ACETYLATION PHENOTYPE AS A SUSCEPTIBILITY MARKER FOR DEVELOPMENT OF NITRATE-CADMIUM INTOXICATION IN YOUNG RATS.

The article solves a current task concerning a substantiated use of acetylation phenotype as susceptibility biomarker to unfavourable effect of chemical substances in scientific studies. Objective: to study a combined effect of sodium nitrate and cadmium chloride on the prooxidant-antioxidant balance of the blood, liver and functional state of the central nervous system in young rats with different acetylation type. The experimental studies were performed on immature male rats 1,5-month of age. The experimental animals were divided into two groups according to the amount of general sulfadimine excreted with urine: "rapid" and "slow" acetylators. 2 subgroups were differentiated in every group: I - control animals, II - animals subjected to administration of cadmium chloride and sodium nitrate. Administration of sodium nitrate and cadmium chloride to animals in the doses 1/15 DL50 and 1/150 DL50 respectively during 14 days found that at the young age "slow" acetylation type is susceptibility marker, and the criteria of a harmful effect in them are the following: 25% increase protein peroxide oxidation in the blood plasma, 34% and 30% increase of average molecular peptides and ceruloplasmin respectively, and 6,7 times increase of methemoglobin (hemiglobin) concentration. Nitrate-cadmium intoxication caused inhibition of the integral behavioural activity both in slow and rapid acetylators. Disturbed behavioural activity in young animals with "slow" acetylation type under conditions of subacute effect of sodium nitrate and cadmium chloride is caused mainly by an increased content of liver lipoperoxidation secondary products and less - by the levels of average molecular peptides and ceruloplasmin in the blood plasma, and in "rapid" acetylators - by increased products of oxidation-modification proteins.

ENALAPRIL EFFECT ON GLUTATHIONE CHAIN OF THE ANTIOXIDANT SYSTEM OF THE BRAIN IN RATS WITH SCOPOLAMINE-INDUCED NEURODEGENERATION.

Objective of the work is to study enalapril effect, a blocker of renin-angiotensin system, on glutathione chain of the antioxidant system of the cerebral cortex and hippocampus of rats with experimental neurodegeneration. The experiments were conducted on nonlinear laboratory albino male rats with their body weight of 0,18-0,20 kg. The model of neurodegeneration was created by means of intraperitoneally administration of scopolamine hydrochloride (Sigma, USA) during 27 days in the dose of 1 mg/kg. Since the 28th day of the experiment enalapril (Zdorovye, Ukraine) was introduced intraperitoneally in the dose of 1 mg/kg in 1 ml of physiological solution once a day during 14 days. The content of reduced glutathione in male rats with scopolamine-induced neurodegeneration after introduction of enalapril increased in the cerebral cortex 1,8 times as much, and in the hippocampus - 1,2 times. Under enalapril effect the content of sulfhydryl groups increased in the cerebral cortex and hippocampus 1,3 and 1,1 times respectively. A positive effect of enalapril was characterized by an increased activity of glutathione reductase in the cerebral cortex 1,7 times as much, and 1,6 times - in the hippocampus. Thus, enalapril improves the indices of glutathione chain of the antioxidant system of the cerebral cortex and hippocampus, which is indicative of its neuroprotective ability under conditions of scopolamine-induced damage and development of neurodegenerative processes in rats.

ENALAPRIL EFFECT ON THE STATE OF NITROGEN OXIDE SYSTEM AND PROOXIDANT-ANTIOXIDANT BALANCE IN BRAIN UNDER CONDITIONS OF BLOCKADE OF CENTRAL CHOLINERGIC SYSTEM.

One of the most important medical-social issues today is the search for new pathogenic directions in pharmacological prevention and treatment of neurodegenerative diseases of the central nervous system. Objective: to investigate enalapril effect on the indices of the nitrogen oxide system and prooxidant-antioxidant balance in the cerebral cortex and hippocampus under conditions of experimental cerebral neurodegeneration. The state of the nitrogen oxide system and prooxidant-antioxidant balance is investigated in the experiment on male rats with scopolamine-induced neurodegeneration (1 mg/kg, 27 days) after enalapril administration in the dose of 1 mg/kg (14 days). Analysis of the obtained data enabled to describe a possible mechanism of enalapril neuroprotective action. It is manifested in decrease of NO2 concentration (1,4 times in both examined structures) and NOS activity (1,6 times in the hippocampus), which is indicative of an increased synthesis of NO as endothelial vasodilator. Correspondingly, a modulating effect on NO system and prooxidant-antioxidant balance (the content of products reacting with 2-thiobarbituric acid 1,1 times decreased in the cerebral cortex, and 1,3 times in the hippocampus compared with untreated rats; catalase activity in the cerebral cortex did not differ reliably from that of the index in the control group, and 1,4 times increased compared with untreated rats) can be considered as constituent mechanisms of enalapril neuroprotective effect under conditions of experimental scopolamine-induced neurodegeneration.

CHANGES OF PROTEINURIA AND ACID-REGULATING KIDNEY FUNCTION IN MATURE RATS WITH SLOW AND RAPID ACETYLATION TYPE UNDER CONDITIONS OF SUBACUTE CADMIUM-NITRATE INTOXICATION.

The experiments conducted on non-linear mature laboratory albino rats determined that under conditions of subacute cadmium-nitrate intoxication the indices of proteinuria and acid-regulating renal function depend on acetylation phenotype. Unlike rapid acetylators considerable increase of protein concentration in urine (192,8%, р<0,05) and standardized by glomerular filtration protein excretion (141,7%, р<0,05) are indicative of higher susceptibility of rats with slow acetylation type to nephrotoxic action of cadmium chloride and sodium nitrate. Lack of protein loss with urine and adaptive-compensative character of acid-regulating renal function changes directed to elimination of hydrogen ions excess from the body give evidence concerning less intensive damage of the nephron tubular portion in rats with rapid acetylation type, and at the same time do not exclude development of nephropathy. In order to confirm the significance of acetylation phenotype for assessment of susceptibility and degree of cadmium-nitrate damage of the kidneys the condition of other renal functions should be examined with analysis of biochemical criteria of nephrotoxicity, which is of an important practical value for the selection of appropriate pharmacotherapy.

PECULIARITIES OF THE INFLUENCE OF STREPTOZOTOCIN-INDUCED DIABETIS AND INCOMPLETE ISCHEMIAREPERFUSION OF THE BRAIN DURING APOPTOSIS OF VARIOUS NEOCORTICAL LOBES OF RATS.

The effect of diabetes mellitus on the dynamics of neurocyte and gliacyte apoptosis intensity in the cortex of the frontal, parietal and temporal lobes of the cerebral hemispheres under conditions of ischemic-reperfusion lesion has been studied in experiments on rats. The level of apoptotic processes in the neuro- and gliacytes of the frontal cortex has been found to be unchanged after 20 minutes of carotid ischemia followed by one hour reperfusion according to the indices examined in animals with out diabetes mellitus. Apoptosis of neurocytes is activated in the cortex of the parietal lobe, and that of the neuro- and gliacytes ­ in the cortex of the temporal lobe. Three-month diabetes mellitus intensifies apoptosis of neurons and glial cells in the cortex of the frontal and temporal lobes, neurons in the cortex of the parietal lobe and decreases apoptosis of gliacytes in it. In early ischemic-reperfusion period the activity of apoptotic processes in the cortex of the frontal and temporal lobes does not change in animals with diabetes mellitus, but it decreases in the cortex of the parietal lobe at the expense of glial cells. On the 12th day of observation the activity of apoptotic processes in neurocytes of the cortex of the temporal lobe increases in rats without diabetes mellitus, and it decreases in the glial cells. We detected a reduced content of the protein p53 in neurons and increased density of р53+-cells. In this period of observation in rats with diabetes mellitus the activity of apoptotic processes decreases in general both in neurons and glial cells of all the lobes. The results obtained point for the availability of regional differences in the dynamics of reaction of the cerebral hemisphere lobes in response to ischemic-reperfusion injury charachterized by the intensity of apoptosis of neurons and glial cells. The results also point for modifying effect of diabetes mellitus on the indices studied.

[Dynamics of changes of p53-positive cells morphofunctional condition in the cerebral cortex of the temporal lobe in rats affected by carotid ischemia-reperfusion].

The influence of bilateral 20-minute carotid ischemia with reperfusion of various duration upon the activity of apoptotic processes in the neurons and glia cells of the cerebral cortex in the temporal lobe of rats has been studied. Bilateral carotid ischemia with one-hour reperjusion has been indicated to increase the location density of p53+-neurocytes in this region of the cerebral cortex, increases percentage and density of p53+-nerve cells and reduces the percentage and density of p53+-glia cells on the 12th day of the post-ischemic period. Ischemic-reperfusion lesion of the brain increases the concentration of p53 protein in glia cells of the cerebral cortex in the temporal region in the early ischemic-reperfusion period and reduces it in nerve and glia cells in the late one.