Intervention in the extensive CNS pathology that underlies fetal alcohol syndrome is a high priority for alcohol researchers and is the long-term goal of this laboratory. There is no treatment for the brain damage associated with fetal ethanol exposure since the cellular and molecular mechanisms by which ethanol causes developmental neuropathogenesis are not yet understood. Although many years of study have focused on the neuronal and macroglial pathology caused by ethanol, the impact of ethanol upon an important, major cell type in the brain - the microolial cell - has not been probed until these recent studies. This is surprising since ethanol damage to microglia may produce serious consequences within developing neuronal populations. Microglia communicate directly with neurons and the immune system to influence neuronal survival and function. They are the first line of defense against CNS insults, are the principal immune cells within the brain, and are active in cytokine secretion, reactive oxygen species secretion, antigen presentation and phagocytosis. Pilot studies reveal that damage to microglia occurs at ethanol concentrations far below that required to cause direct neuronal death. Parallel studies in the cerebellum and cultures of microglia have led to the HYPOTHESIS that ethanol pathogenesis in microglia occurs via specific cellular mechanisms: (1) ethanol inhibits microglial genesis and survival, (2) ethanol suppresses microglial maturation to further reduce the population of mature microglia, (3) the activity and functionality of microglia are impaired as a result, and (4) since there is no turnover of microglia, the impaired microglial functionality persists in the adult. This study will define the mechanisms of ethanol pathogenesis within the microglial population. A causal relationship between microglial pathology and neuronal toxicity will be defined. The critical period of microglial sensitivity to the teratogenic effects of ethanol will be determined. The acute, transient or persistent nature of ethanol pathogenesis within the microglial population will be distinguished. The molecular mechanisms of ethanol activity will be identified. The intracellular signaling pathways underlying ethanol activity will be manipulated in order to block ethanol pathogenesis in microglia. Block of ethanol-induced microglial pathology may provide a new opportunity to intervene in the brain damage caused by fetal ethanol exposure.
| Kane, Cynthia J M; Phelan, Kevin D; Han, Lihong et al. (2011) Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-? agonists. Brain Behav Immun 25 Suppl 1:S137-45 |
| Kane, Cynthia J M; Chang, Jason Y; Roberson, Paula K et al. (2008) Ethanol exposure of neonatal rats does not increase biomarkers of oxidative stress in isolated cerebellar granule neurons. Alcohol 42:29-36 |
| Carter, Charleata A; Kane, Cynthia J M (2004) Therapeutic potential of natural compounds that regulate the activity of protein kinase C. Curr Med Chem 11:2883-902 |
| Light, Kim E; Brown, Donna P; Newton, Bruce W et al. (2002) Ethanol-induced alterations of neurotrophin receptor expression on Purkinje cells in the neonatal rat cerebellum. Brain Res 924:71-81 |
