In experiments on rats, trimetazidine (25 mg/kg) prevented disturbances in energy metabolism and LPO activation in the brain under conditions of acute ischemia aggravated by hypoxia. Key Words: trimetazidine; brain; ischemia; hypoxia; metabolismAcute disturbances of cerebral circulation are an important medical and social problem. Among drugs protecting the brain against ischemia and hypoxia special place is occupied by glutamate antagonists and various modulators of glutamate receptors (ryluzol, lubeluzol), calcium antagonists (nimodipine) [10], antihypoxants (cytochrome C and amtizol) [2,5], and antioxidants (tirilazad mezylate, SOD) [6]. Of particular interest is trimetazidine (TM), a piperazine derivative (Preductal, Servier; Vastarel, Biopharma). This efficient cytoprotective preparation acting at the cellular level is successfully used in the treatment of cardiac ischemia [8,13]. The protective effect of TM against cerebral hypoxia and ischemia was not studied.Our aim was to study the protective effects of TM during acute cerebral ischemia complicated by hypoxia. This combination often develops in patients with acute disturbances of cerebral circulation accompanied by respiratory insufficiency of central origin [11]. MATERIALS AND METHODSThe study was carried out on mature male rats weighing 180-200 g. The animals were divided into three groups (8 rats in each): group 1 comprised sham-operated control rats, group 2 consisted of rats with acute Department of Pharmacology, Military Medical Academy, St. Petersburg ischemia complicated by hypoxia, and group 3 rats were intraperitoneally injected with TM (Vastarel, Biopharma) in a dose of 25 mg/kg 30 min before hypoxia and ischemia modeling. Cerebral ischemia was produced under ether anesthesia by occlusion of both carotid arteries, then the rats were "elevated" to an altitude of 8000 m for 90 min. The rats were killed by decapitation. The brain was frozen in liquid nitrogen. The metabolic status of cerebral hemispheres was assessed by the content of glycogen, glucose, pyruvate, lactate [7], creatine phosphate [1], ATP, ADP, AMP, inorganic phosphate, and energetic charge of the adenine nucleotide system [4]. The intensity of LPO was assessed by the content of lipid hydroperoxides and malonic dialdehyde (MDA), while the functions of antioxidant systems were evaluated by the content of reduced glutathione and activity of catalase and superoxide dismutase (SOD). The results were statistically analyzed using Student's t test. RESULTSHypoxia and occlusion of the carotid arteries profoundly changed cerebral metabolism (Table l). The content of glycogen in the cerebral hemispheres decreased by 53%, glucose content increased by 44%. The content of lactate increased profoundly against the background decreased pyruvate content. The lactate/ pyruvate ratio increased more than 6-fold, which in-
Trimethazidine in a dose of 25 mg/kg prevents disturbances of energy metabolism and activation of lipid peroxidation in rat brain after acute ischemia and hypoxia. Our objective was to study the protective effects of TM under conditions of acute brain ischemia complicated with hypoxia. This combination occurs when acute disorders of cerebral circulation are accompanied by respiratory deficiency of central origin.[11]: of both common carotid arteries under ether anesthesia. The animals were then elevated to an altitude of 8000 m in a pressure chamber tot 90 rain. The brain was fixed by immersing the head in liquid nitrogen. The metabolic state of cerebral hemispheres was assessed by measuring the content of glycogen, glucose, pyruvate, lactate [7], creatine phosphate [1], ATP, ADP, AMP, and inorganic phosphate, and by determining the energy potential of the adenine nucleotide system [4]. The intensity of lipid peroxidation (LPO) was assessed by the content of lipid peroxides and malonic dialdehyde. The functioning of the antioxidant system was assessed by the content of reduced glutathione and catalase and superoxide dismutase (SOD) activities as described previously [8]. The data were analyzed statistically using Student's t test. RESULTS MATERIALS AND METHODSExperiments were carried out on adult male rats weighing 180-200 g. Three groups were formed (8 rats in each): 1) sham-operated (control); 2) exposed to acute ischemia and hypoxia; 3) treated with intraperitoneal TM (Vastarel, Biopharm, 25 mg/kg) 30 min prior to ischemia-hypoxia. Ischemia was caused by occlusion Department of Pharmacology, Military Medical Academy, St, Petersburg Occlusion of the carotid arteries in combination with hypoxia caused dramatic changes in brain metabolism (Table 1). Cerebral content of glycogen decreased by 53% with glucose increasing by 44%. Considerable rise in lactate content occurred simultaneously with the decrease in pyruvate content. As a result, the lactate/pyruvate ratio increased more than six-fold, which was indicative of intensified anaerobic glycolysis. It is known that occlusion of the carotid arteries in rats considerably reduced cerebral circulation, and dis-0007-4888/99/0003-0269522.00 9Kluwer Academic/Plenum Publishers
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