HIV-1, Methamphetamine and Astrocyte Glutamate Regulation: Combined Excitotoxic Implications for Neuro-AIDS
Irma E. Cisneros and Anuja Ghorpade
Affiliation: University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA.
Glutamate, the most abundant excitatory transmitter in the brain can lead to neurotoxicity when not properly
regulated. Excitotoxicity is a direct result of abnormal regulation of glutamate concentrations in the synapse, and is a
common neurotoxic mediator associated with neurodegenerative disorders. It is well accepted that methamphetamine
(METH), a potent central nervous stimulant with high abuse potential, and human immunodeficiency virus (HIV)-1 are
implicated in the progression of neurocognitive malfunction. Both have been shown to induce common neurodegenerative
effects such as astrogliosis, compromised blood brain barrier integrity, and excitotoxicity in the brain. Reduced glutamate
uptake from neuronal synapses likely leads to the accumulation of glutamate in the extracellular spaces. Astrocytes
express the glutamate transporters responsible for majority of the glutamate uptake from the synapse, as well as for
vesicular glutamate release. However, the cellular and molecular mechanisms of astrocyte-mediated excitotoxicity in the
context of METH and HIV-1 are undefined. Topics reviewed include dysregulation of the glutamate transporters,
specifically excitatory amino acid transporter-2, metabotropic glutamate receptor(s) expression and the release of
glutamate by vesicular exocytosis. We also discuss glutamate concentration dysregulation through astrocytic expression
of enzymes for glutamate synthesis and metabolism. Lastly, we discuss recent evidence of various astrocyte and neuron
crosstalk mechanisms implicated in glutamate regulation. Astrocytes play an essential role in the neuropathologies
associated with METH/HIV-1-induced excitotoxicity. We hope to shed light on common cellular and molecular pathways
astrocytes share in glutamate regulation during drug abuse and HIV-1 infection.
Keywords: Astrocytes, EAAT-2, excitotoxicity, GFAP, glutamate, human immunodeficiency virus-1, methamphetamine, METH, HIV-1, intracellular Ca2+.
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