The role of neurological degeneration caused by mitophagic toxicity and autophagic cell death in methamphetamine-induced cognitive impairment

<p dir="ltr">Methamphetamine (METH) is a psychostimulant that is commonly used worldwide. Chronic METH use can produce behavioural change and cognitive impairment that takes a long time to recover, and there are no approved medications for this impairment. Therefore, it is essential to extensively study METH-induced neurotoxic mechanisms and find an alternate treatment to promote recovery of neurological dysfunction and dysregulation.</p><p dir="ltr">The first part of this study aimed to find out the action of METH to alter mitochondrial function via a transporter-independent pathway using molecular dynamics (MD) simulation of METH penetrating the mitochondrial membrane model and investigated METH toxicity-induced mitochondrial dysfunction using flow cytometry-based assays in cell culture models. Furthermore, the second objective was to examine the effect of chronic oral METH self-administration (SA) in mice or intravenous (IV) SA in rats on behavioural and cognitive performance, assessed by stereotyped observation, open field test, attentional set shift tasks (ASST), and a cue-induced METH craving test. Lastly, the third goal was to use proteomic analyses to investigate neurotoxic mechanisms, focused on mitochondrial function and the neuroprotective effect of compounds like melatonin and cannabidiol (CBD) on the recovery of cognitive impairment and prevention of relapse, when treatment occurred during METH abstinence.</p><p dir="ltr">The results of MD simulation showed that METH can potentially penetrate lipid membrane types that are enriched on the cellular and mitochondrial membranes and altered mitochondrial membrane potential even in non-dopamine transporter (DAT)-presenting cell lines. The results of the behavioural study demonstrated hyperactivity and poor cognitive performance in the mice provided with oral-SA METH for 21 consecutive days compared to controls, which partly recovered after the 14-day METH withdrawal period. Interestingly, the abnormal behaviours could be normalized by melatonin treatment. The proteomic analysis revealed the underlying mechanism of METH toxicity on the prefrontal cortex (PFC), through altered synaptic function, mitochondrial dynamics, bioenergetic processes, and overactivated mitophagy process-related autophagy-dependent cell death. These toxic mechanisms were attenuated by melatonin treatment during withdrawal. METH-IVSA rats showed increased active lever pressing and locomotor activity throughout the 22-day SA phase. Following 30 days of abstinence, the rats exhibited impaired cognitive performance compared to controls and greater drug-seeking behaviour. However, when compared to vehicle treated rats, CBD treatment during METH abstinence reduced drug seeking and enhanced the recovery from cognitive impairment. The proteomic profile of mitochondrial isolation revealed the effect of METH-induced mitochondrial dysfunction via induction of mitochondrial calcium regulation and disruption of the regulation of GABA and glutamate receptors, demonstrating the activation of the mitophagy process.</p><p dir="ltr">In conclusion, our findings suggest mechanisms of METH-induced mitochondrial dysfunction, which is a potentially underlying pathway of METH-induced cognitive impairment, with melatonin or CBD treatment showing therapeutic potential to enhance cognitive recovery and prevention of METH relapse.</p>