[The effect of semax and its C-end peptide PGP on Vegfa gene expression in the rat brain during incomplete global ischemia].

Vascular endothelial growth factor (VEGFA) is a hypoxia-inducible signal glycoprotein. VEGFA causes vascular endothelial cell growth and proliferation, that leads to the regeneration of vascular network in brain regions damaged by ischemia. However, this protein is involved in processes of inflammation and edema in early stages of ischemia. Synthetic peptide semax shows neuroprotective and anti-inflammatory properties and is actively used in the treatment of ischemia.We have previously shown that semax reduces vascular injury and activates the mRNA synthesis of neurotrophins and their receptors under global cerebral ischemia in rats. Here we have analyzed the effects of semax and its C-terminal Pro-Gly-Pro tripeptide upon Vegfa mRNA expression in different rat brain regions after common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. It was shown that ischemia increases levels of Vegfa mRNA in the rat brain of animals (4 h after the occlusion--in the cerebellum, cerebral cortex and hippocampus, 8 h--in the cortex and hippocampus, and 24 h in the cortex). Semax treatment reduces Vegfa mRNA levels in the frontal cortex (4, 8 and 12 h after the occlusion) and hippocampus of ischemic rats (2 and 4 h). Effect of PGP on the Vegfa gene expression was almost negligible. Our results showed that semax prevents activating effect ofhypoxia on the Vegfa gene expression in early stages of global ischemia. Furthermore, increase in the level of mRNA Vegfa in the hippocampus (24 h after occlusion) perhaps reflects neuroprotective properties of this drug.

[Analysis of the polymorphic variants of the PDE4D gene in patients with acute stroke in the Moldavian population].

The risk of the ischemic stroke is mediated by both environmental and genetic factors. Recent studies of DeCode group identified the risk of polymorphisms for ischemic stroke in the phosphodiesterase 4D gene (PDE4D). The goal of this study was to explore the role of two variants of the gene encoding PDE4D [SNP41 (rs152312) and SNP87 (rs2910829)] in the Moldavian patients with ischemic stroke and in control. No significant association with ischemic stroke was observed with SNP41 and 87.

[Association of factors of vascular tone regulation with the development of hemorrhagic transformation in patients with ischemic stroke].

Concentrations of plasma vascular tone regulation markers that are indicators of endothelium dysfunction in the acute phase of ischemic stroke and their effect on the development of hemorrhagic transformation (HT) of the lesion focus have been studied. Concentrations of renin, endothelin 1-21, neuron-specific enolase, NT-proCNP, soluble adhesion molecules (sICAM) were measured in 67 patients on days 1, 3-4. Significantly higher concentrations of renin, endothelin 1-21, neuron-specific enolase were found in patients with HT in the first day compared to patients without HT. The level of NT-proCNP was lower in patients with HT; the increase in the severity of hemorrhagic component led to the elevation of neuron-specific enolase and sICAM concentrations. In conclusion, both markers of blood-brain barrier damage and regulating factors of vascular tone may play a predictive role in the development of HT in ischemic stroke.

[The effect of semax and its C-end peptide PGP on expression of the neurotrophins and their receptors in the rat brain during incomplete global ischemia].

Neurotrophins regulate key function of nervous tissue cells. Analysis of neurotrophins mRNA expression is an appropriate tool to assess therapeutic efficiency of the anti-stroke drugs. We have analyzed the effect of synthetic peptide semax and its C-terminal Pro-Gly-Pro tripeptide upon mRNAs expression of neurotrophins Ngf, Bdrf, Nt-3 and their receptors TrkA, TrkB, TrkC, p75 in rat frontal lobes, hippocampus and cerebellum after bilateral common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. The mRNA expression of neurotrophins and their receptors was assessed by relative quantification using real-time RT-PCR. Our showed that ischemia causes a significant decrease in gene expression in the hippocampus. Semax and PGP affected the expression of neurotrophins and their receptors predominantly in the frontal cortex and hippocampus of the ischemized animals. In the frontal cortex, Semax treatment resulted in a decrease of mRNA level of receptors, while PGP treatment increased the level of these mRNA. Maximal neuroprotective effect of both peptides has been observed in the hippocampus 12 h after occlusion. A decrease of gene expression of neurotrophins and their receptors caused by the occlusion was overcome by Semax and PGP. These results clarify the semax mechanism of and present certain features of mRNA's expression of neurotrophins and their receptors in experimental conditions.

[The role of polymorphic variants of gene of inducible NO-synthase NOS2 in brain infarction in patients with acute ischemic stroke].

Cerebrovascular diseases including stroke are an important problem of public health. Stroke development depends on external factors and individual genetic specificity of patient. Excessive NO production by inducible NO-synthase (iNOS) damages brain tissue at various stages of the disease. The goal of this work was to study the role of 4 polymorphic variants of gene of inducible NO-synthase iNOS (-2447C/G, -1659C/T, -0,7(OTTA)n I/D, S608L (150C/T)) in brain infarction in patients with acute ischemic stroke. A statistically significant correlation between S608L (150C/T) polymorphism and infarction dynamics was observed during days 1-3 and 7-21 after infarction. These parameters correlated with neurological status estimated using the Orgogozo scale during days 1-7 of the disease development. It was demonstrated that genotype N150N was associated with ischemic focus propagation regardless of its volume and neurological status by Orgogozo scale in patients with acute stroke. It was also observed that genotype N150N had effect on ischemic damage during days 1-3 in case of low initial volume.

[Phosphodiesterase 4D (PDE4D) gene polymorphism in patients with acute stroke from Moscow].

Two PDE4D gene polymorphisms [SNP41 (rs152312 and SNP87 (rs 2910829)] were studied in patients with acute stroke (n = 577) and in control sample (n = 270). Significant differences in the genotype and allele frequency distribution were found between these samples for polymorphism SNP41. We showed that the AA and AG genotypes of SNP41 polymorphism were associated with higher risk of acute stroke development in the Moscow population (OR = 1.6). No association of SNP87 polymorphism with the disease was observed.

[The effect of cerebrolysin in dosage 50 ml on the volume of lesion in ischemic stroke].

The purpose of this randomized, double-blind, placebo-controlled study was to assess safety and efficacy of cerebrolysin used in dosage 50 ml in acute ischemic stroke. Forty-seven patients with ischemic stroke, aged 45-85 years, who were admitted to a clinical unit within the first 12 h after stroke onset were included in the study. A quantitative time-related MRI analysis of the dynamics of neurological deficit revealed the more rapid decrease of stroke volume to the 28th day in the group treated with cerebrolysin (45.4% versus 43.6% in the placebo-group (p < 0.05)). No side-effects of treatment with cerebrolysin was found. The results of this prospective, randomized, placebo-controlled study suggest the positive effect of cerebrolysin on the dynamics of volume lesion in patients with ischemic stroke.

[The use of citicoline in the acute cerebral stroke].

Data on the mechanism of action of the neuroprotector citicoline, its effectiveness in the experimental models of cerebral ischemia and in patients with ischemic and hemorrhagic stroke are reviewed. Citicoline is a unique drug with neuroprotective properties that demonstrated the positive results in patients with stroke. The effectiveness of the combined thrombolytic and citicoline therapy was demonstrated in the experimental model of ischemic stroke.

[Genome-wide scanning in the study of risk for cerebral stroke].

The role of genetic predisposition to the formation of most multifactorial diseases, including stroke, was demonstrated in a number of investigations. To determine the individual genetic risk of a polygenic disease, the candidate gene approach is used most often. It is based on the analysis of polymorphic variants of certain genes taking into consideration the function of their protein product. But this approach is limited by the analysis of defined genes and does not detect new groups of genes, which involved in the pathogenesis of cerebral stroke. Genome-wide association study is a wide-range analysis of whole-genome polymorphisms, which allows to compare the distribution of allele frequencies in stroke patients and healthy individuals. The use of this method for the determination of individual genetic risk of acute stroke allows to perform molecular-genetic screening of most significant markers of stroke predisposition; to determine patients with the highest risk of stroke and to perform the mass health examination with preventive therapy prescription. The genome-wide association study to determine the individual genetic risk of stroke, taking into account ethnic origin, is performed in the Russian Federation since 2008 on the basis of the Neurological clinic of the Russian State Medical University in collaboration with the Institute of Molecular Genetics, Russian Academy of Sciences.

[The role of polymorphic variants of renin-angiotensin system genes in the development of ischemic stroke in Moscow population]. / Rol' polimorfnykh variantov genov renin-angiotenzinovoi sistemy v razvitii ishemicheskogo insul'ta v moskovskoi populiatsii.

Polymorphic variants of genes for angiotensin-converting enzyme (ACE) and angiotensinogen (ATG) were studied in 110 patients with different types of brain ischemic disease--carotid atherothrombotic ischemic stroke (one of the pathogenic brain infarction variants) as well as in 119 their siblings with the main risk factors of cerebrovascular pathology development being taken into account. No association has been found between ACE and ATG genes polymorphisms and carotid atherothrombotic ischemic stroke. However, the presence of a homozigous DD ACE genotype was shown to be an independent risk factor for development of hemodynamically relevant stenosis of the major brain arteries. The absence of differences in genetic variants distribution in patients with acute ischemic stroke, comparing to those with prolonged chronic brain ischemic disease (without infarction formation) and the highest frequency of this polymorphism in "longevity" group (without lifetime stroke) imply a relatively independent character of the atherothrombogenic process, which may probably underlie a further development of pathological process.

[Role of missense mutation (M235T) in the angiotensinogen gene in development of cerebral ischemia]. / Izuchenie roli missens-mutatsii (M235T) gena angiotenzinogena v razvitii ishemicheskoi bolezni mozga.

Possible correlation of M/T polymorphism of angiotensinogen gene with risk of ischemic stroke and basic risk factors of cerebral pathology (levels of arterial pressure and blood cholesterol; presence of diabetes mellitus, coronary heart disease, or myocardial infarction in anamnesis; and stenosis of major cerebral arteries) was studied. It was shown that M/T polymorphic variants of angiotensinogen gene were factors determining neither clinical variant of cerebral ischemia development (acute ischemic stroke or chronic brain ischemia) nor formation of main risk factors of stroke.