Carbenoxolon Is Capable to Regulate the Mitochondrial Permeability Transition Pore Opening in Chronic Alcohol Intoxication

Abstract

Background: carbenoxolone, which is a derivative of glyceretic acid, is actively used in pharmacology for the treatment of diseases of various etiologies. In addition, we have shown carbenoxolone as an effective inducer of mitochondrial permeability transition pore in rat brain and liver mitochondria. Methods: in the course of this work, comparative studies were carried out on the effect of carbenoxolone on the parameters of mPTP functioning in mitochondria isolated from the liver of control and alcoholic rats. Results: within the framework of this work, it was found that carbenoxolone significantly increased its effect in the liver mitochondria of rats with chronic intoxication. In particular, this was expressed in a reduction in the lag phase, a decrease in the threshold calcium concentration required to open a pore, an acceleration of high-amplitude cyclosporin-sensitive swelling of mitochondria, as well as an increase in the effect of carbenoxolone on the level of mitochondrial membrane-bound proteins. Thus, as a result of the studies carried out, it was shown that carbenoxolone is involved in the development / modulation of alcohol tolerance and dependence in rats.

Effect of erastin and G3139 on rat liver mitochondria in chronic alcoholic intoxication

“…Currently, certain evidence exists that mPTP does not have permanent structural components, and in different situations, different protein components and channels may be involved in its formation [24][25][26]. Based on results of recent studies conducted in our laboratory, we have hypothesized the existence of a compensatory system formed by mPTP regulatory proteins (CNP, VDAC, TSPO) in the liver mitochondria under conditions of chronic alcoholism [14,27,28].…”

Astaxanthin Is Able to Prevent Alcohol-Induced Dysfunction of Liver Mitochondria

“…2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) and translocator protein (TSPO) are involved in the regulation of mitochondrial membrane permeability [ 29 , 30 , 31 ]. According to our data, they took part in the action of the compensatory system in response to negative effects in mitochondria [ 32 , 33 , 34 ]. Figure 2 b shows that AX administration did not affect the content of TSPO and CNPase, whereas ethanol treatment reduced CNPase content by 40% in tissue lysates compared to control (column 3 vs 1).…”

“…At the same time, in chronic alcohol intoxication, the association of CNPase with these complexes decreased, and under the action of AX, it increased to control values (except for C IV, where the effect of AX was less pronounced). We have previously demonstrated a decrease in CNPase expression in mitochondria with aging and ethanol exposure [ 32 , 33 , 34 , 61 ]. We also found a decrease in the association of CNPase with complexes during aging and heart failure [ 22 , 62 ].…”