Role of the NMDA Receptor in Neuronal Apoptosis and HIV-Associated Dementia

Abstract

Neuronal injury and apoptosis may account, at least in part, for neurological complications associated with human immunodeficiency virus (HIV)-1 infection ranging from mild cognitive and motor impairment to dementia. The primary cell types infected in the brain are macrophages and microglia. These cells have been found in vivo and in vitro to release neurotoxic factors. Evidence has accumulated that neuronal apoptosis in HIV-related insults occurs predominantly via an indirect pathway comprising a complex cooperation of cytokines, reactive oxygen species and reactive nitrogen species, lipid mediators, and excitotoxins. These molecules lead to excessive stimulation of the N-methyl-Daspartate subtype of glutamate receptor (NMDAR). Of note, chemokine receptors, which, in conjunction with CD4, mediate HIV infection of macrophages/microglia, are present on neurons and astrocytes in addition to macrophages/microglia. Thus, these receptors potentially allow direct interaction between the virus and neurons (Fig. 2). The fact that specific chemokines ameliorate HIV/gp120induced neuronal apoptosis that is mediated by NMDARs suggests a functional connection between the receptors for chemokines and NMDA. Accordingly, here we review the role of the NMDAR in HIV-1-related and excitotoxic neuronal cell death.