The primary interests of this workgroup 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. Another chronic neurodegenerative disorder under investigation is AIDS dementia complex. We are presently characterizing many of the basic immunological and neurological pathologies of a murine model 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 cytokine synthesis inhibitors, anti-inflammatories, or glutamate receptor antagonists, 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Intramural Research (Z01)
Project #
1Z01DK032200-04
Application #
6432108
Study Section
(LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst Diabetes/Digst/Kidney
Department
Type
DUNS #
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
Espey, M G; Ellis, R J; Heaton, R K et al. (1999) Relevance of glutamate levels in the CSF of patients with HIV-1-associated dementia complex. Neurology 53:1144-5
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

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