TAARGETING ASTROGLIOSIS DURING METH AND HIV-1 EXPOSURE

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2018-03-14

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Mythen, Shannon
Borgmann, Kathleen
Swanta, Naomi
Ghorpade, Anuja

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Abstract

Purpose: As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. METH exacerbates the severity and onset of HIV-associated neurocognitive disorders (HAND), which affect 30-70% of the 37.6 million people globally infected with HIV. Most neurodegenerative diseases share neuroinflammation as a common pathogenic mechanism. Neuroinflammation, HIV and METH dysregulate a wide range of brain functions including neuronal signaling, glial activation, viral infection, oxidative stress and excitotoxicity. Since neuroglia often determine the outcomes of neurological disease, we investigated the mechanisms regulating astrocyte-mediated neurotoxicity in the context of METH and HIV comorbidity. Methods: To these ends, we examined the expression, localization and function of the novel METH astrocyte receptor, trace amine associated receptor 1 (TAAR1) in an in vitro model of HIV-associated activation wherein extended METH exposure is administered to mimic residual METH concentrations that occur in humans between binges of METH-taking. Results: In this model, TAAR1 levels, and its localization to the endoplasmic reticulum (ER) and plasma membranes, increased with METH and HIV-induced astrogliosis. Calcium flux, which mediates ER, mitochondrial, and oxidative stress, also was increased, corroborating our prior studies on astrocyte mitochondrial dysregulation. The astrocyte responses to METH and HIV-relevant stimuli were blocked with the TAAR1-selective antagonist EPPTB. Extended METH and HIV activation impaired excitatory amino acid transporter 2 (EAAT2) expression and activity, which were recovered by following 24 hour exposure with EPPTB. Conclusion: Together, these data highlight several mechanisms regulating METH/HIV-induced, astroglia-mediated neurotoxicity and the potential for astrocyte targeted intervention via TAAR1 during chronic disease.

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