title: Targeting the glutamatergic system for the treatment of HIV-associated neurocognitive disorders.
abstract: 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.
authors.affiliation: Brain Science Institute NeuroTranslational Drug Discovery Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Potter
authors.forename: Mariana
authors.initials: M
authors.lastname: Figuera-Losada
authors.forename: Camilo
authors.initials: C
authors.lastname: Rojas
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D015526:AIDS Dementia Complex / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D003072:Cognition Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D018698:Glutamic Acid / Q000378:metabolism*; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid
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