Caspases determine the vulnerability of oligodendrocytes in the ischemic brain

Although oligodendrocytes (OLGs) are thought to be vulnerable to hypoxia an d ischemia, little is known about the detailed mechanism by which these ins ults induce OLG death. From the clinical viewpoint, it is imperative to pro tect 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 selectiv ely expresses p35, a broad-spectrum caspase inhibitor, in OLGs. After hypox ia, cultured OLGs derived from wild-type mice exhibited significant upregul ation of caspase-11 and substantial activation of caspase-3, which led to c ell loss. Expression of p35 or elimination of caspase-11 suppressed the cas pase-3 activation and conferred significant protection against hypoxic inju ry. Expression of p35 in OLGs in vivo resulted in significant protection fr om 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 e xhibited resistance to brain ischemia in mice deficient in caspase-11, sugg esting that caspase-11 is critically implicated in the mechanism(s) underly ing ischemia-induced OLG death. Caspases may therefore offer a good therape utic target for reducing ischemia-induced damage to OLGs.