Abstract
The aim of this study is to analyse cardiac specimens from human cocaine-related overdose, to verify the hypothesis that cardiac toxicity by acute exposure to high dosage of cocaine could be mediated by unbalanced myocardial oxidative stress, and to evaluate the apoptotic response. To address these issues, biochemical and immunohistological markers of oxidative/nitrosative stress were evaluated. We found that i-NOS, NOX2 and nitrotyrosine expression were significantly higher in the hearts of subjects who had died from high doses of cocaine, compared to the control group. Increase of these markers was associated with a dramatic increase in 8-OHdG, another marker of oxidative stress. A high number of TUNEL-positive apoptotic myocells was observed in the study group compared to the control group. The immunoexpression of TNF-α was significantly higher in the cocaine group compared to the control group. Furthermore, we detected a significantly stronger immunoresponse to anti-SMAC/DIABLO in our study group compared to control cases. Both cardiac Fas-dependent and mitochondria-dependent apoptotic pathways appeared to be activated to a greater extent in the cocaine group than in the control group. Our results highlight the central role of oxidative stress in cocaine toxicity. High levels of NOS can promote the oxidation process and lead to apoptosis.
Highlights
Catecholamines with a resulting increase in their concentration in the synaptic cleft and enhanced post-synaptic transmission, as well as enhanced central sympathetic outflow[12]
We found i-nitric oxide syntase (NOS), NOX2 and nitrotyrosine expression to have significantly increased in the hearts of these subjects with respect to control group subjects whose death was from other causes
Most toxic effects of cocaine on molecular levels are mediated by oxidative stress or mitochondrial dysfunction caused by metabolization of noradrenalin or norcocaine[23,28,29]
Summary
Catecholamines (dopamine and norepinephrine) with a resulting increase in their concentration in the synaptic cleft and enhanced post-synaptic transmission, as well as enhanced central sympathetic outflow[12]. In the light of these previous findings, this study reports an evaluation of myocardial oxidative damage, analysing cardiac specimens from subjects who have died suddenly from acute cocaine intoxication This is in order to verify the hypothesis that cardiac toxicity caused in humans by acute exposure to high doses of cocaine could be mediated, at least in part, by unbalanced myocardial oxidative stress. To this end, we selected cases of young people who had died from a high-level dose of cocaine, for which the term overdose is correctly used.
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