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.

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.

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.

[Experimental study of the basic pharmacokinetic characteristics of dipeptide carnosine and its efficiency of penetration into brain tissues].

We have used an original chromatography/mass spectrometry technique to study the pharmacokinetics of dipeptide carnosine in C57 Black/6 mice after intra-peritoneal administration of the drug at a dose of 1 g/kg. The basic pharmacokinetic characteristics of carnosine were measured the in the blood and brain. The obtained concentration-time curve has a biexponential character. It is shown that the maximum concentration of carnosine in the blood plasma is Cmax = 1081.75 ± 124.24 µg/mL and it is achieved in a time interval of Tmax = 0.25 h. We showed that i.p. administration of exogenous carnosine could significantly increase the concentration of that substance in the brain. Tissue availability of dipeptide carnosine for brain tissue is relatively good and constitutes 59% from the total amount of blood carnosine. It was found that the maximum concentration of carnosine in the brain occurs at the sixth hour after i.p. administration when the concentration of drug in the blood is minimal.

[Biological activity of regulatory peptides in model experiments in vitro].

Biological effects of short regulatory peptides, pinealon, vesugen, vilon and epitalon were studied in model experiments in vitro. These peptides were found not to demonstrate direct antioxidant activity but be able to restrict lipid peroxidation of human lipoproteins by modification of their structure. The short peptides increase stability of red blood cell membranes toward osmotic hemolysis. They also elevate the stationary level of intracellular reactive oxygen species and at the same time decrease (all excepting epitalon) percent of dead cells in neuronal population. The suggestion was made that under in vivo conditions, short peptides may participate in apoptosis/necrosis regulation.

[Carnosine: endogenous physiological corrector of antioxidative system activity].

The results of research of camosine as an antioxidative system corrector in conditions of oxidative stress caused by the action of damaging factors (y-rays, overcooling, hypobaric hypoxia, brain ischemia, neurotoxin impact) are summarized in the present review. The effects of carnosine are characterized not only at the level of the whole organism but also in "in vitro" models with use of a whole series of enzymatic systems. The results of the experiments conducted displayed the ability of carnosine to protect animals from oxidative stress based on the combination of direct antioxidative effects and a modulation of enzymes' activities which participate in controlling of reactive oxygen species level in tissues.

[Neurodegenerative alterations induced by MPTP neurotoxin in senescence accelerated mice essay].

Behavioral modifications and alterations in biochemical pathways induced by neurotoxin MPTP in Senescence Accelerated Mice (SAM) brains are discussed. MPTP injections lead to specific injuries of dophaminergic neurons and to reinforcement of oxidative stress conditions. The ability of neuropeptide carnosine to protect animals from oxidative injuries induced by MPTP injections is also described.

[Biochemical and immunological induces of the blood in Parkinson's disease and their correction with the help of laser therapy]. / Biokhimicheskie i immunologicheskie pokazateli krovi pri bolezni Parkinsona i vozmozhnosti ikh korrektsii s pomoshch''iu lazernoi terapii.

The influence of laser therapy on the course of Parkinson's disease (PD) was studied in 70 patients. This influence appeared adaptogenic both in the group with elevated and low MAO B and Cu/Zn SOD activity. Laser therapy resulted in reduction of neurological deficit, normalization of the activity of MAO B, Cu/Zn-SOD and immune indices. There was a correlation between humoral immunity and activity of the antioxidant enzymes (SOD, catalase). This justifies pathogenetically the use of laser therapy in PD.

Laser modification of the blood in vitro and in vivo in patients with Parkinson's disease.

The effect of He-Ne laser radiation on activity of MAO B, Cu/Zn-SOD, Mn-SOD, and catalase in blood cells from patients with Parkinson's disease was studied in vivo and in vitro. The effects of intravenous in vivo irradiation (intravenous laser therapy) were more pronounced than those observed in similar in vitro experiments. It is concluded that generalized effect of laser therapy involves interaction between blood cells.

Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivo.

Natural hydrophilic antioxidant carnosine protects cerebral cytosolic Cu,Zn-superoxide dismutase (SOD) under conditions of oxidative stress in various in vivo models: short-term hypobaric hypoxia in rats and accumulation of age-related changes in senescence-accelerated mice (SAMP). Administration of carnosine preventing Cu,Zn-SOD inactivation reduced mortality in rats and prolonged average life span in SAMP-mice.

[Antioxidant therapy in ischemic stroke]. / Antioksidantnaia terapiia pri ishemicheskom insul'te.

The paper presents the results of investigation of emoxipin, an antioxidant synthetic drug, for treatment of patients with ischemic disorders of cerebral circulation. The drug produced a beneficial clinical effect in patients with lacunar and cardioembolic strokes of moderate severity. Therapy with emoxipin increased endogenic antioxidant activity and improved a clinical status of the patients. The protective effect of carnosine was demonstrated in experimental acute hypobaric hypoxia and cerebral ischemia in rats. The results obtained permit to recommend an inclusion of both emoxipin and carnosine in a combined treatment of ischemic disorders of cerebral circulation.

[Carnosine stabilization of the normal erythrocyte membranes and in experimental diabetes]. / Stabilizatsiia karnozinom membran éritrotsitov v norme i pri éksperimental'nom diabete.

The effect of carnosine on red blood cell membranes was studied in the in vitro and in vivo experiments. Carnosine (70-720 microM) is shown to protect healthy donors' red blood cells from acidic hemolysis increasing population of stable red blood cells and postponing time to maximal rate of hemolysis. It was demonstrated on the model of streptozotocin-induced diabetes in rats that carnosine treatment (50 mg/kg/day during 7 days, per os) prevents a decrease in the hemolytic stability of red blood cells in diabetic animals. The findings suggest usefulness of carnosine as a possible treatment of diabetes patients.

[Characterization of the anti-ulcer effectiveness of carnosine]. / Kharakteristika protivoiazvennoi éffektivnosti karnozina.

The protective effect of natural dipeptide carnosine on gastric and duodenal mucosal lesions induced by acetic acid application was studied on rats. An increase in total area of the erosions on the stomach and duodenum was significantly inhibited by oral and intraperitoneal administration of carnosine. In addition, carnosine normalized the level of amino acids undergoing change during gastric mucosal injury. Histological evidence showed effective healing of the mucosal defects as a result of carnosine administration.

[The pharmacological activity of carnosine]. / Farmakologicheskaia aktivnost' karnozina.

The properties of the histidine-containing dipeptide carnosine (beta-alanyl-L-histidine) and its possible biological role are considered. The agent is discussed in terms of its antioxidative and immunomodulating effects on the body. A history of its discovery and investigations of the therapeutical benefits are outlined. The data given indicate that there are great perspectives in expensively using carnosine as a drug.