Nrf2 Deficiency Exacerbates Methamphetamine-Induced Neuronal Apoptosis and Cognitive Dysfunction in Male Mice

Area of Science:

• Neuroscience
• Toxicology
• Molecular Biology

Background:

• Methamphetamine (MA) abuse is a significant public health issue linked to neuropsychiatric effects and neurotoxicity.
• The exact mechanisms of MA-induced neurotoxicity are not fully understood, and effective treatments are limited.
• Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a crucial role in cellular defense against oxidative stress.

Purpose of the Study:

• To investigate the role of Nrf2 in methamphetamine-induced cognitive impairment and neuronal apoptosis.
• To elucidate the molecular mechanisms underlying Nrf2's involvement in MA neurotoxicity.

Main Methods:

• Primary mouse neurons and Nrf2 knockout C57BL/6J mice were treated with methamphetamine (MA).
• Evaluated cognitive function, neuronal apoptosis, oxidative stress, mitochondrial dynamics (Drp1, p-Drp1, Mfn1), and mitophagy (PINK1, Parkin) markers.
• Utilized in vitro and in vivo models to assess MA exposure effects with and without Nrf2.

Main Results:

• MA exposure activated Nrf2 and caused cognitive dysfunction, oxidative stress, disrupted mitochondrial dynamics, enhanced mitophagy, and increased apoptosis.
• Nrf2 knockout or silencing exacerbated MA-induced cognitive deficits, oxidative stress, and mitochondrial dysfunction.
• Nrf2 deficiency led to impaired mitophagy and increased neuronal apoptosis following MA exposure.

Conclusions:

• Nrf2 activation is a response to MA exposure, attempting to counteract neurotoxicity.
• Nrf2 deficiency significantly worsens methamphetamine-induced neurotoxicity, including cognitive impairment and neuronal death.
• Targeting Nrf2 presents a potential therapeutic strategy for mitigating the neurotoxic effects of methamphetamine abuse.