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Nrf2 Deficiency Exacerbates Methamphetamine-Induced Neuronal Apoptosis and Cognitive Dysfunction in Male Mice
Qianyun Nie1,2, Wenjuan Dong1,3, Peng Zhang2
1National Health Commission (NHC) Key Laboratory of Drug Addiction Medicine, School of Forensic Medicine, Kunming Medical University, Kunming 650500, China.
Abstract:
Methamphetamine (MA) abuse, a growing global public health concern, has been linked to the emergence of neuropsychiatric effects, largely attributed to MA-induced neurotoxicity. Despite its significant impact, the precise mechanisms underlying this neurotoxicity remain poorly understood, and current therapeutic options for MA abusing patients are limited. In the present study, primary mouse neurons with 400 μM MA treatment and Nrf2 knockout C57BL/6J mice with 10 mg/kg MA treatment were used to investigate the regulatory mechanisms of Nrf2 in MA-induced cognitive impairment and neuronal apoptosis. Results revealed that Nrf2 activation occurred with in vitro and in vivo exposure to MA, with pronounced cognitive dysfunction in mice. In both primary neurons and prefrontal cortex and hippocampus tissues, MA exposure induced oxidative stress, disrupted mitochondrial dynamics (characterized by elevated Drp1 and p-Drp1 expression and reduced Mfn1 expression), enhanced mitophagy (characterized by high PINK1 and Parkin expression), and increased apoptosis. Notably, silencing or knocking out Nrf2 exacerbated MA-induced cognitive dysfunction, oxidative stress, and disruptions in mitochondrial dynamics, while further impairing mitophagy through reduced PINK1 and Parkin expression, ultimately leading to increased apoptosis. These results suggest that Nrf2 deficiency exacerbates MA-induced neuronal apoptosis and cognitive dysfunction. Consequently, Nrf2 may represent a promising therapeutic target for mitigating neurotoxic effects induced by MA.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) activation is observed in methamphetamine (MA) exposure. Nrf2 deficiency worsens MA-induced cognitive decline and neuronal apoptosis, suggesting Nrf2 as a therapeutic target.
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.
