Redoks-posredovani mehanizmi farmakoloških efekata ibogaina na ženke pacova
Redox-mediated mechanisms of ibogaine pharmacological effects on female rats
Abstract:
Ibogaine is an indole alkaloid isolated from the iboga root (Tabernanthe iboga Baill.) and is used in alternative medicine as an anti-addictive drug whose use is associated with risks such as fatal cardiac arrhythmia. In addition to the direct pharmacological effects achieved through interaction with different types of receptors, ibogaine leads to the depletion of ATP reserves, an increase in the rate of energy metabolism and the formation of ROS, and an increase in the activity of antioxidant enzymes via an as yet unknown mechanism. The aim of this dissertation was to determine the nature and mechanisms of the physiological reactivity of ibogaine and possible ROS-mediated effects by a combination of in vivo treatment (per os) and ex vivo experiments on isolated organs. Since the bioavailability of ibogaine and the effects at the CNS level are greater in females than in males, the experiments in this dissertation were performed in females. Per os treatment was shown to have a moderate glycogenolytic effect in the liver. The changes in redox balance are highly tissue specific, with no clear dose (1 or 20 mg/kg) or time (6 or 24 hours) dependence. Ibogaine causes acute necrosis of cardiomyocytes, which could be the cause of potentially fatal cardiac arrhythmias. The mechanism of action of ibogaine at the physiological level is not directly related to the change in ATP concentration, but mainly involves interaction with receptors: pharmacological effects on the contractile activity of the isolated uterus are achieved through interaction with 5-HT receptors, while changes in the activity of antioxidant enzymes are mediated by β-adrenergic receptors and KATP channels. Their blockade prevents the increase in antioxidant enzyme activity. Although it is considered a general pro-antioxidant, the effects of ibogaine are very tissue-specific and depend on the presence of the receptors through which ibogaine achieves its effects.