Periventricular leukomalacia (PVL) is the principal form of brain injury in preterm neonates. In addition to the vasculopathy associated with hypoxicischemic injury, PVL is characterized by the loss of progenitor oligodendrocytes (OLs). Oxidant stress and lipid peroxidation increase in hypoxic-ischemic injuries, particularly in the immature brain. We hypothesized that the major lipid peroxidation products isoprostanes 15-F2t-IsoP and 15-E2t-IsoP, and lysophosphatidic acid (LPA) could be implicated in the pathogenesis of PVL by affecting the survival of brain OLs and microvascular endothelial cells (ECs). / Cytotoxicity of the lipid peroxidation products was assessed on cultured rat progenitor and mature OLs and piglet cerebromicrovascular ECs using the MTT assay. The two isoprostanes displayed different cytotoxic profiles. 15-E 2t-IsoP induced progenitor OL death but did not affect mature OL or microvascular EC survival. In contrast, 15-F2t-IsoP induced death of ECs but not of progenitor and mature OLs. As well, LPA triggered brain microvascular EC death. In all cases, cells did not exhibit classical features of apoptosis (nuclear condensation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL), caspases activation) but displayed signs of oncotic necrosis (propidium iodide incorporation, cell swelling, lactate dehydrogenase release). Cytotoxicity conveyed by both isoprostanes involved TxA2 synthesis, as determined by radioimmunoassay and by the protective effect of TxA2 synthase inhibitors. In addition, progenitor OLs were susceptible to 15-E2t-IsoP due to their low antioxidant defenses. On the other hand, LPA caused EC death through the LPA1 receptor which activated the stress activated protein kinases p38 MAPK and JNK; these kinases were responsible for the decreased intracellular glutathione content observed and the induction of iNOS which caused protein nitrosylation. EC death and neuromicrovascular degeneration caused by 15-F2t-IsoP and LPA were observed ex vivo on isolated microvessels and brain explants and in vivo, with intracerebroventricular infusion and intraocular injections. / These novel data implicate 15-E2t-IsoP, 15-F2t-IsoP and LPA as major lipid peroxidation products that may contribute to the genesis of PVL by affecting the survival of progenitor OLs and microvascular ECs.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.102480 |
| Date | January 2006 |
| Creators | Brault, Sonia. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology & Therapeutics.) |
| Rights | © Sonia Brault, 2006 |
| Relation | alephsysno: 002566055, proquestno: AAINR27756, Theses scanned by UMI/ProQuest. |
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