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We compared the direct neuroprotective effect of minor food components, antioxidants hesperetin and carnosine, and analyzed their influence on the parameters of the oxidative status of the penumbra zones in the cerebral cortex during focal ischemia (1 h) of with reperfusion in Wistar rats. The animals received hesperetin and carnosine included in the diet in daily doses of 50 and 150 mg/kg, respectively, for 7 days before ischemia induction. The neuroprotective effect of hesperetin manifested in reduction of the ischemic lesion size by 30%, which was comparable with the effect of carnosine. Both hesperetin and carnosine reduced the level of MDA in the penumbra zone of the cerebral cortex and increased the total antioxidant activity of the brain tissue. Hesperetin also increased SOD activity to a level observed in the sham-operated control group.

Ischemic stroke is one of the most socially important diseases characterized by impaired cerebral circulation with focal damage of the brain tissue and decreased functionality. Despite the successes of modern pharmacology, possibilities of pharmacotherapy for stroke remain limited, and the research for new drugs with neuroprotective effects that can prevent brain cell death is still relevant. In this study we have investigated the neuroprotective activity of ubiquinol as a part of an innovative form on a rat model of irreversible 24 h-cerebral ischemia with evaluation of the mechanisms of its neuroprotective effect. Ubiquinol (30 mg/kg), administered intravenously in the acute period of irreversible 24 h focal cerebral ischemia, had a direct neuroprotective effect, characterized by a decrease in the volume of brain tissue necrosis. The protective effect of ubiquinol is due to its ability to inhibit the development of oxidative stress by the direct anti-radical action, preventing the increase in the lipid hydroperoxide content in the brain tissue adjacent to the focus of necrosis, lowering the lipid oxidation rate in plasma against under conditions of increased total antioxidant activity in the brain and blood of experimental animals. In vitro experiments have shown the ability of ubiquinol to prevent cell death in primary culture of cerebral neurons of rat brain under 4 h oxygen/glucose deprivation followed by 20 h reoxygenation.

Carnosine (b-alanyl-L-histidine) is an endogenous dipeptide widely distributed in excitable tissues, such as muscle and neural tissues-though in minor concentrations in the latter. Multiple benefits have been attributed to carnosine: direct and indirect antioxidant effect, antiglycating, metal-chelating, chaperone and pH-buffering activity. Thus, carnosine turns out to be a multipotent protector against oxidative damage. However, the role of carnosine in the brain remains unclear. The key aspects concerning carnosine in the brain reviewed are as follows: its concentration and bioavailability, mechanisms of action in neuronal and glial cells, beneficial effects in human studies. Recent literature data and the results of our own research are summarized here. This review covers studies of carnosine effects on both in vitro and in vivo models of cerebral damage, such as neurodegenerative disorders and ischemic injuries and the data on its physiological actions on neuronal signaling and cerebral functions. Besides its antioxidant and homeostatic properties, new potential roles of carnosine in the brain are discussed.

Oxidative status was assessed in different areas of the cerebral cortex of male Wistar rats under normal condition and during permanent 24-h focal ischemia. In intact animals, the level of lipid hydroperoxides in the frontal lobes of both hemispheres was by 36% higher than in other cortical areas, while total antioxidant activity was by 25% higher than in other areas. During ischemia, changes in oxidative status were localized only in the ischemic focus and penumbra zone and did not involve other cortical areas. We demonstrated for the first time a neuroprotective effect of therapeutic administration of carnosine in low doses (50 mg/kg) on parameters of the oxidative status under conditions of focal ischemia comparable to its effect of high doses (500 mg/kg) as well as its local effect in the penumbra zone. A dose-dependent effect of carnosine on antioxidant activity in the penumbra zone during ischemia was also demonstrated. These findings confirm effectiveness of not only preventive carnosine administration, but also its application in the postischemic period of the stroke.

Oxidative stress is one of the key factors in brain tissue damage in ischemia, which indicates the appropriateness of using antioxidants under these conditions. One of the promising antioxidants for the therapy of ischemic stroke is the natural dipeptide carnosine. The neuroprotective effect of dietary carnosine administration was investigated in an experimental model of focal cerebral ischemia/reperfusion in Wistar rats. Animals received carnosine with a diet at a daily dose of 150 mg/kg for 7 days before temporary occlusion of the middle cerebral artery (MCA), performed for 60 min. At 24 h after the onset of ischemia the effect of carnosine on the area of the necrotic core was evaluated in animals. In brain tissue of animals the content of malondialdehyde (MDA), protein carbonyls (PC), total antioxidant capacity (TAC), total activity of superoxide dismutase (SOD), glutathione peroxidase (GP), catalase (CAT) and glutathione transferase (GT), content of isoprostanes and cytokines were measured. Carnosine significantly reduced the infarct size. Carnosine also increased TAC and reduced the level of MDA and isoprostanes in brain tissue. Influence of carnosine on other parameters was not detected. Thus carnosine consumed prophylactically with the diet for 7 days before the induction of ischemia by means of MCA occlusion in rats provides the direct neuroprotective effect, retains high antioxidant activity of brain tissue, reduces the level of oxidative damage markers (MDA and isoprostanes) but does not have any effect on the activity of antioxidant enzyme systems and production of cytokines in brain tissue.

Parameters of the oxidative status of the brain and blood plasma were measured in rats 24 h after 1-h focal cerebral ischemia. In the brain of rats exposed to cerebral ischemia, activities of superoxide dismutase and catalase were elevated. Ischemia reduced the total antioxidant activity of the brain and the levels of malonic dialdehyde and protein carbonyl derivatives. In the blood plasma of experimental rats, superoxide dismutase activity and malonic dialdehyde level increased and total antioxidant activity decreased, i.e. the shifts were similar to those in the brain. The ischemia-induced changes in the brain and blood were not always co-directed.

Aim: To assess neuroprotective properties of preventive injections of carnosine in experimental focal cerebral ischemia in rats., Material and Methods: A focal ischemia in Wistar rats induced by the 60 min-occlusion of the middle cerebral artery with the following 24h-reperfusion was used. Animals received carnosine mixed with ration in daily dose of 150 mg/kg of body mass during 7 days before surgery., Results and Conclusion: Carnosine decreased the size of the lesion by 20%, neurological deficit by 43% with a simultaneous increase in the antioxidant status of blood plasma and brain tissue compared to the animals of the control group. The authors showed for the first time the neuroprotective effect of low dose of carnosine (150 mg/kg of body mass) mixed with ration used in preventive treatment courses in the experimental focal cerebral ischemia-reperfusion model.

Carnosine, a specific constituent of excitable tissues of vertebrates, exhibits a significant antioxidant protecting effect on the brain damaged by ischemic-reperfusion injury when it was administered to the animals before ischemic episode. In this study, the therapeutic effect of carnosine was estimated on animals when this drug was administered intraperitoneally (100 mg/kg body weight) after ischemic episode induced by experimental global brain ischemia. Treatment of the animals with carnosine after ischemic episode under long-term (7-14 days) reperfusion demonstrated its pronounced protective effect on neurological symptoms and animal mortality. Carnosine also prevented higher lipid peroxidation of brain membrane structures and increased a resistance of neuronal membranes to the in vitro induced oxidation. Measurements of malonyl dialdehyde (MDA) in brain homogenates showed its increase in the after brain stroke animals and decreased MDA level in the after brain stroke animals treated with carnosine. We concluded that carnosine compensates deficit in antioxidant defense system of brain damaged by ischemic injury. The data presented demonstrate that carnosine is effective in protecting the brain in the post-ischemic period.

Rheologic properties of blood cells and a state of oxidative-reductive processes and blood systems have been studied in 75 patients in acute period of ischemic stroke. The signs of oxidative stress development and simultaneous augmentation of blood cells aggregation were found. Shifts of redox-equilibrium in thiol-disulfide and ascorbate oxidative-reductive blood systems and cells aggregation dependence on their state were detected. An interrelation of oxidative processes and blood cells aggregation with clinical course severity and outcome was revealed. The authors discuss possible mechanisms for blood cells aggregation in oxidative stress. Including of antioxidants in the pathogenetic therapy and their earlier usage reduce essentially the intensity of oxidative stress and blood cells aggregation and promote neurological symptoms regress. The results obtained allow considering antioxidant treatment as a pathogenic modality for prevention and treatment of ischemic stroke. Clinico-laboratory correlations suggest a pathogenic role of oxidative stress in ischemic stroke as a factor augmenting aggregation processes and promoting intravascular thrombogenesis.

Lipid peroxidation (LP) was analysed in the blood and atherogenic lipoproteins of 36 patients with ischemic stroke in the internal carotid arteries at the acute stage (1, 7 and 21 days). During 1-7 days 22 patients (group 1) were treated with haemocorrecting drugs (rheopolyglucin, euphyllin, aspirin, curantyl, trental) and 14 patients (group 2) were treated with vasoactive and metabolic drugs (cavinton, complamin, actovegin). On days 8-21 all the patients received the same treatment: pyracetam and essential. Before the treatment both activation of LP and exhaustion of endogenic antioxidant background were observed in blood samples of all the patients. Significant changes of LP parameters were observed in group 1 up to day 7, but they reached the basic level on the 21 day. No significant changes were observed in group 2. Thus, haemocorrecting drugs had some antioxidant effects, but to provide a steady antioxidant effect it is necessary to use special antioxidants.

Lipid peroxidation was studied in the brain of Mongolian gerbils under conditions of complete ischemia followed by recirculation in the left hemisphere without recirculation in the right hemisphere. Thiobarbituric acid reactive products and the intensity of Fe2+-induced chemiluminescence were determined. The content of lipid peroxidation products in the brain tissue was increased not only under conditions of recirculation, but also at the ischemia stage during the limited access of oxygen. Thus, the destructive effect of free radicals may occur even during the early stage of ischemic injury of the brain.

The results of experiments performed in Wistar rats are indicative of the catecholamine release during the first hours of developing cerebral ischemia, and their role in activation of lipid peroxidation (LP). These events were characteristically enhanced in the ischemic hemisphere where EEG changes were most pronounced. Maximal changes in slow parieto-occipital EEG waves amplitude and malonic dialdehyde levels in the brain tissue were also correlated. This metabolic-electrophysiological link than could be of major importance for EEG monitoring of brain pathochemistry and pathology needs, however, further investigation. Among pathological findings, the relationship between the degree of ischemic neuronal changes on one hand, and brain swelling and hyperemia on the another, was worth attention. The lack in distinct correlations between metabolic, electrophysiological and structural changes in the ischemic brain can be accounted for by a substantial spread of ischemic damage over the brain.