Potentiation of Excitotoxicity in HIV-1 Associated Dementia and the Significance of Glutaminase

Abstract

HIV-1 Associated Dementia (HAD) is a significant consequence of HIV infection. Although multiple inflammatory factors contribute to this chronic, progressive dementia, excitotoxic damage appears to be an underlying mechanism in the neurodegenerative process. Excitotoxicity is a cumulative effect of multiple processes occurring in the CNS during HAD. The overstimulation of glutamate receptors, an increased vulnerability of neurons, and disrupted astrocyte support each potentiate excitotoxic damage to neurons. Recent evidence suggests that poorly controlled generation of glutamate by phosphate-activated glutaminase may contribute to the neurotoxic state typical of HAD as well as other neurodegenerative disorders. Glutaminase converts glutamine, a widely available substrate throughout the CNS to glutamate. Inflammatory conditions may precipitate unregulated activity of glutaminase, a potentially important mechanism in HAD pathogenesis.

Figure 1

HAD Potentiation of Excitotoxicity. HAD causes an increase in extracellular glutamate and enhances the susceptibility of neurons to damage by excitotoxins. Infected mononuclear phagocytes (MP) produce soluble factors including inflammatory cytokines and viral proteins, inducing functional changes in the astrocyte population and causing damage to neurons via excitotoxic insult. Astrocytes can also express inflammatory cytokines and trophic support of neurons may be altered. In addition, changes in glutamate uptake leads to altered glutamate homeostasis. Extracellular glutamine, a widely available amino acid, may be converted to glutamate by glutaminase, leading to further glutamate increase and neuronal damage.

Figure 2

Glutamine-Glutamate Interconversion. Glutamine is deaminated to glutamate in an energy free process mediated by the enzyme phosphate-activated glutaminase. The reverse reaction is an energy dependent process carried out by the enzyme glutamine synthetase.

Figure 3

Pathways to Excitotoxicity. Over-stimulation of glutamate receptors initiates multiple cascades with the potential to induce cellular damage and death. NMDAR activation by agonists, notably glutamate, leads to the influx of Ca2+ and Na+ ions, an effect potentiated by AMPA receptors. MGluR activation, particularly mGluR1, leads to additional Ca2+ release. The excess Ca2+ triggers multiple pathways including nNOS, JNK, and Phospholipase, as well as leading to mitochondrial stress and dysfunction.

Figure 4

Model for Glutaminase Activity in HAD. Infected and/or activated mononuclear phagocytes (MP) release functional glutaminase to the glutamine rich extracellular space. Glutaminase then converts glutamine to glutamate in an energy free process. This increase in glutamate leads to over-stimulation of glutamate receptors, notably NMDA-R, causing excitotoxic neuron death.