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Central nervous system disorders are the leading cause of mortality and disability in the world. Unfortunately, the possibility of pathogenetic therapy is limited and it is important to search for new drugs with neuroprotective mechanism of action. One of the most promising groups of drugs are antioxidants--substances that can neutralize free radicals and reduce oxidative stress. This review focuses on preclinical and clinical studies of new antioxidants.

It is established that intravenous injection of solubilized coenzyme Q10 provides quick and lasting increase in its level in the brain as compared to control intact rats and those with cerebral ischemia. These new data provide a basis for studying the efficacy of coenzyme Q10 as a neuroprotective agent in ischemic stroke.

The influence of coenzyme Q10 (CoQ10) on early ischemic deterioration was studied on Wistar rats with experimental myocardial infarction. CoQ10 (30 mg/kg) was injected intravenously 10 min after coronary artery occlusion, and morphometric analysis was performed for 72 h after the onset of ischemia. CoQ10-treated rats had restricted total myocardial damage (by 52%), including areas of necrosis (by 84%) and areas of cellular inflammatory infiltration (by 38%) as compared to saline-treated rats (p < 0.001).

Cardioprotective effects of coenzyme Q10 (CoQ10) injected intravenously 30 min before coronary artery occlusion were assessed on the model of myocardial ischemia/reperfusion in Wistar rats. Rats treated with CoQ10 after 30 min of ischemia and 120 min of reperfusion exhibited smaller (by 35%, p < 0.01) size of irreversibly damaged myocardium, shorter duration and decreased number of arrhythmias during reperfusion, and increased content of myocardial CoQ10 (by 210%, p < 0.01) as compared to saline-treated rats. Increased CoQ10 levels in myocardium were accompanied by smaller size of damaged myocardium (r = -0.77, p = 0.0002). Thus, there is evidence of the cardioprotective effect of CoQ10 injected intravenously before myocardial ischemia/reperfusion.

Possible mechanisms of the development of depression as a side effect of the a-interferon are reviewed. Methods used for the characterization of depressive states in experiment are considered.

A comparative study of the generation of hydroxyl radicals (OH*) in the hypertrophic myocardium of SHR-SP rats (n = 8) and in the myocardium of WKY (n = 5) and Wistar (n = 12) rats was performed using the microdialysis technique. The experiments were carried out on anesthetized open-chest male rats (ketamine intraperitoneally, 10 mg/kg) with artificial ventilation. The amount of OH* produced was estimated by high-performance liquid chromatography with electrochemical detection using as a marker 2,3-dihydroxybenzoic acid (2,3-DHBA), a product of the reaction of the hydroxyl radical with salicylic acid added to the perfusate. The quantity of 2,3-DHBA in the dialysate was estimated by the external standard method and expressed in percent of the 2,3-DHBA concentration in the perfusion fluid. The mean baseline value of 2,3-DHBA in dialysate samples in SHR-SP rats (157 +/- 22%, n = 8) was significantly higher than in Wistar (90 +/- 15%, n = 12, p = 0.0001) and Wistar-Kyoto rats (106 +/- 12%, n = 5, p = 0.005). The basal 2,3-DHBA level in SHR-SP rats was positively correlated (r = 0.831, n = 7, p < 0.05) with the degree of hypertrophy of the left ventricle expressed as the ratio of the left ventricle weight to the body weight. The data presented demonstrate that the hypertrophy of the left ventricle in SHR-SP rats is accompanied by the elevation of the level of free oxygen radicals.

Rats with experimental cardiosclerosis detected 21 days after embolization of the coronary arteries were subjected to early chronic perindopril administration (per os, 2 mg/kg once a day on days 2-20 after immobilization. As a result, the number of scars reduced, focal cardiosclerosis, dystrophy and hypertrophy of the cardiomyocytes were less pronounced, and the content of cellular glycogen increased. The cardioprotective effect was attended with a normalizing influence on the renin-angiotensin system parameters which were significantly changed after experimental damage to the myocardium: perindopril restored angiotensin I clearance and the level of angiotensin II production in the lungs.

The effect of chronic administration of perindopril (given per os daily for 21 days) and a single i.v. injection of perindoprilate (0.5 mg/kg) on the mean circulatory filling pressure (MCFP), mean arterial pressure (MAP), and heart rate (HR) was evaluated in conscious rats with heart failure caused by embolization of the coronary vessels with microspheres 21 days prior to the experiment. In the group of rats with cardiac failure perindoprilate reduced MAP by 10% and MCFP by 15%, but did not change AP and MCFP in animals which had been subjected to a sham-operation. Perindopryl reduced AP by 41% and MCFP by 20% in rats with heart failure, and by 37% and 13%, respectively, in rats which had undergone a sham-operation. It is concluded that the venous vessels in rats with heart failure possess increased sensitivity to perindopril.

The effect of intravenous perindoprilat, 0.5 mg/kg, on regional blood flow (radioactive microspheres, 15 microns), systemic hemodynamics, vein tone and cardiac functions was evaluated in conscious rats with congestive heart failure. Experimental heart failure was induced by embolization of coronary vessels with microspheres 21 days before the experiment. Perindoprilat reduced mean arterial pressure, total peripheral resistance, and end-diastolic left ventricular pressure. Perindoprilat induced an increase in cardiac index, stroke volume and heart rate. Blood flow in the renal, small intestinal and skin vascular beds was more profound in the heart failure group than in sham-operated animals. Perindoprilat unchanged the mean circulatory filling pressure in sham-operated animals and decreased it by 15% in rats with heart failure.

The changes in the parameters of systemic and regional hemodynamics during thermal stress were followed up in awake male Wistar rats. The cardiac output (CO) and blood flow in 16 zones of the body were measured by means of 15 microns microspheres labeled by 4 different isotopes. The blood flow increased in the skin of the tail, the liver, heart, adrenals, and skeletal muscles and reduced in the organs of the splanchnic region and kidneys. When body temperature reached 42 degrees C the CO decreased. The shifts in the regional blood flow maintained their direction, with the exception of a sharp increase of blood flow in the small intestine which preceded or coincided with the beginning of a fall in arterial pressure. The rate of increase of left ventricular pressure remained at a high level. It is assumed that the disruption of celiac vasoconstriction is among the earlier developing links of hemodynamic disorders in thermal affections and is caused by the vasodilative effect of the factors of local control of the vascular functions.

The response of the rat cardiovascular system to the cardiac glycoside ouabain was studied in an original model of heart failure developed on day 21 of coronary embolization with 15 microns radioactive microspheres introduced into the left ventricular cavity during ascending aortic occlusion. To examine systemic and regional hemodynamic parameters, the tracer technique with microspheres. Ouabain infused to rats with heart failure caused an increase in the index of left ventricular contractility, cardiac output, stroke volume, myocardial contractility, blood flow in most viscera and a decrease in end-diastolic pressure. The findings suggest that 21 days after coronary embolization the rats with heart failure proved more sensitive to the glycoside than did those sham-operated and thus, the presented model adequately reflects the status of the cardiovascular system when heart failure is evolving.

Changes in captopril sensitivity as a result of coronary embolization by 15 um microspheres were studied in rats. Selective coronary embolization was produced by injection of microspheres into the left ventricle during ascending aorta occlusion. The hemodynamic data were examined in conscious rats 21 days after embolization or sham operation before and after captopril bolus injection (1 mg/kg) by using microspheres method. Captopril injection caused a significant increase of the blood flow in the heart, kidneys, skin and some intestinal organs.

The heat stress induced common responses in rats and guinea pigs: an increase in the blood flow at the sites of heat radiation and in the diaphragm, and its decrease in splanchnic area's organs and in kidneys while cardiac output remained constant. The species differences occurred in the responses of intestine and skeletal muscles' vessels. The differences seem to be due mainly to the differences in behavioral responses to the heat stress in these animals.

Rats were given intraperitoneal injections of adriamycin (cumulative dose 20 mg/kg). Two weeks after the last injection left-ventricular function and systemic and regional hemodynamics were studied before and during isoprenaline infusion (0.64 mcg/kg/min) in conscious rats with no signs of cardiac insufficiency. In the controls isoprenaline increased the left-ventricular contractility index by 45% and the heart rate by 30%. The contractility index in rats given adriamycin did not change, the heart rate increased only by 14%, but in contrast to the controls, a significant increase of the cardiac index by 36% and diminution of total peripheral resistance by 36% were revealed. The sensitivity of the baroreflex chronotropic component in the control animals was twice that in the experimental rats. It is concluded that adriamycin cardiomyopathy in rats is attended by reduced sensitivity of the baroreflex mechanisms and diminished myocardial adrenergic reactivity.

The ultrasound Doppler technique was used for the determination of cardiac output in conscious Wistar rats. The cuff probes were placed on the ascending aorta and calibrated with the radioactive microsphere technique. The results of experiments show that Doppler ultrasound technique determines the cardiac output with high linearity. The possibility of using both methods in one and the same animal was also confirmed.

Left ventricle (LV) function and systemic hemodynamic changes after coronary artery embolization by 15 microns radioactive microspheres were studied in anesthetized rats. Selective coronary embolization was produced by microsphere injection during ascending aorta occlusion in closed chest animal by using "L"-shaped wire. Maximal pressure (Pmax) developed was evaluated during ascending aorta occlusion. Coronary embolization evoked dose-dependent reduction in Pmax and dP/dtmax and then decrease in basal LV systolic pressure. dP/dt/P, with parallel increase in end diastolic LV pressure. Changes of cardiac output were bidirectional: after administration of relatively small amount of microspheres cardiac output increased. This method can be used for producing quantitative myocardial ischemia and we suggest that it may be a suitable model of the chronic heart failure.

Chronic experiments on cats were made to study the relationship between reflex tachycardia in response to the drug-induced arterial blood pressure fall and spontaneous variations in the initial cardiac rhythm. The existence of inverse linear correlation was shown between the magnitude of chronotropic response and control heart rate before and after beta-adrenergic blockade. The significance of the correlation disclosed for the interpretation of the research data on the relative role of the sympathetic and parasympathetic heart regulation performed in different experimental conditions is discussed.

Systemic hemodynamic parameters in 5-month-old and 10-month-old normotensive Wistar-Kyoto and spontaneously hypertensive (SHR) conscious rats were studied with microsphere technique. Cardiac index was similar in both strains of rats and was not significantly different between 5 and 10 months. Left ventricle catheter implantation through the right common carotid artery evoked the development of heart failure in 10-month-old SHR (in the first day after operation). This model can be used for screening of new drugs for heart failure treatment.