Cytotoxicity of the E(2)-isoprostane 15-E(2t)-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 TxA(2) receptor (TP) expression, which was far less in progenitor than in mature OLs. However, TxA(2) synthase was detected in precursor but not in mature OLs, and TxA(2) 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.
Brault
Sonia
S
Research Center of Hôpital Sainte-Justine, Department of Pediatrics and Pharmacology, Université de Montréal, Québec, Canada.
Martinez-Bermudez
Ana Katherine
AK
Roberts
Jackson
J
Cui
Qiao-Ling
QL
Fragoso
Gabriela
G
Hemdan
Sandy
S
Liu
Hsueh-Ning
HN
Gobeil
Fernand
F
Quiniou
Christiane
C
Kermorvant-Duchemin
Elsa
E
Lachance
Christian
C
Almazan
Guillermina
G
Varma
Daya R
DR
Chemtob
Sylvain
S
D000818:Animals; D000831:Animals, Newborn; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D028421:Isoprostanes / Q000633:toxicity*; D008297:Male; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D011454:Prostaglandins A / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects*; D013928:Thromboxane A2 / Q000378:metabolism
D028421:Isoprostanes; D011454:Prostaglandins A; D013928:Thromboxane A2; C100008:prostaglandin A2