Mechanisms of Free Radical Mediated Injury

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Periventricular leukomalacia (PVL) is the predominant pathology underlying cerebral palsy in premature infants. The primary cell type that is injured in PVL is the oligodendrocyte (OL). Because the period of peak incidence for PVL is prior to the onset of myelination, PVL appears to be a lesion involving premyelinating OLs (preOLs), as opposed to mature, myelin basic protein expressing, OLs. We now know that microglia are an important constituent of the PVL lesion, and that inducible nitric oxide synthase is strongly expressed in microglia as well as in reactive astrocytes and OLs. The hypothesis of this project is that peroxynitrite, a highly toxic reactive nitrogen species formed by reaction of nitric oxide and superoxide, plays an important role in the death of preOLs that occurs in PVL. Our preliminary results suggest that the toxicity of activated microglia to OLs is dependent upon the formation of peroxynitrite. Moreover, we have begun to characterize the mechanisms by which peroxynitrite is toxic to cells, and have found that this substance appears to activate the poly(ADP-ribose) polymerase (PARP) suicide pathway in preOLs that has been well-characterized in other cell types. Interestingly, we have also obtained evidence that peroxynitrite toxicity to mature OLs and preOLs involves activation of arachidonic acid metabolism, although by distinct pathways. These results suggest a greater complexity to the activation of the PARP pathway by peroxynitrite, at least in some cells, than has been appreciated. The specific aims of this project are to: 1) characterize the mechanisms of injury to OLs triggered by activation of microglia; 2) characterize the pathway(s) of injury to preOLs activated by peroxynitrite; 3) test for a role for peroxynitrite in hypoxic/ischemic injury and inflammatory injury to white matter of the developing brain. These studies will help to elucidate the molecular mechanisms of injury to developing white matter pertinent to the pathogenesis of PVL, and provide a foundation for the design of rational treatments for this disorder.