Targeting the Glutamatergic System for the Treatment of HIV-Associated Neurocognitive Disorders

• Published in: Journal of neuroimmune pharmacology 2013-06, Vol.8 (3), p.594-607
• Main Authors: Potter, Michelle C., Figuera-Losada, Mariana, Rojas, Camilo, Slusher, Barbara S.
• Format: Article
• Language: English
• Subjects: AIDS Dementia Complex - diagnosis; AIDS Dementia Complex - drug therapy; AIDS Dementia Complex - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cognition Disorders - diagnosis; Cognition Disorders - drug therapy; Cognition Disorders - metabolism; Drug Delivery Systems - methods; Excitatory Amino Acid Antagonists - administration & dosage; Glutamic Acid - metabolism; HIV; HIV Infections - diagnosis; HIV Infections - drug therapy; HIV Infections - metabolism; Human immunodeficiency virus; Humans; Immunology; Invited Review; Neurosciences; Neurotoxicity; Pharmacology/Toxicology; Receptors, Glutamate - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Treatment Outcome; Virology
• ISSN: 1557-1890; 1557-1904
• DOI: 10.1007/s11481-013-9442-z

The accumulation of excess glutamate in the extracellular space as a consequence of CNS trauma, neurodegenerative diseases, infection, or deregulation of glutamate clearance results in neuronal damage by excessive excitatory neurotransmission. Glutamate excitotoxicity is thought to be one of several mechanisms by which HIV exerts neurotoxicity that culminates in HIV-associated neurocognitive disorders (HAND). Excess glutamate is released upon HIV infection of macrophage/microglial cells and has been associated with neurotoxicity mediated by gp120, transactivator of transcription (Tat) and other HIV proteins. Several strategies have been used over the years to try to prevent glutamate excitotoxicity. Since the main toxic effects of excess glutamate are thought to be due to excitotoxicity from over activation of glutamate receptors, antagonists of these receptors have been popular therapeutic targets. Early work to ameliorate the effects of excess extracellular glutamate focused on NMDA receptor antagonism, but unfortunately, potent blockade of this receptor has been fraught with side effects. One alternative to direct receptor blockade has been the inhibition of enzymes responsible for the production of glutamate such as glutaminase and glutamate carboxypeptidase II. Another approach has been to regulate the transporters responsible for modulation of extracellular glutamate such as excitatory amino acid transporters and the glutamate-cystine antiporter. There is preliminary experimental evidence that these approaches have potential therapeutic utility for the treatment of HAND. These efforts however, are at an early stage where the next steps are dependent on the identification of drug-like inhibitors as well as the development of predictive neuroAIDS animal models.