HIV-associated dementia (HIVAD) is a challenging illness in healthcare field today. This disease occurs as a result of HIV-infected monocytes and macrophages crossing into the brain via the blood-brain barrier. These infected cells then release various neurotoxins including tumor necrosis alpha (TNF-alpha), nitrous oxide, and chemokines which creates an inflammatory environment in the brain. Additionally, HIV infection typically spreads to microglia while astrocytes become latently infected. The infection of these two cell types can lead to the release of the HIV proteins Tat and gp120 in addition to the neurotoxins previously mentioned. The release of the viral proteins and neurotoxins leads to significant injury and death in neurons, which are not directly infected by the HIV. Neuronal injury and cell death are directly related to the cognitive dysfunctions observed in patients diagnosed with HIVAD;therefore, a neuroprotective agent would be a powerful aid in the fight against this illness. Preliminary studies in our laboratory have identified the FDA-approved antifungal agent fluconazole as a neuroprotective agent against HIV Tat protein and 3-nitroproprionic acid, a toxin used to mimic the oxidative damage, reactive oxygen species production, and ensuing neurodegenration resulting form HIV infection in the brain. The applicant will characterize the neuroprotective effects observed with the drug fluconazole by determining the activity of the drug against HIV gp120, its effect on neuroprogenitor cells, and whether some actions of the drug are mediated by a direct effect on the mitochondria or the cell membrane. Additionally, this grant proposes to investigate the in vivo effects of fluconazole on HIV protein transgenic mouse models. Finally, this grant proposes to investigate the mechanism by which fluconazole is responsible for its neuroprotective effects. Our preliminary studies show that the presence of fluconazole leads to decreased intracellular levels of cyclic adenosine monophosphate (cAMP), an important secondary messenger. We plan to investigate if this inhibition of intracellular cAMP is responsible for fluconazole's neuroprotective effects, and if these effects are mediated by the triazole functional groups present in the drug's structure.

Public Health Relevance

The research is important to public health since HIV-associated neurocognitive disorder (HAND) is becoming more and more prevalent in HIV-infected populations. Additionally, although the use of antiretroviral therapy is now becoming more accessible worldwide, antiretroviral therapy is unable to halt the progression of neurocognitive dysfunction observed in individuals with HAND. Therefore, the identification of fluconazole as a potent neuroprotective agent would greatly reduce the disease burden of HAND.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS066790-02
Application #
8072571
Study Section
Special Emphasis Panel (ZRG1-AARR-H (22))
Program Officer
Wong, May
Project Start
2010-03-15
Project End
2012-03-14
Budget Start
2011-03-15
Budget End
2012-03-14
Support Year
2
Fiscal Year
2011
Total Cost
$41,800
Indirect Cost
Name
Johns Hopkins University
Department
Neurology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218