Cocaine is a commonly abused
illicit drug that causes significant morbidity and mortality. The most severe and common complications are
seizures,
ischemic strokes,
myocardial infarction, and acute liver injury. Here, we demonstrated that acute
cocaine intoxication promoted seizure along with acute liver damage in mice, with intense inflammatory infiltrate. Considering the protective role of the
endocannabinoid system against cell toxicity, we hypothesized that treatment with an
anandamide hydrolysis inhibitor,
URB597, or with a phytocannabinoid,
cannabidiol (CBD), protects against
cocaine toxicity.
URB597 (1.0 mg/kg) abolished
cocaine-induced seizure, yet it did not protect against acute liver injury. Using confocal liver intravital microscopy, we observed that CBD (30 mg/kg) reduced acute liver
inflammation and damage induced by
cocaine and prevented associated seizure. Additionally, we showed that previous liver damage induced by another hepatotoxic
drug (
acetaminophen) increased seizure and lethality induced by
cocaine intoxication, linking hepatotoxicity to seizure dynamics. These findings suggest that activation of
cannabinoid system may have protective actions on both liver and brain induced by
cocaine, minimizing inflammatory injury promoted by
cocaine, supporting its further clinical application in the treatment of
cocaine abuse.