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

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.