Matrix metalloproteinase-2 plays a critical role in the pathogenesis of white matter lesions after chronic cerebral hypoperfusion in rodents.
OBJECTIVE
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.
Nakaji
Kayoko
K
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan. kann@kuhp.kyoto-u.ac.jp
Ihara
Masafumi
M
Takahashi
Chiaki
C
Itohara
Shigeyoshi
S
Noda
Makoto
M
Takahashi
Ryosuke
R
Tomimoto
Hidekazu
H
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009413:Nerve Fibers, Myelinated / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2