Caspases determine the vulnerability of oligodendrocytes in the ischemic brain
Mamoru Shibata, … , Hideyuki Okano, Masayuki Miura
Mamoru Shibata, … , Hideyuki Okano, Masayuki Miura
Published September 1, 2000
Citation Information: J Clin Invest. 2000;106(5):643-653. https://doi.org/10.1172/JCI10203.
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Article

Caspases determine the vulnerability of oligodendrocytes in the ischemic brain

Abstract

Although oligodendrocytes (OLGs) are thought to be vulnerable to hypoxia and ischemia, little is known about the detailed mechanism by which these insults induce OLG death. From the clinical viewpoint, it is imperative to protect OLGs as well as neurons against ischemic injury (stroke), because they are the only myelin-forming cells of the central nervous system. Using the Cre/loxP system, we have established a transgenic mouse line that selectively expresses p35, a broad-spectrum caspase inhibitor, in OLGs. After hypoxia, cultured OLGs derived from wild-type mice exhibited significant upregulation of caspase-11 and substantial activation of caspase-3, which led to cell loss. Expression of p35 or elimination of caspase-11 suppressed the caspase-3 activation and conferred significant protection against hypoxic injury. Expression of p35 in OLGs in vivo resulted in significant protection from ischemia-induced cell injury, thus indicating that caspases are involved in the ischemia-induced cell death of OLGs. Furthermore, the induction of caspase-11 was evident in the ischemic brains of wild-type mice, and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism(s) underlying ischemia-induced OLG death. Caspases may therefore offer a good therapeutic target for reducing ischemia-induced damage to OLGs.

Authors

Mamoru Shibata, Shin Hisahara, Hideaki Hara, Takemori Yamawaki, Yasuo Fukuuchi, Junying Yuan, Hideyuki Okano, Masayuki Miura

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Temporal profiles of ischemia-induced death of OLGs. In wild-type mice, ...
Temporal profiles of ischemia-induced death of OLGs. In wild-type mice, focal cerebral ischemia resulted in a time-dependent decrease in the density of OLGs in the cerebral cortex under ischemia (a–c). In Cre/p35 tg, ischemia-induced death of OLGs was attenuated (d–f). Original magnification, ×100. (g) OLG survival after MCAO. The numbers of pi-GST–positive cells in the granular insular cortex under ischemia were counted at a magnification of ×100 on 12- to 14-μm-thick frozen sections obtained from five to seven different animals from each genotype: wild-type littermates, p35 tg, Cre/p35 tg, and caspase-11–/– mice (caspase-11 KO). The data were expressed as means ± SEM per visual field. Statistical analysis was performed using ANOVA followed by Scheffé’s post hoc test. AP < 0.01, compared with sham-operated animals in each group.