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-inflammitories, or glutamate receptor antagonists, and then noting their efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK032200-01
Application #
6161955
Study Section
Special Emphasis Panel (LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Hernandez-Sanchez, C; Basile, A S; Fedorova, I et al. (2001) Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death. Proc Natl Acad Sci U S A 98:3549-54
Koustova, E; Sei, Y; Fossom, L et al. (2001) LP-BM5 virus-infected mice produce activating autoantibodies to the AMPA receptor. J Clin Invest 107:737-44
Barger, S W; Basile, A S (2001) Activation of microglia by secreted amyloid precursor protein evokes release of glutamate by cystine exchange and attenuates synaptic function. J Neurochem 76:846-54
Iida, R; Saito, K; Yamada, K et al. (2000) Suppression of neurocognitive damage in LP-BM5-infected mice with a targeted deletion of the TNF-alpha gene. FASEB J 14:1023-31
Koustova, E; Sei, Y; McCarty, T et al. (2000) Accelerated development of neurochemical and behavioral deficits in LP-BM5 infected mice with targeted deletions of the IFN-gamma gene. J Neuroimmunol 108:112-21
Allen, J W; Ivanova, S A; Fan, L et al. (1999) Group II metabotropic glutamate receptor activation attenuates traumatic neuronal injury and improves neurological recovery after traumatic brain injury. J Pharmacol Exp Ther 290:112-20
Basile, A S; Brichta, A M; Harris, B D et al. (1999) Dizocilpine attenuates streptomycin-induced vestibulotoxicity in rats. Neurosci Lett 265:71-4
Espey, M G; Basile, A S (1999) Glutamate augments retrovirus-induced immunodeficiency through chronic stimulation of the hypothalamic-pituitary- adrenal axis. J Immunol 162:4998-5002
Segal, J A; Harris, B D; Kustova, Y et al. (1999) Aminoglycoside neurotoxicity involves NMDA receptor activation. Brain Res 815:270-7
Kustova, Y; Grinberg, A; Basile, A S (1999) Increased blood-brain barrier permeability in LP-BM5 infected mice is mediated by neuroexcitatory mechanisms. Brain Res 839:153-63

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