Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice

Abstract

Hyperthermia is a potentially lethal side effect of Methamphetamine (Meth) abuse, which involves the participation of peripheral thermogenic sites such as the Brown Adipose Tissue (BAT). In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia. Here, we have further explored the ability of NAC to modulate Meth-induced hyperthermia in correlation with changes in BAT. We found that NAC treatment in controls causes hypothermia, and, when administered prior or upon the onset of Meth-induced hyperthermia, can ameliorate the temperature increase and preserve mitochondrial numbers and integrity, without affecting locomotor activity. This was different from Dantrolene, which decreased motor activity without affecting temperature. The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth. In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione. Treatment with S-adenosyl-L-methionine, which improves glutathione activity, had an effect in ameliorating Meth-induced hyperthermia, but also modulated motor activity. This suggests a role for the remaining glutathione for controlling temperature. However, the mechanism by which NAC operates is independent of glutathione levels in BAT and specific to temperature. Our results show that, in spite of the absence of a clear mechanism of action, NAC is a pharmacological tool to examine the dissociation between Meth-induced hyperthermia and motor activity, and a drug of potential utility in treating the hyperthermia associated with Meth-abuse.

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

“…The Meth-induced sensitization, on the other hand, had a very severe impact on gene expression with a strong focus on pathways within mitochondria and endoplasmic reticulum. The suppression of mitochondrial function by Meth has been extensively described in the brain and in tissues that are rich in these organelles [75][76][77][78]. Meth-associated stress to the endoplasmic reticulum has been associated with blood-brain barrier disruption [79], and loss of astrocytes by apoptosis [80].…”

Mitochondrial reactive oxygen species and adipose tissue thermogenesis: Bridging physiology and mechanisms

“…NAC-mediated inhibition of cellular thiol oxidation blunts activation of UCP1-dependent thermogenesis upon cold exposure or following ␤3-adrenergic stimulus (18). Additionally, acute activation of thermogenesis by methamphetamine, which requires functional BAT (41) and UCP1 (42), is substantially inhibited by NAC (43).…”

Inhibitory Effect of Chebulic Acid on Alveolar Epithelial to Mesenchymal Transition in Response to Urban Particulate Matter Using Co-treatment and Post-treatment Exposure

“…Naturally occurring components from Terminalia chebula, possess antioxidant activities and useful as a treatment for asthma. 32) Our previous published studies have shown that pre-treatment of CA isolated from T. chebula reduces UPM-induced alveolar epithelium inflammation and junctional molecules-related barrier integrity. 17) Therefore, in the current study, we extended our study to investigate whether CA attenuates the damage of alveolar EMT by UPM.…”