Efficacy of ademol in experimental cranial injury on the effect of oxidative stress
Objective. To evaluate the effectiveness and safety of ademol for oxidative stress in the brain of rats with traumatic brain injury (TBI).
Materials and methods. In 260 male-rats weighing 160-180 g, the preclinical efficacy of ademol was studied against the background of the actual developed TBI model. Several groups of animals were formed: pseudo-operated (TBI + 0.9 % NaCl intravenously), control pathology (TBI + 0.9 % NaCl intravenously), TBI + ademol 2 mg/kg intravenously, comparison drug (TBI + amantadine sulfate). The experimental model was induced by the action of a stream of carbon dioxide under pressure using a gas-balloon air pistol “Baikal MR-654K”, evaluated only severe trauma (the air pistol hole is close to the center of the trepanation hole in rats). Ademol (Ademol-Darnytsia, Ukraine) was administered in several doses to determine the conditionally effective dose, and the reference drug amantadine sulfate (PC-Merz, Switzerland) was administered slowly with infusomate for 2 h after 12 h for 8 days, 60 min after injury. Biochemical processes in traumatically damaged brain (in homogenates and postnuclear supernatant) were studied on the 8th day, oxidative stress parameters were evaluated by the content of malonic dialdehyde (MDA) by reaction with thiobarbituric acid, carbonyl groups of proteins (CGP) – by reaction with dinitrophenylhydrazine, activity of antioxidant enzymes – by reaction with superoxide dismutase (SOD), glutathione peroxidase (GPO) and catalase. Statistical processing was performed according to StatPlus programs, by parametric and nonparametric criteria, the differences were considered significant at p<0.05.
Results and discussion. Hyperactivation of free radical oxidation of biomembrane lipids is registered in the brain structures of injured rats. In the group of pseudooperated animals, the median content of the secondary metabolite of lipoperoxidation MDA in the brain was 13.2 (95 % confidence interval (CI) 12.8-14.2) μmol/g of dry tissue. In the control pathology group, the MDA index is 2.28 times (p<0.05) higher than in pseudooperated animals, the median is 30.8 (95 % CI 28.6-33.3) μmol/g of dry tissue. The use of the studied drugs reduces the activation of lipid peroxidation processes in brain tissues. Ademol had the most active influence. In the group of animals treated with this drug, the content of MDA in the brain was lower by 58.3 % (p<0.05) than in the control pathology group, the median was 14.6 (95 % CI 12.6-15.5) μmol/g of dry tissue. Amantadine sulfate was inferior to ademol: the content of MDA in the brain was lower by 48.4 % (p<0.05), the median was 16.1 (95 % CI 14.9-16.7) μmol/g of dry tissue.
The development of TBI was associated with the activation of oxidative modification of CGP. In pseudooperated animals, the median content of CGP in the brain was 4.73 (95 % CI 4.29-5.01) μmol/g of dry tissue, the level of CGP is 1.77 times higher (p<0.05) in control pathology group. The active preventive drug was ademol: the content of CGP in the brain decreased by 40.1 % (p<0,05) than in animals of the control pathology group, the median was 4.90 (95 % CI 4.62-5.54) μmol/g of dry cloth. Amantadine was slightly inferior to ademol in this effect: the content of CGP in the brain was lower by 39.1 % (p<0.05), against control pathology, the median was 4.99 (95 % CI 4.65-5.59) μmol/g of dry cloth. Oxidative stress occurred against the background of decreasing the rate of inactivation of the superoxide anion radical: the median activity with the participation of SOD in the brains of pseudooperated animals was 2.68 (95 % CI 2.23-3.05) um. od/mg protein; there was also a decrease in the activity of SOD in the brain by 51.7 % (p<0.05) in the control pathology group, the median activity of the enzyme was 1.31 (95 % CI 0.97-1.57) um. od/mg protein. Pharmacotherapy prevented a drop in the reaction rate of SOD: on the background of ademol, it was 105 % higher than the control pathology group, the median of its activity was 2.69 (95 % CI 2.17-3.16) um. od/mg protein. Amantadine sulfate was slightly inferior to ademol: the activity of SOD in the brain was less by 101 %, the median of its activity was 2.53 (95 % CI 2.09-3.11) um. od/mg of protein. TBI is also accompanied by inhibition of hydrogen peroxide inactivation by the enzymes GPO and catalase: a decrease in brain tissues activity of GPO by 55.3 % and catalase by 53.0 %. When corrected with ademol, the activity of GPO in brain was higher by 70.9 %, as well as the activity of catalase – by 89.5 % (ranged from 6.39 to 7.45 μcatal/mg protein), against levels in the control pathology group. Amantadine sulfate contributed to an increase in the activity of GPO by 44.5 % (from 55.5 to 61.2 μmol/min per 1 mg of protein), an increase in catalase – by 79.0 % (from 6.21 to 6.75 μcatal/mg of protein) than indicators in the control pathology group.
Conclusions. The use of ademol in rats with TBI contributes to the probable restraint of oxidative stress: reducing the prooxidative effect of trauma and activation of antioxidant enzymes.
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