Mechanisms of Neuroprotective Action of Hesperetin and Carnosine in Focal Ischemia of the Brain in Rats.

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.

[Neuroprotective mechanisms of the ubiquinol action in experimental focal ischemia]. / Issledovanie neiroprotektornykh mekhanizmov deistviia ubikhinola pri éksperimental'noi fokal'noi ishemii.

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 as an effective neuroprotector in brain pathology and potential neuromodulator in normal conditions.

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 in Different Areas of the Cerebral Cortex of Wistar Rats during Focal Ischemia and Its Modulation with Carnosine.

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.

[Study of the neuroprotective effects of carnosine in an experimental model of focal cerebral ischemia/reperfusion]. / Issledovanie neiroprotektornykh mekhanizmov deistviia karnozina pri éksperimental'noi fokal'noi ishemii/reperfuzii.

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.

Assessment of Oxidative Status of the Brain and Blood Plasma in Rats with Modeled Focal Cerebral Ischemia/Reperfusion Injury.

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.

[A neuroprotective action of carnosine in conditions of experimental focal cerebral ischemia-reperfusion]. / Neiroprotektivnoe deistvie karnozina v usloviiakh éksperimental'noi fokal'noi ishemii-reperfuzii golovnogo mozga.

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.

Antioxidant Defense System after Single and Chronic Administration of Obestatin and Its Fragment (1-4) to Normal and Overweight Male Rats.

We studied the effects of anorectic peptide obestatin and its fragment (1-4) on the antioxidant defense system in animals with normal and experimentally induced increased body weight. In rats with normal body weight, no changes in activity of the antioxidant defense system 1 week after single administration of the substances. After chronic administration of obestatin and fragment (1-4) for 1 week, total antioxidant capacity of the plasma decreased; obestatin also lowered the content of TBA-reactive products. In the overweight rats, SOD-like activity in the plasma increased 1 week after chronic administration of obestatin. Hence, obestatin and its fragment (1-4) induced changes in the antioxidant defense system only after chronic administration.