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Evidence for enduring cardiac and multiorgan toxicity after repeated exposure to the synthetic cannabinoid JWH-018 in male rats.
Pintori, Nicholas; Serra, Maria Pina; Carai, Antonio; Lobina, Carla; Isola, Raffaella; Noli, Roberta; Piras, Gessica; Spano, Enrica; Baumann, Michael H; Quartu, Marina; De Luca, Maria Antonietta.
Afiliação
  • Pintori N; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy. Electronic address: nicholas.pintori@unica.it.
  • Serra MP; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Carai A; Department of Medical Sciences and Public Health, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Lobina C; Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Isola R; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Noli R; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Piras G; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Spano E; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • Baumann MH; Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), Baltimore, MD 21224, USA.
  • Quartu M; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  • De Luca MA; Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy. Electronic address: deluca@unica.it.
Toxicology ; 507: 153878, 2024 Sep.
Article em En | MEDLINE | ID: mdl-38972446
ABSTRACT
The use of synthetic cannabinoid receptor agonists (SCRAs) represents a public health concern. Besides abuse liability and cognitive impairments, SCRAs consumption is associated with serious medical consequences in humans, including cardiotoxicity. The precise mechanisms underlying cardiac or other toxicities induced by SCRAs are not well understood. Here, we used in silico, in vivo, and ex vivo approaches to investigate the toxicological consequences induced by exposure to the SCRA JWH-018. Along with in silico predictive toxicological screening of 36 SCRAs by MC4PC software, adult male Sprague-Dawley rats were repeatedly exposed to JWH-018 (0.25 mg/kg ip) for 14 consecutive days, with body temperature and cardiovascular parameters measured over the course of treatment. At 1 and 7 days after JWH-018 discontinuation, multiorgan tissue pathologies and heart mitochondria bioenergetics were assessed. The in silico findings predicted risk of cardiac adverse effects specifically for JWH-018 and other aminoalkylindole SCRAs (i.e., electrocardiogram abnormality and QT prolongation). The results from rats revealed that repeated, but not single, JWH-018 exposure induced hypothermia and cardiovascular stimulation (e.g., increased blood pressure and heart rate) which persisted throughout treatment. Post-mortem findings demonstrated cardiac lesions (i.e., vacuolization, waving, edema) 1 day after JWH-018 discontinuation, which may contribute to lung, kidney, and liver tissue degeneration observed 7 days later. Importantly, repeated JWH-018 exposure induced mitochondrial dysfunction in cardiomyocytes, i.e., defective lipid OXPHOS, which may represent one mechanism of JWH-018-induced toxicity. Our results demonstrate that repeated administration of even a relatively low dose of JWH-018 is sufficient to affect cardiovascular function and induce enduring toxicological consequences, pointing to risks associated with SCRA consumption.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ratos Sprague-Dawley / Cardiotoxicidade / Indóis / Naftalenos Limite: Animals Idioma: En Revista: Toxicology Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ratos Sprague-Dawley / Cardiotoxicidade / Indóis / Naftalenos Limite: Animals Idioma: En Revista: Toxicology Ano de publicação: 2024 Tipo de documento: Article