.178079 AU - Kanako Shichi AU - Wakako Fujita-Hamabe AU - Shinichi Harada AU - Hiroyuki Mizoguchi AU - Kiyofumi Yamada AU - Toshitaka Nabeshima AU - Shogo Tokuyama Y1 - 2011/01/01 UR - http://jpet.aspetjournals.org/content/early/2011/05/20/jpet.110.178079.abstract N2 - 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 an involvement of MMP-mediated proteolysis of NCAM in the development of ischemic neuronal damage. Male ddY and MMP-9 knock-out (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 day 1 and day 3 after MCAO. Protein levels of MMP-2 and MMP-9 were significantly increased on day 1 and day 3 after MCAO. In addition, full-length of NCAM (180 kDa) was significantly decreased, but its metabolite levels increased on day 1 by ischemic stress per se. NCAM siRNA significantly increased the neuronal damage induced by MCAO. MMP inhibition or MMP-9 gene knockout attenuated the infarction, behavioral abnormalities and decrease of NCAM (180kDa) 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. ER -