The primary interests focus on the pathogenesis and treatment of chronic neurodegenerative diseases, many of which involve alterations in neurotransmitter receptor systems subserving normal CNS function as a result of derangements in peripheral organ function. For example, hepatic encephalopathy (HE) is a neuropsychiatric syndrome accompanying acute or chronic liver failure. It is characterized by personality changes, sleep inversion, generalized cognitive slowing, incoordination, and ataxia leading to coma. We are investigating the role that endogenous benzodiazepine receptor ligands, neurosteroids, and ammonia play in the pathogenesis of this syndrome and developing pharmacological interventions to deal with these changes. Present projects include: isolation and identification of the structures of benzodiazepine receptor agonists found in elevated levels in the brains of experimental models of acute liver failure; determination of the sources of these compounds and their regulation; investigation of the modulation of GABA-gated Cl- currents by pathophysiologically relevant concentrations of ammonia in cultured neuronal cell lines; determination of the efficacy of neurosteroid receptor antagonists and 5a-reductase inhibitors in reversing the physiological and behavioral manifestations of HE; determining the role of glutamatergic neurotransmission in the manifestations of HE. Another chronic neurodegenerative disorder under investigation is AIDS dementia complex. We are presently characterizing many of the basic immunological and neurological pathologies of two murine models of retrovirus-induced cognitive deficits. These models are being used to investigate the role of excitotoxins, cytokines and autoimmune factors in the pathogenesis of the behavioral and neurochemical abnormalities associated with retroviral infections in these mice, and treating them with with cytokine synthesis inhibitors, anti-inflammatory agents, or glutamate receptor antagonists, and then noting their efficacy. In addition to investigations of pharmacological techniques for limiting neurodegeneration and cognitive loss, we are phasing in behavioral characterizations of knockout and transgenic mouse models of disease, as well as development of modalities for imaging transplanted pancreatic islet cells and other imaging techniques. - Hepatic Coma, AIDS Dementia, Excitotoxicity
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