Involvement of matrix metalloproteinase-mediated proteolysis of neural cell adhesion molecule in the development of cerebral ischemic neuronal damage

Kanako Shichi, Wakako Fujita-Hamabe, Shinichi Harada, Hiroyuki Mizoguchi, Kiyofumi Yamada, Toshitaka Nabeshima, Shogo Tokuyama

研究成果: Article査読

28 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)701-710
ページ数10
ジャーナルJournal of Pharmacology and Experimental Therapeutics
338
2
DOI
出版ステータスPublished - 08-2011

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 薬理学

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