University of Kentucky
Neurotoxic Effects of HIV-1 and Identification of Drugs That Are Protective in a Rat Model of HIV-related Brain Damage
Institution
University of Kentucky
Faculty Advisor/ Mentor
Mark Prendergast
Abstract
The present study investigated how individuals infected with human immunodeficiency virus type-I (HIV-1) develop neurological symptoms such as motor and memory problems. These symptoms most likely occur after HIV-1 releases proteins in the brain following replication. Our laboratory has studied the neurotoxic effects of the HIV replication promoter Tat in isolated portions of the rat brain that were maintained for several days to: (1) identify the mechanism by which this HIV protein injures the brain and (2) identify types of medications that may reduce the toxic effects of HIV-1 proteins. We observed that brief exposure to Tat (5 min) produced large increases in neuronal Ca2+ content and significant damage in the rat hippocampus, even at very low concentrations. Both effects of Tat were reduced by co-exposure to drugs (MK-801 and arcaine) that reduced the function of NMDA-type glutamate receptors. Further, co-exposure of the brain to a novel cholinergic receptor agonist, MHP-133, also reduced the toxic effects of Tat exposure. In sum, these data suggest that the HIV-1 replication promoter Tat damages brain tissue, in part, by activating NMDA receptors. Additionally, exposure to drugs that moderate the function of this excitatory receptor or which stimulate the function of cholinergic receptors may possess a therapeutic efficacy in the treatment of HIV-related brain damage.
Neurotoxic Effects of HIV-1 and Identification of Drugs That Are Protective in a Rat Model of HIV-related Brain Damage
The present study investigated how individuals infected with human immunodeficiency virus type-I (HIV-1) develop neurological symptoms such as motor and memory problems. These symptoms most likely occur after HIV-1 releases proteins in the brain following replication. Our laboratory has studied the neurotoxic effects of the HIV replication promoter Tat in isolated portions of the rat brain that were maintained for several days to: (1) identify the mechanism by which this HIV protein injures the brain and (2) identify types of medications that may reduce the toxic effects of HIV-1 proteins. We observed that brief exposure to Tat (5 min) produced large increases in neuronal Ca2+ content and significant damage in the rat hippocampus, even at very low concentrations. Both effects of Tat were reduced by co-exposure to drugs (MK-801 and arcaine) that reduced the function of NMDA-type glutamate receptors. Further, co-exposure of the brain to a novel cholinergic receptor agonist, MHP-133, also reduced the toxic effects of Tat exposure. In sum, these data suggest that the HIV-1 replication promoter Tat damages brain tissue, in part, by activating NMDA receptors. Additionally, exposure to drugs that moderate the function of this excitatory receptor or which stimulate the function of cholinergic receptors may possess a therapeutic efficacy in the treatment of HIV-related brain damage.