The overall goal of this project is to delineate the mechanisms that contribute to the neurotoxicity of HIV-1 derived peptides in the developing brain. Our primary focus will be to assess the influence of the HIV-1 envelope protein gp120 on excitatory amino acid (EAA)-mediated brain injury. This proposal will test the hypothesis that gp120 is neurotoxic in the developing brain, and that neurotoxicity is mediated, at least in part, by enhanced activation of EAA receptors. Our preliminary data demonstrate that in 7 day old (P7) rats:(i) intra-hippocampal injection of gp120 together with the EAA agonist N-methyl-D-aspartate (NMDA) selectively increases the extent of neuronal loss and tissue atrophy, in comparison with injection of the same dose of NMDA alone; and (ii) in a perinatal rodent stroke model in which NMDA receptor over-activation by endogenous EAA contributes to irreversible neuronal injury, preceding intra-hippocampal injection of gp120 markedly increases the extent of ischemic brain injury. The first Specific Aim includes assessment of intrinsic gp 120 neurotoxicity, evaluation of the impact of concurrent gpl20 administration on the severity of EAA agonist-mediated brain injury, and identification of the neurotoxic moiety of gp120 in P7 rats. The second Specific Aim is to dissect the mechanisms by which gp120 may influence NMDA receptor activation: we will determine if intracerebral injection of gp120 alters the distribution or density of NMDA-type EAA receptors or high affinity EAA re-uptake activity, and if EAA antagonists attenuate gpl20 neurotoxicity. The third Specific Aim is to determine if gp120 increases susceptibility to brain injury resulting either from pathophysiologic insults that stimulate synaptic accumulation of endogenous EAA (e.g. hypoxia-ischemia, hypoglycemia) or from pharmacologic interventions that stimulate synaptic EAA accumulation (e.g. treatment with EAA uptake inhibitors). Understanding these potential mechanisms of HIV neurotoxicity in the perinatal brain may provide the scientific foundation for development of more effective neuroprotective interventions for HIV- infected infants.
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