NEUROCHEMICAL STATUS OF NITRIC OXIDE IN THE SETTINGS OF THE NORM, ISHEMIC EVENT OF CENTRAL NERVOUS SYSTEM, AND PHARMACOLOGICAL BN INTERVENTION.

The purpose of the given research is to study the efficiency of different inhibitors of NO-synthase in conditions of experimental cerebral ischemia by their capability to limit reactions of oxidative and nitrosative stress. In the given study a non-selective NOS inhibitor - N-nitro-L-arginine; a highly selective inhibitor of neuronal NOS - N-propyl-L-arginine and a highly selective competitive inhibitor of inducible NOS - (S)-methylurea were used. Cerebral circulation impairment was simulated by means of double-sided occlusion of common carotid arteries. It has been established that neurotoxic NO effect depends on definite enzyme of NO-synthase. Analysis of the obtained data shows a limited role of neuronal isoform in conditions of experimental impairment of blood circulation. The most relevant target for pharmacological regulation of NO-dependent mechanisms of neurodestruction is iNOS because of the fact that its activity begins to increase 12 hours after ischemia development and its action is implemented during several following days.

MANAGEMENT OF AMNESTIC AND BEHAVIORAL DISORDERS AFTER KETAMINE ANESTHESIA.

General anesthesia may cause damage of the central nervous system and cognitive dysfunction in the postoperative period. A new intranasal form of Noopept (N-Phenylacetyl-L-prolylglycine ethyl ester) was developed by our team at the Department of the medical technology (Zaporizhzhia State Medical University, Ukraine). The objectives of this investigation were the study of neuroprotective action of Noopept and to prove using in the clinic for correction of amnestic and behavioral disorders after ketamine anesthesia. We discovered that the intranasal administration of noopept after ketamine anesthesia significantly decreases anxiety and excitability, raises the animal's activity, shows an intensive antiamnesic effects and increases animal's training ability. Noopept significantly exceeds piracetam and cerebrocurin according to neuroprotective effects.

SYNTHESIS OF THE NEW 2-(3,4-DIHYDRO-3-OXO-2H-[1,2,4]TRIAZINO[4,3-C]QUINAZOLIN-4-YL) ACETIC ACID DERIVATIVES AND ANALYSIS OF THEIR ANTIOXIDANT ACTIVITY IN NITROSATIVE STRESS MODELS.

Today we know that NO· and ONOO- are clue pathophysiological factors for progression some ischemic diseases of the central nervous system. So investigation of the antioxidants which will be able to decrease NO· and ONOO- toxicity seems to be very of current interest. The six esters and three amides of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid were synthesized for this study, and we showed evidence of antioxidant activity of these new original derivatives. We studied the effect of 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid derivatives on superoxide dismutase activity under the condition of excessive NO· and ONOO- production. NO· induction was performed by the action of light on sodium nitroprusside Na2[Fe(NO)(CN)5]×2H2O in vitro. Also, the investigation of the substances was carried out in the brain supernatant obtained from the white Wistar rats in vivo. For nitrosative stress modeling dinitrozolic complex of Fe2+ and cysteine were utilized. Our data showed that 2-(3,4-dihydro-3-oxo-2H-[1,2,4]triazino[4,3-c]quinazolin-4-yl)acetic acid is not active compound while its esters and amides have antioxidant activity. Compound benzyl ester of this acid revealed the most effective antioxidant activity.

[INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals.

[NO-dependent mechanisms of cardioprotective activity of MT preparation during course administration to SHR rats].

Chronic (15 days) single daily intraperitoneal insertion of the new preparation MT (5 mg/kg) and metoprolol (10 mg/kg) into SHR rats leads to the same decrease (18%) in arterial pressure. In addition, MT exhibits a cardioprotective effect because of NO-mimetic properties, increasing NO formation in myocardium via increasing general NOS activity and eNOS expression. MT normalizes iNOS expression in myocardium mitochondria and decreases nitrotyrosine (nitrosation stress marker) formation. At the same time, the reference preparation metoprolol did not exhibit NO-mimetic properties in myocardium of SHR rats.

[Effect of anticonvulsants on the nitric oxide system].

The effect of phenobarbital, carbamazepine, valproate sodium, depakine, topiramate and lamotrigine on the content of NO and NO-synthase activity in white rat brain tissues has been studied. It was established that the action of carbamazepine, valproate sodium, topiramate and lamotrigine decreases the activity of NO-synthase and the level of NO in the brain tissues. The amount of NO does not change while NO-synthase activity increases with the introduction of phenobarbital. The involvement of nitric oxide in the mechanism of action of the studied anticonvulsant drugs is discussed.

Glycidipine, a promising hypotensive and cardioprotective agent.

Toxicological pharmacological study of the molecular complex of nifedipine and glycyrrhizic acid 1:10 (glycidipine) obtained using mechanochemical technique was carried out. High hypotensive and cardioprotective effects of the agent were demonstrated. Chronic administration (45 days) produced no toxic effects in vital organs and systems of Wistar rats and ISIAH rats.

[Pharmacological modulation of nitrogen oxide system in experimental chronic alcoholic intoxication in rats].

The modeling of chronic alcohol intoxication for 30 days in rats leads to an increase in the level of free metabolites of nitrogen oxide and NO-synthase with simultaneous decrease in the levels of L-arginine, catalase, and superoxide dismutase. The subsequent 14-day treatment with neuropeptide cerebroprotectors cerebrocurin, cortexin, and cerebrolysin led to normalization of the parameters of nitrogen oxide system. The maximum therapeutic activity was shown by cerebrocurin, which can be recommended for inclusion as component of alcoholic encephalopathy treatment.

[Neuroprotective effect of cerebrocurin in a model of acute cerebral stroke].

Chronic administration of cerebrocurin and cerebrolysin to Mongolian jirds with acute cerebral stroke model led to a decrease in the mitochondrial dysfunction on the 4th day, which was manifested by their ability to inhibit the mitochondrial permeability transition pore opening, normalize the energy metabolism, and enhance c-fos gene expression. In addition, cerebrocurin restored the morphofunctional state of neurons and favored the cell loss mechanism switching from necrosis to apoptosis. With respect to all characteristics under consideration, the effect of cerebrocurin exceeded with statistical confidence that of cerebrolysin.

[The influence of N-, S-containing chinasolone derivatives (NC-224) on the biochemical and physicochemical parameters of membrane endoplasmatic reticulum and nuclear chromatine fractions of rats liver cells in conditions of its injury by tetrachloromethane].

Using biochemical and physicochemical methods of investigation in vivo, the effect of the substance NC-224, N-, S-chinasolone-derivative, on the lipoperoxidation activity in rat liver endoplasmatic reticulum membranes and nuclear chromatin fractions under tetrachloromethane intoxication have been studied. It was shown that NC-224 has pronounced antioxidant activity which is the biochemical basis of the substance membrane- and genome-protective effects and its ability to restore physicochemical properties of the surface and hydrophobic zones of hepatocyte membranes and structural parameter nuclear chromatin fractions in the conditions of chemical liver injury.

[Antioxidant activity of condensed [1,2,4]-triazinone derivatives in nitrosative stress].

Antioxidant activity of nine [1,2,4]-triazinone derivatives was studied in the work. Our data show that [1,2,4]-triazinone derivatives with benzyl alcohol, propyl alcohol, me-thyl alcohol and tolyl residues in their structure have antioxidant activity in condition of in vitro NO formation. KO-17 compound proved to have the greatest antioxidant activity which exceeded N-acetyl cysteine's one.

[Pharmacological correction of neuronal damage in sensomotor zone of frontal cortex under conditions of experimental cerebral blood flow pathology].

The administration of thiotriazoline, emoxypine and magnelong (a combined glycine-magnesium preparation) to animals with acute cerebral circulatory insufficiency showed significant neuroprotective effect in both acute and late ischemic periods, as indicated by the indices of cell density and number and the characteristics of apoptic and destructed neurons approaching those in the group of intact rats. Pyracetam showed cerebroprotective effect only in late ischemic period. Magnelong exhibited the most significant neuroprotective effect, maintaining cell density on the intact control level and reducing the number of apoptotic and destructed neurons.

[Pharmacological neuroprotection against experimental acute cerebral ischemia of neurons of sensomotor area of frontal cortex and hippocampus in rats].

Emoxypine, thiotriazoline, and NN-103 (a 4-hydrazinoquinasoline derivative) exhibit a pronounced neuroprotective action during acute cerebral stroke. Emoxypine and thiotriazoline are more effective in inhibiting death of neurons in the sensomotor area of the frontal cortex, while NN-103 is more active in the hippocampus. The ischemic death of neurons in the sensomotors area of the frontal cortex with equal probability takes place by karyopyknosis or cytolysis, while in the hippocampus, mainly by cytolysis. All preparations (except for piracetam) with antioxidants properties are powerful membranoprotective agents, which is confirmed by a considerable decrease in the rate of cytolysis both in the cortex and in the hippocampus. The use of piracetam in the case of acute cerebral stroke increases the rate of neuronal death in various areas of the cortex, up to complete destruction of nerve tissues with the formation of cysts (in hippocampus). The tested preparations exhibit different mechanism of neuroprotection: emoxypine and NN-103 (in the sensomotor area of the frontal cortex and hippocampus) and thiotriazoline (in the hippocampus) produce the neuroprotection action on the background of increased activity of transmissions and transcription processes, while thiotriazoline (in the sensomotor area of the frontal cortex) offers neuroprotection on the background of inhibited transcription and transmission activity.

[The antioxidant activity of S-(4-quinazolyl)mercaptoacetic acid benzylidene hydrazides in vitro in the "nitrosation stress" model]. / Izuchenie antioksidantnoi aktivnosti benzilidengidrazidov S-(4-khinazolil)merkaptouksusnoi kisloty na modeli "nitroziruiushchego stressa" in vitro.

The "nitrozation stress" causes modification of the antioxidant enzymes leading to a decrease in their activity. A decrease in this activity and the resulting increase in the production of OH* and NO2* radicals via ONOO* decomposition leads to a significant increase in the extent of free-radical peroxidation during the "nitrozation stress". These factors are unfavorable from the standpoint of oxidative phosphorylation, which is manifested by inhibited activity of the oxidative enzymes. S-(4-Quinazolyl)mercaptoacetic acid benzylidene hydrazides exhibit a high antiradical activity related to the presence of a mercapto group in the quinazoline fragment. The activity depends on the position of this group on and the number of substituents in the benzylidene fragment. The compounds studied reduce the extent of damage in the brain homogenates of rats under conditions of nitrozation stress. This is manifested by inhibition of the free-radical peroxidation and an increase in the activity of antioxidant and prooxidant enzymes.

[Antiradical and antioxidant activity of derivatives of 1,2,4-triazole and quinazoline in cerebral ischemia]. / Antiradikal'naia i antiokislitel'naia aktivnost' proizvodnykh 1,2,4-triazola i khinazolina pri ishemii golovnogo mozga.

Antioxidant and antiradical activity of 1,2,4-triazole and quinazoline derivatives inhibiting superradical at the initial stages of free-radical oxidation have been studied in vitro by the method of Hara P, Mista, 1972. It is acceptable for the determination of antiradical and antioxidant activity of newly synthesized compounds.

[The clinical use of the new antioxidant thiotriazoline in ischemic ophthalmopathies]. / Klinicheskoe primenenie novogo antioksidanta tiotriazolina pri ishemicheskikh oftal'mopatiiakh.

The new antioxidant Thiotriazoline was used in the treatment of patients with retinal vascular occlusive processes. The agent improved retinal metabolism by inhibiting free radical oxidation. Thiotriazoline is superior to alpha-tocopherol acetate in its activity. Unlike the latter, it has no vasodilating effect.

[Free-radical oxidation in patients with stage-II hypertension]. / Sostoianie svobodnoradikal'nogo okisleniia u bol'nykh gipertonicheskoi bolezn'iu II stadii.

Free-radical oxidation was studied in 40 patients with hypertension stage II. The oxidation was found activated as blood and red cell levels of dien, trien conjugates, malon dialdehyde increased. The antioxidant protection was depressed: catalase, glutathione reductase activity reduced as did alpha-tocopherol deposits. This led to a growth of cerebral BB-creatine phosphatase and, consequently, to impairment of cerebral membranes.

[Antioxidant activity of a new derivative of 4-hydrazinoquinazoline in experimental cerebral hypoxia]. / Antioksidantnaia aktivnost'novogo proizvodnogo 4-gidrazinokhinazolina pri éksperimental'noi gipoksii golovnogo mozga.

It is established that KS-79 compound possesses the high level of antioxidant activity and realizes its antioxidant effect at initial stages of free-radical hydrogen peroxide oxidation of lipids. Due to this ability it differs from the oxidants of direct-type action.

[Pharmacologic protection of brain in surgery of the brachiocephalic arteries]. / Medikamentoznaia zashchita golovnogo mozga pri vypolnenii operatsii na plechegolovnykh arteriiakh.

On the basis of experimental and clinical data, the subclinical ischemic brain damage resulting from temporary clamping of the carotid artery during performance of the reconstructive operation has been established. The changes were revealed in sufficient, according to the existing criteria, collateral circulation. Before placing the clamp onto the carotid artery as a preventive method for intraoperative medicamental brain protection, intraarterial administration of piracetam, which possesses anti-ischemic, membrane stabilizing and antioxidant properties, has been suggested.