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p-Nrf2/HO-1 Pathway Involved in Methamphetamine-induced Executive Dysfunction through Endoplasmic Reticulum Stress

Tao Wei1,2, Jun-Da Li1, Yu-Jing Wang1

  • 1School of Mental Health, Bengbu Medical College, Bengbu, 233030, Anhui, China.

Neurotoxicity Research
|May 18, 2023
PubMed

Insights

Methamphetamine abuse impairs executive function by affecting the p-Nrf2/HO-1 pathway. Activating this pathway with TBHQ can reverse methamphetamine-induced damage and restore cognitive function.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Methamphetamine (METH) abuse is a significant public health issue linked to executive dysfunction.
  • The precise molecular mechanisms driving METH-induced cognitive deficits, particularly executive dysfunction, are not fully understood.

Purpose of the Study:

  • To investigate the molecular underpinnings of METH-induced executive dysfunction.
  • To explore the role of oxidative stress, endoplasmic reticulum (ER) stress, and apoptosis in the dorsal striatum following METH exposure.

Main Methods:

  • A Go/NoGo experiment was used to assess executive function in mice exposed to METH.
  • Immunoblot analysis, Malondialdehyde (MDA) levels, glutathione peroxidase (GSH-Px) activity, and TUNEL staining were employed to evaluate molecular changes.
  • The Nrf2 agonist Tert-butylhydroxyquinone (TBHQ) was microinjected into the dorsal striatum to assess its protective effects.

Main Results:

  • METH exposure significantly impaired inhibitory control, a key aspect of executive function.
  • METH treatment led to decreased expression of phosphorylated Nrf2 (p-Nrf2) and heme-oxygenase-1 (HO-1), alongside increased markers of ER stress and apoptosis in the dorsal striatum.
  • TBHQ administration reversed METH-induced deficits in p-Nrf2, HO-1, GSH-Px, ER stress, apoptosis, and executive dysfunction.

Conclusions:

  • The p-Nrf2/HO-1 pathway plays a crucial role in mediating METH-induced executive dysfunction.
  • Targeting the p-Nrf2/HO-1 pathway may offer a therapeutic strategy to mitigate the cognitive impairments associated with METH abuse by reducing ER stress and apoptosis.
Keywords:
Dorsal striatumEndoplasmic reticulum (ER) stressExecutive dysfunctionMethamphetamineNuclear factor-E2-related factor 2/ heme-oxygenase-1 pathwayOxidative stressTert-butylhydroxyquinone (TBHQ)

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