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MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity

David M Thomas1, Donald M Kuhn

  • 1Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 2125 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA.

Brain Research
|July 1, 2005
PubMed

Insights

Methamphetamine damages dopamine neurons. NMDA receptor antagonists like MK-801 and dextromethorphan protect these neurons by blocking microglial activation, a key factor in methamphetamine neurotoxicity.

Area of Science:

  • Neuroscience
  • Neuropharmacology
  • Neuroimmunology

Background:

  • Methamphetamine (MA) causes long-term dopamine (DA) neurotoxicity in the striatum.
  • Microglia, the brain's immune cells, are implicated in neuronal damage but their role in MA neurotoxicity is understudied.
  • Lipopolysaccharide (LPS) and HIV Tat protein activate microglia, increasing cyclooxygenase-2 and tumor necrosis factor-alpha.

Purpose of the Study:

  • To investigate the role of microglial activation in methamphetamine-induced neurotoxicity.
  • To determine if NMDA receptor antagonists, MK-801 and dextromethorphan, can prevent microglial activation and subsequent neurotoxicity.

Main Methods:

  • In vitro studies using cultured mouse microglial cells exposed to LPS and HIV Tat.
  • In vivo studies administering MK-801 and dextromethorphan to mice exposed to methamphetamine.
  • Assessment of microglial activation markers (e.g., cyclooxygenase-2, tumor necrosis factor-alpha) and dopamine nerve terminal damage in the striatum.

Main Results:

  • LPS and HIV Tat induced microglial activation in vitro.
  • MK-801 and dextromethorphan inhibited LPS- and HIV Tat-induced microglial activation.
  • In vivo, MK-801 and dextromethorphan reduced methamphetamine-induced microglial activation in the striatum.
  • Both drugs protected dopamine nerve endings from methamphetamine-induced damage.

Conclusions:

  • Microglial activation contributes to methamphetamine neurotoxicity.
  • MK-801 and dextromethorphan protect dopamine neurons by inhibiting microglial activation.
  • Targeting microglial activation represents a potential therapeutic strategy against methamphetamine-induced neurotoxicity.

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