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

Sanchez-Alavez M, Bortell N, Galmozzi A, Conti B, Marcondes MC - Temperature (Austin) (2014 Oct-Dec)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Neurosciences; The Scripps Research Institute; La Jolla, CA USA.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of NAC and Meth on intra-BAT glutathione levels - BAT tissue was harvested 2 hours after the injection of Meth or Vehicle, deproteinized and processed for measurements of (A) reduced glutathione (GSH) and (B) oxidized glutathione (GSSH), using a colorimetric assay. Results represent the average ± SD, analyzed by One-Way ANOVA, followed by Bonferroni’s test. *p < 0.05, compared to indicated groups.
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Figure 8: Effects of NAC and Meth on intra-BAT glutathione levels - BAT tissue was harvested 2 hours after the injection of Meth or Vehicle, deproteinized and processed for measurements of (A) reduced glutathione (GSH) and (B) oxidized glutathione (GSSH), using a colorimetric assay. Results represent the average ± SD, analyzed by One-Way ANOVA, followed by Bonferroni’s test. *p < 0.05, compared to indicated groups.

Mentions: To explore the mechanisms by which NAC can reduce Meth-hyperthermia and preserve mitochondrial integrity in BAT, we measured the levels of glutathione in both, its reduced (GSH) and oxidized (GSSG) states. NAC is regarded as a source of cysteines for the synthesis of glutathione, which has an important anti-oxidant role, and a role as an electron donor to reduce disulfide bonds in various proteins. We examined whether NAC had an effect on glutathione levels within BAT at 2 hours after the injection of Meth, which corresponds to the time point when core body temperature started to rise (Fig. 8). The levels of both reduced and oxidized forms of glutathione were significantly decreased by the administration of Meth (P = 0.02 and 0.025, respectively, Fig. 7A and 7B). However, somewhat surprisingly, NAC treatment prior to or 1 hr after Meth did not significantly impact glutathione levels in BAT.


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

Sanchez-Alavez M, Bortell N, Galmozzi A, Conti B, Marcondes MC - Temperature (Austin) (2014 Oct-Dec)

Effects of NAC and Meth on intra-BAT glutathione levels - BAT tissue was harvested 2 hours after the injection of Meth or Vehicle, deproteinized and processed for measurements of (A) reduced glutathione (GSH) and (B) oxidized glutathione (GSSH), using a colorimetric assay. Results represent the average ± SD, analyzed by One-Way ANOVA, followed by Bonferroni’s test. *p < 0.05, compared to indicated groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557806&req=5

Figure 8: Effects of NAC and Meth on intra-BAT glutathione levels - BAT tissue was harvested 2 hours after the injection of Meth or Vehicle, deproteinized and processed for measurements of (A) reduced glutathione (GSH) and (B) oxidized glutathione (GSSH), using a colorimetric assay. Results represent the average ± SD, analyzed by One-Way ANOVA, followed by Bonferroni’s test. *p < 0.05, compared to indicated groups.
Mentions: To explore the mechanisms by which NAC can reduce Meth-hyperthermia and preserve mitochondrial integrity in BAT, we measured the levels of glutathione in both, its reduced (GSH) and oxidized (GSSG) states. NAC is regarded as a source of cysteines for the synthesis of glutathione, which has an important anti-oxidant role, and a role as an electron donor to reduce disulfide bonds in various proteins. We examined whether NAC had an effect on glutathione levels within BAT at 2 hours after the injection of Meth, which corresponds to the time point when core body temperature started to rise (Fig. 8). The levels of both reduced and oxidized forms of glutathione were significantly decreased by the administration of Meth (P = 0.02 and 0.025, respectively, Fig. 7A and 7B). However, somewhat surprisingly, NAC treatment prior to or 1 hr after Meth did not significantly impact glutathione levels in BAT.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cellular and Molecular Neurosciences; The Scripps Research Institute; La Jolla, CA USA.

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.

No MeSH data available.


Related in: MedlinePlus