Mechanisms of oxidative damage and protection of oligodendrocytes
Oligodendrocytes, the myelin-forming glial cells of the central nervous system (CNS), are targets of various neurodegenerative conditions, including multiple sclerosis, spinal cord injury and hypoxic injury. Like neurons, oligodendrocytes and myelin are vulnerable to the destructive process of membrane lipid peroxidation (MLP). This occurs because oligoendrocytes are thought to be biochemically predisposed to an overproduction of oxygen free radicals, the initiators of MLP, without sufficient antioxidant defenses to detoxify them. Research on Alzheimer's disease has revealed a neurotoxic mechanism by which reactive aldehydes released from cell membranes as MLP byproducts cause neuronal death and dysfunction. One of these aldehydes, 4-hydroxynonenal (HNE), is postulated to be the principal cytotoxic second messenger mediating MLP-induced neuronal death. Our laboratory has found that oligodendrocytes, are also very sensitive to HNE. Using model cultures of oligodendrocytes grown outside of the brain, we are investigating the molecular mechanism by which HNE causes oligodendrocyte death and impaired function at sublethal concentrations. Other studies are seeking evidence of HNE damage in multiple sclerosis lesions. We are also investigating ways to augment oligodendrocyte defenses against MLP and HNE damage by enhancing the cell's endogenous mechanisms for oxyradical detoxification and exogenous administration of antioxidants having high CNS bioavailability.
Developmental Biology: Cytokines regulating ontogeny and differentiation of neural stem cells
A second interest in the laboratory concerns the identification of neural signaling molecules responsible for inducing the differentiation of neural stem cells along specific lineages in the developing and adult CNS. We have recently discovered that cardiotrophin-1 (CT-1), a member of the interleukin-6 cytokine family, plays an important physiologic role in brain homeostasis as it is expressed by cell types (choroid epithelium, ependyma, leptomeninges) lining the cerebrospinal fluid compartment and induces development of cultured neural stem cells into astrocytes. These findings predict a role for CT-1 in the regulation of neural stem cells now known to persist into adulthood as a potential source of regenerating neurons. We are testing this hypothesis by coupling in vitro/in vivo approaches with the analysis of knockout mice deficient in CT-1 gene expression. A better understanding of the signals controlling neural stem cell differentiation could lead to ways of enhancing the regenerative potential of the injured and diseased CNS.
Mechanisms of oxidative damage and protection of oligodendrocytes; Cytokines regulating ontogeny and differentiation of neural stem cells.
Keywords:Regulation of CNS cell differentation.
