THE ROLE OF KHAT IN EXACERBATING MANGANESE-INDUCED DELETERIOUS EFFECTS AND PUTATIVE RESCUE BY COENZYME-Q10 IN A MOUSE MODEL

Abstract

ABSTRACT Khat, a plant containing phytochemicals that act as psychostimulants is widely grown and used in Kenya and East Africa. It contains amphetamine-like chemicals, cathine and cathinone, largely responsible for hematotoxicity and organ damage. There is growing use of this herb in rural and urban areas heavily polluted with environmental toxicants. Limited research has been done on khat toxicity, more so, on how to counter it. In addition, there is limited information on the biochemical, physiological and neurological changes due to co-exposure to khat and the other metal toxicants commonly present in polluted environments, such as manganese. This study was conducted to elucidate the toxicological profile of khat with or without manganese and the putative ability of coenzyme-Q10 (CoQ10) to modulate negative physiological and biochemical processes due to khat and manganese-induced toxicities. This laboratory-based research involved the use of a well characterized mouse model in which the groups of Swiss albino mice were either treated with khat or manganese or CoQ10 or the three treatments combined. Group one was the control group that was not given any of the treatments; group two was supplemented with CoQ10 (200mg/kg b/w); group three was given khat extract (1500mg/kg b/w); group four had free access to water dissolved in manganese ad libitum (4g/L); group five was co-treated with CoQ10 (200mg/kg b/w) and khat (1500mg/kg b/w); group six was given CoQ10 (200mg/kg b/w) and had free access to manganese in water (4g/L); group seven was given khat (1500mg/kg b/w) and had free access to manganese dissolved in water (4g/L b/w), lastly, group eight was treated with CoQ10 (200mg/kg b/w) and khat (1500mg/kg b/w) and had free access to manganese in water ad libitum (4g/L). The study was conducted in two phases to simulate subchronic (90 days) and chronic (132 days) exposure to khat. A series of experiments were performed according to the study objectives. They included: monthly body weight measurements and rapid murine and behavioral score (RMCBS), biochemical assay for liver and kidney biomarkers, reduced glutathione (GSH) assay for oxidative damage, cytokine assay for changes in immune response and histology for organ pathology. Subchronic and chronic exposure to khat induced hematological perturbations leading to anemia that were nullified in the presence of CoQ10. During the subchronic phase, khat caused neurological disturbance that was exacerbated on exposure to manganese (khat+Mn++). However, CoQ10 appeared to restore the khat and manganese-induced neurological dysfunctions. Additionally, there was severe hepatotoxicity and nephrotoxicity following simultaneous exposure to khat and manganese as depicted by the elevated liver (AST, ALT, GGT, total bilirubin) and kidney (creatinine) biomarkers. Notably, supplementation with CoQ10 attenuated khat and/or manganese-induced hepatotoxicity and nephrotoxicity. Exposure to khat for 90 days and 132 days resulted in oxidative damage in the brain, liver and kidney as depicted by the significant GSH elevation. Nonetheless, supplementation with CoQ10 nullified the oxidative damage. Further findings revealed that, in the presence of manganese, the oxidative damage was enhanced; with CoQ10 suppressing the heightened oxidative damage. Lastly, subchronic and chronic exposure to khat caused inflammation which was enhanced in the presence of manganese as exhibited by the increased levels of the pro-inflammatory cytokines (TNF-α and IFN-γ). Notably, CoQ10 modulated khat and/or manganese driven proliferation of inflammatory cytokines. The results in the current study demonstrate that khat negatively affects vital physiological and biochemical processes and induces multiple organ damage and affects the immune system. Moreover, and for the first time, the results show that chronic exposure to manganese exacerbated multiple forms of toxicities following co-exposure with khat. Additionally, the outcomes demonstrate that CoQ10 may be considered as an appropriate pharmacological mitigation against khat-driven toxicity.