Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66 mg synthetic CBD or 0.66 mg/1.33 mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.

1st Department of Pathology St Anne's University Hospital and Faculty of Medicine Masaryk University Pekarska 664 53 656 91 Brno Czech Republic

Department of Advanced Materials and Organic Synthesis Institute of Chemical Process Fundamentals of the Czech Academy of Sciences v v i Rozvojova 135 165 02 Prague 6 Czech Republic

Department of Analytical Chemistry Faculty of Science Palacky University 17 listopadu 12 771 46 Olomouc Czech Republic

Department of Medical Chemistry and Biochemistry Faculty of Medicine and Dentistry Palacky University Hnevotinska 3 775 15 Olomouc Czech Republic

Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic; Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 753 5 625 00 Brno Czech Republic

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