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 4

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Translocation of cytochrome c from mitochondria in OLGs after hypoxia. (...
Translocation of cytochrome c from mitochondria in OLGs after hypoxia. (a) A WT-OLG under normal conditions showing a punctate immunostaining pattern for cytochrome c that coincided with the localization of mitochondria, as revealed by the mitochondrial marker MitoTracker Red (b). (c) A merged image of a and b. (d–f) A WT-OLG subjected to 6 hours of hypoxia exhibiting a diffuse pattern of immunostaining for cytochrome c. The cell assumed a round morphology without processes, a morphological sign indicative of an unhealthy state. (g–i) A p35-expressing OLG showing a diffuse staining pattern for cytochrome c but maintaining processes. Original magnification, ×400. (j) The proportions of OLGs showing a diffuse pattern of cytochrome c immunostaining. Quantification was performed with ten random samplings of approximately 100 cells each. The data are expressed as a percentage of the total cell number (means ± SEM). Statistical analysis was performed by ANOVA followed by Scheffé’s post hoc test. AP < 0.01.