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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Figure 3

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Activation of caspase-3 in OLGs after hypoxia. All the samples of hypoxi...
Activation of caspase-3 in OLGs after hypoxia. All the samples of hypoxia-treated OLGs were prepared 6 hours after hypoxia. (a) Western blot analysis showing that the cleavage of procaspase-3 occurred in wild-type, but not in Cre/p35, OLGs after hypoxia. (b and c) Under normal conditions, WT-OLGs did not exhibit immunoreactivity for the active form of caspase-3. (d and e) WT-OLGs showing immunoreactivity for the active form of caspase-3 and a condensed nuclear morphology. Note that a neighboring OLG that did not display immunoreactivity for the active form of caspase-3 had a normal nuclear morphology even after hypoxia (arrows). Original magnification, ×200. (f) Hypoxia-induced caspase-3–like protease (DEVDase) activation in wild-type and Cre/p35 cells. The measurements were carried out in triplicate for two different samples. The changes in DEVDase activity after hypoxia were expressed as a percentage. Statistical analysis was performed with a nonpaired t test. AP < 0.01. (g) Hypoxia-induced caspase-1–like protease (YVADase) activation in wild-type and Cre/p35 OLGs. The changes in YVADase activity after hypoxia were expressed as a percentage (means ± SEM). The measurements were carried out in triplicate for two different samples.