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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Hypoxic injury to OLG cultures. OLGs were examined 6 hours after hypoxia...
Hypoxic injury to OLG cultures. OLGs were examined 6 hours after hypoxia. We counted the numbers of MBP-positive cells with morphological features consistent with mature oligodendrocytes. (a) The numbers of mature OLGs with intact arborizations counted at a magnification of ×100. The quantification was carried out in 18 independent visual fields from three distinct cultures for each group. Statistical analysis was performed using ANOVA followed by Scheffé’s post hoc test. AP < 0.01. (b and d) OLGs from wild-type mice (wild-type, b) and p35 tg (Cre/p35, d), both of which were treated with the cre recombinase expression adenovirus vector, immunostained with an MBP-specific antibody. OLGs were characterized morphologically by extensive arborization of processes and myelin formation. (c) In cultures of wild-type OLGs subjected to 6 hours of hypoxia, cell lysis, destruction of processes, and scattered cell debris were seen. (e) The hypoxia-induced morphological changes were attenuated in Cre/p35. Original magnification, ×200. (f) The proportions of TUNEL-positive cells after hypoxia in wild-type and Cre/p35 OLGs. The quantification was performed in six independent random samplings of approximately 150 cells each, and the data were expressed as a percentage of the total cell number (means ± SEM). Statistical analysis was performed using a nonpaired t test. AP < 0.01.