Cytotoxicity of the E2-isoprostane 15-E2t-IsoP on oligodendrocyte progenitors

Oxidant stress plays a significant role in the pathogenesis of periventricular leukomalacia (PVL). Isoprostanes (IsoPs) are bioactive products of lipid peroxidation abundantly generated during hypoxic-ischemic injuries. Because loss of oligodendrocytes (OLs) occurs early in PVL, we hypothesized that IsoPs could induce progenitor OL death. 15-E-2t-IsoP but not 15-F-2t-IsoP elicited a concentration-dependent death of progenitor OLs by oncosis and not by apoptosis, but exerted minimal effects on mature OLs. 15-E-2t-IsoP-induced cytotoxicity could not be explained by its conversion into cyclopentenones, because PGA(2) was hardly cytotoxic. On the other hand, thromboxane A(2) (TxA(2)) synthase inhibitor CGS12970 and cyclooxygenase inhibitor ibuprofen attenuated 15-E-2t-IsoP-induced cytotoxicity. Susceptibility of progenitor OLs was independent of TxA2 receptor (TP) expression, which was far less in progenitor than in mature OLs. However, TxA2 synthase was detected in precursor but not in mature OLs, and TxA2 mimetic U46619 induced hydroperoxides generation and progenitor OL death. The glutathione synthesis enhancer N-acetylcysteine prevented 15-E-2t-IsoP-induced progenitor cell death. Depletion of glutathione in mature OLs with buthionine sulfoximine rendered them susceptible to cytotoxicity of 15-E-2t-IsoP. These novel data implicate 15-E-2t-IsoP as a product of oxidative stress that may contribute in the genesis of PVL. (C) 2004 Elsevier Inc. All rights reserved.