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Methamphetamine potentiates HIV-1gp120-induced microglial neurotoxic activity by enhancing microglial outward K+

Jianuo Liu1, Enquan Xu1, Guihua Tu1

  • 1The Neurophysiology Laboratory, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, United States.

Molecular and Cellular Neurosciences
|May 30, 2017
PubMed

Insights

Methamphetamine and HIV-1 glycoprotein 120 (gp120) together worsen neurotoxicity by increasing microglial KV1.3 channel activity and caspase-3 signaling. Blocking KV1.3 reduces this combined neurotoxic effect.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Methamphetamine (Meth) abuse exacerbates HIV-1-associated neurocognitive disorders (HAND).
  • Microglia, the brain's immune cells, express the voltage-gated potassium channel KV1.3.
  • The interaction between Meth, HIV-1, and microglial KV1.3 in neurotoxicity is not fully understood.

Purpose of the Study:

  • To investigate if KV1.3 serves as an intersection point for Meth and HIV-1 effects on microglia.
  • To determine the role of KV1.3 in Meth-potentiated HIV-1 glycoprotein 120 (gp120)-induced microglial neurotoxicity.

Main Methods:

  • Cultured rat microglial cells were treated with Meth and/or gp120.
  • KV1.3 expression, KV1.3 current, and neurotoxin production (TNF-α, iNOS) were measured.
  • The effects of KV1.3 antagonists (PAP, 4-AP) and caspase-3 inhibitors were assessed.

Main Results:

  • Meth potentiated gp120-induced microglial neurotoxicity, increasing KV1.3 expression and current.
  • KV1.3 blockade significantly reduced Meth/gp120-induced neurotoxin production and neuronal injury.
  • Meth/gp120 enhanced caspase-3 activation, which was attenuated by KV1.3 blockers and caspase-3 inhibition.

Conclusions:

  • Microglial KV1.3 channel activity is a key mediator of the combined neurotoxic effects of Meth and HIV-1 gp120.
  • The Meth/gp120 co-morbid effect on neurotoxicity involves KV1.3-dependent activation of caspase-3 signaling.
  • Targeting microglial KV1.3 may offer a therapeutic strategy for HAND in individuals with Meth abuse.
Keywords:
Drug abuseHIV proteinMicrogliaNeurodegenerationVoltage-gated K channel

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