Neuroprotective Effects of Tryptanthrin-6-Oxime in a Rat Model of Transient Focal Cerebral Ischemia.

The activation of c-Jun N-terminal kinase (JNK) plays an important role in stroke outcomes. Tryptanthrin-6-oxime (TRYP-Ox) is reported to have high affinity for JNK and anti-inflammatory activity and may be of interest as a promising neuroprotective agent. The aim of this study was to investigate the neuroprotective effects of TRYP-Ox in a rat model of transient focal cerebral ischemia (FCI), which involved intraluminal occlusion of the left middle cerebral artery (MCA) for 1 h. Animals in the experimental group were administered intraperitoneal injections of TRYP-Ox 30 min before reperfusion and 23 and 47 h after FCI. Neurological status was assessed 4, 24, and 48 h following FCI onset. Treatment with 5 and 10 mg/kg of TRYP-Ox decreased mean scores of neurological deficits by 35-49 and 46-67% at 24 and 48 h, respectively. At these doses, TRYP-Ox decreased the infarction size by 28-31% at 48 h after FCI. TRYP-Ox (10 mg/kg) reduced the content of interleukin (IL) 1ß and tumor necrosis factor (TNF) in the ischemic core area of the MCA region by 33% and 38%, respectively, and attenuated cerebral edema by 11% in the left hemisphere, which was affected by infarction, and by 6% in the right, contralateral hemisphere 24 h after FCI. TRYP-Ox reduced c-Jun phosphorylation in the MCA pool at 1 h after reperfusion. TRYP-Ox was predicted to have high blood-brain barrier permeability using various calculated descriptors and binary classification trees. Indeed, reactive oxidant production was significantly lower in the brain homogenates from rats treated with TRYP-Ox versus that in control animals. Our data suggest that the neuroprotective activity of TRYP-Ox may be due to the ability of this compound to inhibit JNK and exhibit anti-inflammatory and antioxidant activity. Thus, TRYP-Ox may be considered a promising neuroprotective agent that potentially could be used for the development of new treatment strategies in cerebral ischemia.

Antihypertensive activity of a new c-Jun N-terminal kinase inhibitor in spontaneously hypertensive rats.

c-Jun N-terminal kinases (JNKs) are involved in the myocardial and aortic remodeling, increased arterial tone, and arterial blood pressure elevation associated with hypertension. The aim of the present study was to investigate the antihypertensive effect of a new JNK inhibitor, 1H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), on spontaneously hypertensive rats (SHRs). Experiments were performed using normotensive Wistar-Kyoto (WKY) rats and SHRs. Experimental groups of SHRs received IQ-1S intragastrically for 6 weeks in daily doses of 5 and 50 mg/kg; experimental groups of WKY rats received 50 mg/kg IQ-1S according to the same regimen. The IQ-1S administration regimen induced decreases in systolic blood pressure, mean arterial blood pressure, total peripheral resistance, blood viscosity, hematocrit, myocardial cell cross-sectional area, and aortic wall thickness in SHRs vs untreated SHRs. There were no significant differences in systolic blood pressure values between the control and experimental groups of WKY rats during the treatment period. A concentration-dependent decrease in the tone of carotid arterial rings isolated from SHRs was observed after JNK inhibitor application in vitro. Application of the JNK inhibitor diminished endothelin-1 secretion by human umbilical vein endothelial cells in vitro. The main mechanisms of the antihypertensive effect of IQ-1S included the attenuation of blood viscosity due to decreased hematocrit, a vasodilatory effect on arterial smooth muscle cells, and a decrease in endothelin-1 production by endothelial cells.

Antihyperglycaemic, haemorheological and antioxidant activities of Lychnis chalcedonica L. extract in a streptozotocin-induced rat model of diabetes mellitus.

Background New therapeutic strategies, such as the use of agents to correct rheological disorders, are needed for the prevention and treatment of angiopathy in diabetic patients. The aim of this work was to study the antihyperglycaemic, haemorheologic and antioxidant activities of an extract from the flowering plant Lychnis chalcedonica L. (ELC) and 20-hydroxyecdysone using the streptozotocin-induced model of diabetic rats. Methods The streptozotocin-induced model of diabetes was produced using streptozotocin at a dose of 50 mg/kg (ip). Animals from the experimental groups were treated with ELC (150 mg/kg) or 20-hydroxyecdysone (1.1 mg/kg) intragastrically in 1% aqueous starch mucilage daily, for 14 days; rats of control groups received an equal volume of starch mucilage. The following parameters were measured: glucose concentration (GC) in blood, whole blood viscosity (WBV), conjugated dienes in RBC membranes. Macro- and microrheological indicators (viz. plasma viscosity, haematocrit, RBC aggregation (T1/2) and the RBC elongation index (EI)) were additionally measured in rats that received ELC, and in the control group. Results After treatment with ELC, the GC in rats was 19% lower than that in the control group (14.7 ± 0.9 mM compared to 18.2 ± 1.1 mM). Rats with streptozotocin-induced diabetes have hyperviscosity syndrome, which is characterized by increased WBV, increased RBC aggregation and decreased deformability. ELC treatment reduced WBV at shear rates of 10-90 s-1 by 5-8%, and T1/2 and EI in the experimental group were 31% and 5-10% higher compared to the control group. 20-Hydroxyecdysone decreased WBV at shear rates of 10-90 s-1 by 3-11%. Finally, ELC and 20-hydroxyecdysone lowered the content of conjugated dienes by 27% and by 26% compared to the control groups. Conclusion In the streptozotocin-induced diabetic rat model, ELC showed measurable antihyperglycaemic activity; ELC and 20-hydroxyecdysone demonstrated similar haemorheological, and antioxidant activities.

Effect of p-tyrosol on hemorheological parameters and cerebral capillary network in young spontaneously hypertensive rats.

BACKGROUND: Many pathological mechanisms are involved in the development of arterial hypertension; disturbance of the rheological properties of blood and microvascular rarefaction are among those mechanisms. OBJECTIVE: The effect of p-tyrosol (Tyr) on hemorheological parameters and microvascularization in the cerebral cortex of spontaneously hypertensive rats (SHRs) at the stage of blood pressure rising (5-11 weeks) was studied. METHODS: Blood viscosity (BV), plasma viscosity (PV), hematocrit, erythrocyte aggregation and deformability, the oxygen transport capacity index (OTCI), and the capillary network in the cerebral cortex after the course of treatment of Tyr (50 mg/kg daily i.g. for 6 weeks) were studied. Control normotensive Wistar-Kyoto (WKY) rats and control SHRs received an equivalent amount of 1% starch mucilage. RESULTS: In comparison with WKY rats, disturbances of rheological blood parameters and a decrease in OTCI were revealed in control SHRs at the 11 weeks of life. By the end of the experiment, brain microvascular rarefaction was observed in the control SHRs (the average density of the capillary bed was reduced due to a decrease in the number of capillaries with a diameter of 3-7 µm). In SHRs rats treated with Tyr, BV and PV, the indices of erythrocyte aggregation were lower, and OTCI was higher in comparison with control SHRs. The density of the capillary network and the number of capillaries of 3-7 µm in the cerebral cortex of SHRs rats receiving Tyr were significantly higher than the corresponding values in control SHRs. CONCLUSION: When Tyr is administered to young SHRs during the development of hypertension, it limits the development of hyperviscosity syndrome, improves the oxygen transport capacity and eliminates microvascular rarefaction in the cerebral cortex.

Pentoxifylline treatment enhances antihypertensive activity of captopril through hemorheological improvement in spontaneously hypertensive rats during development of arterial hypertension.

The rheological properties of blood play a significant role in the onset and progression of arterial hypertension. The aim of our work was to evaluate the effect of the angiotensin-converting enzyme inhibitor captopril (20 mg/kg/d), pentoxifylline (PTX; 100 mg/kg/d), and the combination of captopril + PTX (20 + 100 mg/kg/d) on the hemodynamic and hemorheological parameters in spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. In the group of animals that received captopril, the mean arterial pressure (MAP) was significantly lower by 30% due to a decrease in cardiac output of 23% and in total peripheral resistance (TPR) of 26% compared with the control group, whereas blood viscosity did not change significantly. PTX-treated SHRs had significantly lower MAP and TPR (by 19% and 31%, respectively) and blood viscosity (by 4%-6%) and a higher erythrocyte deformability index (by 1.5%-2%) than the control group. In the group of animals that received captopril + PTX, MAP and TPR were significantly lower, by 41% and 46%, than those in the control group, and by 16% and 27% than those in the captopril group. The combination of the angiotensin-converting enzyme inhibitor captopril and the hemorheological agent PTX, affecting various systems that are involved in blood pressure regulation, exhibits synergism and prevents an increase in arterial blood pressure during the development of arterial hypertension in SHRs (ie, from 5 to 11 weeks of life).

Effects of pentoxifylline on hemodynamic, hemorheological, and microcirculatory parameters in young SHRs during arterial hypertension development.

The most common form of hypertension in young adults is isolated diastolic hypertension. Diastolic arterial pressure is determined by the total peripheral resistance and depends on both vascular hindrance and blood viscosity. The aim of our work was to study the efficiency of pentoxifylline (PTX) in young spontaneously hypertensive rats (SHRs) during the development of arterial hypertension. The effects of a treatment course with PTX (100 mg/kg/day p.o. for 6 weeks, from 5 to 11 weeks old) on the mean, systolic, and diastolic blood pressure (BP); stroke volume; cardiac output; total peripheral resistance (TPR); whole blood viscosity (BV); plasma viscosity; hematocrit; RBC aggregation and deformability; local cerebral blood flow (lCBF); and microvascularization of the visual cortex were studied in SHRs in comparison with control SHRs and Wistar Kyoto rats. PTX-treated SHRs had significantly lower systolic, diastolic, and mean BP (by 24%, 26%, and 15%, respectively) and BV (by 5-9%) and a higher erythrocyte deformability index (by 1.5-2%), lCBF (by 42%), average diameter of capillaries (by 11%), density of the capillary network (by 23%), and percentage of capillaries with a diameter of 3-7 µm in comparison with control SHRs. In conclusion, PTX exerted positive effects on the hemodynamic, hemorheological, and microcirculatory parameters in SHRs during the development of arterial hypertension.

Hemorheological effects of amlodipine in spontaneously hypertensive rats.

OBJECTIVES: The effect of course administration of amlodipine on whole blood viscosity and on macro- and microrheological parameters was evaluated. MATERIALS AND METHODS: SHRs were treated intragastrically with amlodipine at a dose of 10 mg/kg for 6 weeks. After finishing the course, hemodynamic and hemorheological parameters were measured. RESULTS: The antihypertensive treatment with amlodipine resulted in a significant decrease in mean blood pressure by 29% and left ventricular to body weight mass index by 7%. Nevertheless, BV tended to increase. The administration of amlodipine had no effect on PV, plasma fibrinogen concentration, RBC aggregation, and RBC deformability, but hematocrit was higher (by 6%) than it was in control group. CONCLUSIONS: These results demonstrate that amlodipine has no positive hemorheological improvements when administered to SHRs.

Relationship between arterial blood pressure and blood viscosity in spontaneously hypertensive rats treated with pentoxifylline.

BACKGROUND: Systemic arterial pressure (AP) depends on two physiological variables: cardiac output (CO) and total peripheral resistance (TPR). The latter depends on vascular hindrance and blood viscosity (BV). However, the relative contributions of the vascular and rheological factors to TPR remain unclear. OBJECTIVE: The aim of our work was to study the haemodynamic and haemorheologic effects of a treatment course with pentoxifylline (PTX) in SHRs in an effort to assess the impact of the rheological factor on TPR and AP. METHODS: The effects of the treatment course with PTX (100 mg/kg/day p.o. for six weeks) on BV, plasma viscosity, haematocrit, erythrocyte aggregation and deformability, mean AP (MAP), stroke volume (SV), CO, and TPR were studied in SHRs and in control Wistar Kyoto (WKY) rats. RESULTS: PTX-treated SHRs had a lower BV, lower erythrocyte aggregation, and higher erythrocyte deformability index compared with the controls. The TPR level was higher by 43% compared with that in WKY rats and did not differ from the values obtained from control SHRs. In SHRs, moderate and strong positive correlations were found between BV and MAP and between BV and TPR. PTX-treated SHRs did not have any significant correlations between the above mentioned parameters. CONCLUSIONS: Treatment with PTX attenuated whole blood viscosity, but did not affect the AP and hemodynamic parameters in the experimental SHRs compared with the control SHRs. The magnitude of the rheologic effects of PTX was insufficient to cause appreciable decreases in TPR and AP.

Hemorheological effects of secoisolariciresinol in ovariectomized rats.

BACKGROUND: Postmenopausal women often develop hemorheological disorders which may affect the systemic blood circulation and present a cardiovascular risk factor. OBJECTIVE: We evaluated effects of secoisolariciresinol (SECO), a phytoestrogen, on hemorheological parameters and lipid peroxidation in a model of the age-related and/or surgical menopause induced by ovariectomy in rats. METHODS: Arterial blood was sampled from sham-operated female rats, ovariectomized rats (OVX), and OVX treated with SECO (OVXSECO) (20 mg/kg/day intragastrically for two weeks). Plasma estrogen concentration and the following hemorheological parameters were measured: RBC aggregation (half-time of aggregation, T1/2; amplitude of aggregation, AMP; aggregation index, AI), RBC deformability (elongation index, EI), whole blood viscosity at the shear rate of 3-300 s-1, plasma viscosity, hematocrit, plasma fibrinogen. Lipid peroxidation was evaluated by measuring conjugated dienes (CD) and thiobarbituric acid reactive substances (TBARS) in plasma. RESULTS: Ovariectomy in rats caused a 60% decrease in plasma estrogen level and triggered the development of macro- and microhemorheological abnormalities. Blood viscosity increased by 12-31%, RBC elongation index reduced by 16-28%, and T1/2 and AI increased by 35% and 29% respectively. The increase in blood viscosity correlated predominantly with reduced RBC deformability. Plasma CD and TBARS were elevated by 47% and 104% respectively. SECO therapy for OVX rats reduced blood viscosity by 9-18% and T1/2 by 32%, and increased EI by 4-17%. SECO therapy disrupted the correlation between blood viscosity and RBC deformability. Lipid peroxidation was significantly inhibited, as shown by the reduction in CD and TBARS plasma concentrations by 89% and 70% respectively. SECO did not affect plasma viscosity, estrogen or fibrinogen levels. CONCLUSIONS: SECO treatment for OVX rats improves blood macro- and microrheological parameters, possibly through antioxidant protection of RBC.