c-Jun N-terminal kinase (JNK) is activated by various brain insults and is implicated in neuronal injury triggered by reperfusion-induced oxidative stress. Some JNK inhibitors demonstrated neuroprotective potential in various models, including cerebral ischemia/reperfusion injury. The objective of the present work was to study the neuroprotective activity of a new specific JNK inhibitor, IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt), in the model of global cerebral ischemia (GCI) in rats compared with citicoline (cytidine-5′-diphosphocholine), a drug approved for the treatment of acute ischemic stroke and to search for pleiotropic mechanisms of neuroprotective effects of IQ-1S. The experiments were performed in a rat model of ischemic stroke with three-vessel occlusion (model of 3VO) affecting the brachiocephalic artery, the left subclavian artery, and the left common carotid artery. After 7-min episode of GCI in rats, 25% of animals died, whereas survived animals had severe neurological deficit at days 1, 3, and 5 after GCI. At day 5 after GCI, we observing massive loss of pyramidal neurons in the hippocampal CA1 area, increase in lipid peroxidation products in the brain tissue, and decrease in local cerebral blood flow (LCBF) in the parietal cortex. Moreover, blood hyperviscosity syndrome and endothelial dysfunction were found after GCI. Administration of IQ-1S (intragastrically at a dose 50 mg/kg daily for 5 days) was associated with neuroprotective effect comparable with the effect of citicoline (intraperitoneal at a dose of 500 mg/kg, daily for 5 days).The neuroprotective effect was accompanied by a decrease in the number of animals with severe neurological deficit, an increase in the number of animals with moderate degree of neurological deficit compared with control GCI group, and an increase in the number of unaltered neurons in the hippocampal CA1 area along with a significant decrease in the number of neurons with irreversible morphological damage. In rats with IQ-1S administration, the LCBF was significantly higher (by 60%) compared with that in the GCI control. Treatment with IQ-1S also decreases blood viscosity and endothelial dysfunction. A concentration-dependent decrease (IC50 = 0.8 ± 0.3 μM) of tone in isolated carotid arterial rings constricted with phenylephrine was observed after IQ-1S application in vitro. We also found that IQ-1S decreased the intensity of the lipid peroxidation in the brain tissue in rats with GCI. 2.2-Diphenyl-1-picrylhydrazyl scavenging for IQ-1S in acetonitrile and acetone exceeded the corresponding values for ionol, a known antioxidant. Overall, these results suggest that the neuroprotective properties of IQ-1S may be mediated by improvement of cerebral microcirculation due to the enhanced vasorelaxation, beneficial effects on blood viscosity, attenuation of the endothelial dysfunction, and antioxidant/antiradical IQ-1S activity.

The dynamics of systolic and diastolic BP and vasodilatory activity of the endothelium in SHR and Wistar-Kyoto rats was studied from the 5th to the 12th week of life. Systolic and diastolic BP did not differ in 5-week-old SHR and Wistar-Kyoto rats. After the 6th week of life, two stages of arterial hypertension development were observed in SHR. Stage 1 (weeks 6-8) was characterized by a significant increase in systolic and diastolic BP that exceeded the corresponding parameters in Wistar-Kyoto rats by 26-32%. Vasodilatory activity of the endothelium was similar in rats of both strains at the age of 5-7 weeks. Stage 2 (weeks 9-12) in SHR rats was characterized by further increase in systolic and diastolic BP that exceeded the corresponding parameters in Wistar-Kyoto rats by 54-89%. The increase in BP during this period was accompanied by a significant decrease in endothelium-dependent relaxation (by 14-16% compared to that in Wistar-Kyoto rats of the same age).

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Blood rheological status is studied in Wistar rats with cerebral ischemia induced by ligation of the left coronary artery and reduced blood flow via the right coronary artery. Substantial changes in blood rheology and manifestations of the sludge syndrome are noted. The results obtained are compared with clinical observations, and the informativeness of each parameter is evaluated. Key Words: cerebral ischemia; blood rheologyNumerous clinical trials show that the sludge syndrome aggravates myocardial infarction [ 1,6], ischemic stroke [10,13], essential hypertension [11], etc. Therefore, it is necessary to investigate the mechanisms of this syndrome and develop pharmacological means of correcting blood rheological disorders. The aim of the present study was to create an adequate animal model of the sludge syndrome in cerebral ischemia to analyze the interplay and informativeness of rheological parameters. MATERIALS AND METHODSExperiments were carried out on 20 male rats weighing 200-250 g. Ischemia was modeled as described previously [8]. The following parameters were measured 5, 7, and 10 days after ischemia: relative viscosity of the blood and plasma (on a VK-4 capillary viscosimeter), erythrocyte aggregation (half-time of aggregate formation, Tin, i.e., the time during which the signal amplitude decreased 2-fold), hematocrit (in an MGC-8 microcentrifuge), and plasma content of fibrinogen [2]. The results were processed using Student's t test, nonparametric Wilcoxon test, correlaInstitute of Pharmacology, Tomsk Research Center, Siberian Division -of the Russian Academy of Medical Sciences tion analysis, and a geometrical approach to evaluation of informativeness of the parameters [7]. RESULTSOn day 5 after cerebral ischemia, blood viscosity in rats with cerebral ischemia was significantly higher than in intact controls and remained at this level up to the 10th day; the tendency towards normalization (on day 7) was statistically insignificant (Table 1). The increase in blood viscosity is consistent with that occurring in patients with cerebral ischemia [5,12]. In our experiments, blood viscosity was increased due to enhanced aggregation of erythrocytes and hyperfibrinogenemia persisting throughout the experiment. This conclusion is based on the results of correlation analysis showing that blood viscosity positively correlates with both spontaneous erythrocyte aggregation (r=0.96, p=0.04) and fibrinogen content (r=0.97, p--0.03). The presence of the mechanisms responsible for the increase in blood viscosity upon enhanced erythrocyte aggregation is confirmed by the finding that erythrocyte aggregation correlates with plasma fibrinogen content (r=0.95, p=0.048). Despite sustained hyperfibrinogenemia, plasma viscosity in rats with cerebral ischemia did not differ from that in the controls. Plasma viscosity tended to decrease on days

The effects of dihydroquercetin (50 mg/kg intragastrically daily for 6 weeks) on the density of capillary network (mean number of capillaries per mm), mean capillary diameter, structure of capillary network, capillary diameter distribution (<3, 3-5, 5-7, and 7-9 μ), and local cerebral blood flow (by laser Doppler) in the visual cortex were studied in SHR rats during the development of arterial hypertension (from the 6th to the 12th week of life). Normally, the systolic and diastolic BP progressively increased in SHR rats during this period. Dihydroquercetin did not affect the development of arterial hypertension. At the same time, the drug significantly increased the mean diameter of capillaries (by 11%), capillary network density (by 23%), and in the percentage of capillaries with a diameter of 3-9 μ (passable for erythrocytes; by 42%). Positive effects of dihydroquercetin on the structure of microcirculatory bed improved microcirculation: local cerebral blood flow in the visual cortex of SHR rats was significantly higher (by 36%) than in rats receiving no flavonoid and close to the value in Wistar-Kyoto rats. Dihydroquercetin improved microvascularization and microcirculation in the cerebral cortex of SHR rats during the formation of arterial hypertension.

We studied the effect of dihydroquercetin (20 mg/kg/day intragastrically for 6 weeks) on mean BP and macro- and microrheological blood parameters in hypertensive SHR rats; in vitro effect of dihydroquercetin on the tone in thoracic aorta rings isolated from hypertensive SHR rats were also examined. At the end of the treatment course, the mean BP in the experimental rats decreased by 11%; the left ventricular mass index by 2%, and whole blood viscosity by 7-10% in comparison with control SHR rats; erythrocyte aggregation half-time increased by 15%; plasma viscosity, hematocrit, and erythrocyte deformability did not change. In in vitro experiments, dihydroquercetin (10-10M) induced relaxation of the isolated thoracic aorta rings in a dose-dependent manner. Hence, the antihypertensive effect of dihydroquercetin results from the decrease in blood viscosity and vasodilation.

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Considerable hemorheological changes and depression of EEG parameters were revealed in rats with cerebral ischemia. Course peroral treatment with scarlet lightning extract in a daily dose of 150 mg/kg for 5 days reduced the severity of hemorheological disorders. It manifested in a decrease in whole blood viscosity, plasma viscosity, erythrocyte aggregation, and fibrinogen concentration and increase in deformability. The extract of lightning extract improved EEG activity in rats with cerebral ischemia.