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Professor of Anatomy and Cell Biology
Primary Office: 1-530 BSBIowa City, IA 52242
Primary Office Phone: 319-335-7732
BS, Chemistry, Lehigh UniversityPhD, Biochemistry, Harvard University
Post Doctorate, Biochemistry, Yale UniversityFellowship, Anatomy, Harvard Medical School, Harvard University
Biosciences Graduate ProgramDepartment of Anatomy and Cell Biology Graduate Program
Discovery of a neuroprotective mechanism, mediated by nitric oxide (NO), which ameliorates alcohol-induced neuronal death in the developing brain.
Alcohol (ethanol) is highly toxic to the developing fetal brain and can result in Fetal Alcohol Syndrome (FAS), a severe public health problem and one of the leading causes of mental retardation. Although there has been extensive research on FAS, there are several significant questions, which remain unanswered, and our work focuses on two of them. First, alcohol exposure of the developing brain induces neuronal death in various brain regions, cerebellum, hippocampus, and neocortex. What is the underlying mechanism by which alcohol induces this neuronal death in the immature brain? Second, although the fetal brain is highly vulnerable to alcohol, for unknown reasons, the mature brain is much less so. This raises the question, are there neuroprotective mechanisms in the mature brain, which protect it against alcohol neurotoxicity? Our research goals are to identify potential neuroprotective mechanisms, characterize their molecular components, determine whether neuroprotection is dependent on brain maturation, and establish whether neuroprotection ameliorates the neuropathological and functional deficits caused by alcohol exposure of the developing brain. Understanding how a neuroprotective mechanism prevents alcohol-induced neuronal death will also provide insight into the neuronal damage caused by alcohol, which eventually leads to the death of the neuron.
Utilizing primary cultures of cerebellar granule neurons, we identified a neuroprotective mechanism, which ameliorated alcohol-induced neuronal death in these cultures. This neuroprotection was induced by nitric oxide (NO), a remarkably simple molecule, which belies the complexity of its functions. Since the in vitro studies suggested a key role for NO in neuroprotection against alcohol toxicity, experiments were designed to test whether NO similarly functions as a neuroprotective agent in vivo. The model system for our in vivo studies was a mutant mouse strain, which had a null mutation of the neuronal nitric oxide synthase (nNOS) gene, the synthetic enzyme for NO in neurons. We hypothesized that since NO cannot be synthesized by neurons in these mutant mice; these neurons would lack NO-mediated neuroprotection, and therefore would be more vulnerable to alcohol neurotoxicity. Experimental results supported out hypothesis and indicated that nNOS-deficient mice were more vulnerable to alcohol toxicity and had greater alcohol-induced neuronal losses in the cerebellum, hippocampus, and neocortex compared to wild type mice. In other experiments, we found that neurons, which were obtained from these nNOS-deficient mice and placed in culture, are highly vulnerable to alcohol-induced death. However, introduction of the nNOS gene into these neurons reverses this alcohol vulnerability, and neurons are now relatively alcohol resistant.
In summary, the combination of in vitro and in vivo experiments provides strong evidence that NO ameliorates the neuronal losses caused by alcohol exposure of the immature brain. Current and future molecular studies will investigate the underlying signaling mechanism by which NO induces this neuroprotective effect. Although our studies have clearly shown the NO can reduce alcohol-induced neuronal death, we hypothesize that this reduction in neuropathology by NO correlates with reductions in the functional deficits caused by alcohol exposure of the developing brain. Future behavioral studies in mice will investigate whether NO can ameliorate alcohol-induced functional deficits in the immature brain. Our exciting results suggest that a neuroprotective gene, such as nNOS, can protect neurons against alcohol toxicity and may foster a gene therapy approach to prevent alcohol-induced damage to the developing nervous system.
Date Last Modified: 06/07/2014 -
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