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(Stroke. 2006;37:2816.)
© 2006 American Heart Association, Inc.

Original Contributions

Matrix Metalloproteinase-2 Plays a Critical Role in the Pathogenesis of White Matter Lesions After Chronic Cerebral Hypoperfusion in Rodents

Kayoko Nakaji, MD; Masafumi Ihara, MD; Chiaki Takahashi, MD; Shigeyoshi Itohara, PhD; Makoto Noda, PhD; Ryosuke Takahashi, MD Hidekazu Tomimoto, MD

From the Department of Neurology (K.N., M.I., R.T., H.T.), Horizontal Medical Research Organization (M.I.), the Department of Molecular Oncology (M.N.), and The 21st Century Center of Excellence Program, Department of Oncology (C.T.), Kyoto University Graduate School of Medicine, Kyoto, Japan; and the Laboratory for Behavioral Genetics (S.I.), RIKEN Brain Science Institute, Wako, Japan.

Correspondence to Kayoko Nakaji, MD, Department of Neurology, Graduate School of Medicine, Kyoto University, 54 Kawaharamachi, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kann{at}kuhp.kyoto-u.ac.jp

Background and Purpose— Cerebrovascular white matter (WM) lesions contribute to cognitive impairment and motor dysfunction in the elderly. A disruption of the blood–brain barrier (BBB) is believed to be a critical early event leading to these WM lesions. Previous studies have suggested the involvement of matrix metalloproteinase-2 (MMP-2) in BBB disruptions and the upregulation of MMP-2 after chronic cerebral hypoperfusion in a rat model. In the present study, we asked whether MMP-2 is involved in the BBB disruption and the subsequent WM lesions after chronic cerebral hypoperfusion.

Methods— We compared the severity of white matter lesions in rats after chronic cerebral hypoperfusion with or without an MMP inhibitor. Then, we also induced the chronic cerebral hypoperfusion in wild-type and MMP-2-null mice.

Results— In the rats treated with a relatively selective MMP-2 inhibitor, AG3340, the WM lesions after chronic cerebral hypoperfusion were significantly less severe, and the number of activated astroglia and microglia were also significantly lower as compared with the vehicle-treated rats. Gene knockout of MMP-2 also reduced the severity of the WM lesions and the number of activated astroglia and microglia in a mice system. In both rodents, the disruption of BBB function, as assessed by IgM staining and the Evans blue extravasation test, was less severe when MMP-2 activity was attenuated.

Conclusions— These findings indicate that MMP-2 plays a critical role in the BBB disruption, glial cell activation, and WM lesions after chronic cerebral hypoperfusion and suggest the potential value of MMP-2 inhibitors as a therapeutic tool in cerebrovascular WM lesions.

Key Words: blood–brain barrier • chronic cerebral hypoperfusion • MMP inhibitor • MMP-2 • white matter lesion

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