The N-methyl-D-aspartate receptor (NMDAR) is a highly Ca2+-permeable, ligand-gated ion channel in neurons and a member of the ionotropic glutamate receptor family. Excessive stimulation of the NMDAR leads to excessive intracellular Ca2+ influx, generation of free radicals such as nitric oxide and reactive oxygen species, collapse of the mitochondrial membrane potential, loss of ATP, and eventually neuronal apoptosis or necrosis depending on the intensity of the initial insult and the extent of energy recovery. This process is termed excitotoxicity and appears to be an integral component in a final common pathway to neuronal injury in neurodegenerative disorders including HIV-associated dementia. Infection by HIV-1 is mediated by interaction of the virus' envelope protein, gp120, with chemokine receptors in addition to CD4. These HIV co-receptors are expressed on all cell types in the CNS, although microglia are the predominant if not the sole cell type that is productively infected. HIV-associated neuronal damage occurs predominantly via an indirect pathway that involves the release of various excitotoxins by macrophages. Both NMDAR antagonists and specific chemokines can protect neuron, at least in vitro, against apoptosis induced by HIV/gp120 or by NMDA, suggesting cross-talk in the signaling pathways triggered by chemokine and NMDA receptors. The present review discusses neuronal apoptosis and HIV-associated dementia in light of recent findings concerning NMDARs and chemokine receptors.
