Due to its nootropic, neuroprotective, and immunomodulatory effects, the peptide Semax is utilized in the treatment of ischemic stroke. Our earlier RNA-Seq analysis of the transcriptome in an ischemic model of transient occlusion of the middle cerebral artery showed an increase in the mRNA levels of many proinflammatory genes, and the suppression of their induction by Semax. However, for many relevant genes, including Il1a, Il1b, Il6 and Tnfa, the levels of their expression were too low for detailed quantitative evaluation. Here we utilize qRT-PCR to analyze the effects of the Semax peptide on the expression of weakly expressed mRNAs encoding several proinflammatory mediators, and show that exposure to Semax leads to a statistically significant decrease in the Il1a, Il1b, Il6, Ccl3, and Cxcl2 mRNAs, which compensates for the increase in the transcription of these genes induced by ischemia-reperfusion. We conclude that the observed protective effect of Semax in the model of stroke may be due to its anti-inflammatory effects. We also discuss the limitations of the RNA-Seq when applied to quantifying less abundant transcripts as compared to the real-time RT-PCR method.

Human placenta mesenchymal stromal cells were injected to healthy rats either stereotaxically into the striatum or intra-arterially through the internal carotid artery. Some cells injected into the brain migrated along the corpus callosum both medially and laterally or concentrated around small blood vessels. A small fraction of MSC injected intra-arterially adhered to the endothelium and stayed inside blood vessels for up to 48 hours mostly in the basin of the middle cerebral artery. Neither stereotaxic, nor intra-arterial transplantation of mesenchymal stromal cells modulated the proliferation of neural stem cells in the subventricular zone of the brain, but stereotaxic transplantation suppressed activation of their proliferation in response to traumatization with the needle.

Синтетический пептид АКТГ(4-7)PGP ускоряет регресс неврологических нарушений при ишемическом инсульте, однако молекулярные механизмы его действия полностью не известны. На модели полуторачасовой окклюзии средней мозговой артерии крыс был проведен анализ влияния пептида на экспрессию ряда генов и белков, вовлеченных в сигнальные пути, приводящие к воспалению и гибели клеток в условиях ишемии-реперфузии. Показано, что пептид через 24 ч от начала окклюзии снижает повышенный при ишемии уровень экспрессии в ишемизированной ткани мозга крыс мРНК провоспалительных цитокинов и хемокинов IL-1α, IL-1β, IL-6, TNF-α, Cxcl2 и Ccl3. Пептид снижал повышенные при ишемии уровни экспрессии белков металлопротеиназы ММР-9, транскрипционного фактора c-Fos, активных JNK киназ и предотвращал ишемическое снижение уровня активного транскрипционного фактора CREB. The synthetic peptide ACTH (4-7) PGP accelerates the regression of neurological disorders in ischemic stroke, but the molecular mechanisms of its action are not completely known. On the model of an hour and a half occlusion of the rat middle cerebral artery, an analysis was made of the effect of the peptide on the expression of a number of genes and proteins involved in signaling pathways leading to inflammation and cell death under conditions of ischemia-reperfusion. It was shown that the peptide 24 hours after the onset of occlusion reduces the level of expression of mRNA of pro-inflammatory cytokines and chemokines IL-1α, IL-1β, IL-6, TNF-α, Cxcl2 and Ccl3 in ischemic brain tissue. The peptide decreased the levels of expression of proteins metalloproteinase MMP-9, transcription factor c-Fos, active JNK kinases wich were increased under ischemia, and prevented ischemic decrease in the level of active transcription factor CREB.

Методом ПЦР в реальном времени в подкорковых структурах мозга крыс, содержащих очаг ишемического повреждения, показано активирующее влияние ишемии на экспрессию циклических РНК (циклоРНК) генов Ece1, Mvp, Egfem1 и Cdyl, а также репрессирующее влияние на экспрессию циклоРНК гена Rgs9. Биоинформатический анализ выявил возможные цис-регуляторные взаимодействия между микроРНК, а также циклоРНК и мРНК исследуемых генов, что указывает на функциональную роль данных циклоРНК в ответе клеток мозга на ишемию. Using real-time PCR, the activating effect of ischemia on the expression of circular RNAs (circRNAs) of Ece1, Mvp, Egfem1 and Cdyl genes, as well as the repressing effect on the expression of circRNA of the Rgs9 gene, is shown in the subcortical structures of the rat brain containing the focus of ischemic damage. Bioinformatics analysis revealed possible cis-regulatory interactions between miRNAs, as well as circRNAs and mRNAs of the studied genes. The result indicates the functional role of these circRNAs in the response of brain cells to ischemia.

The use of induced pluripotent stem cells (IPSC) is a promising approach to the therapy of CNS diseases. The undeniable advantage of IPSC technology is the possibility of obtaining practically all types of somatic cells for autologous transplantation bypassing bioethical problems. The review presents integrative and non-integrative methods for obtaining IPSC and the ways of their in vitro and in vivo application for the study and treatment of neurological diseases.

We compared the effects of placental mesenchymal stromal cells and neural progenitor cells derived from induced human pluripotent cells after their intravenous administration to rats in 24 h after transitory occlusion of the middle cerebral artery. The therapeutic effects were evaluated by the dynamics of animal survival, body weight, neurological deficit, and the volume of infarction focus in 7, 14, 30, and 60 days after surgery. Intravenous injection of neural progenitor cells produced a therapeutic effect on the course of experimental ischemic stroke by increasing animal survival in the most acute period and accelerating compensation of neurological deficit and body weight recovery. Neural progenitor cells were more effective than mesenchymal stromal cells from human placenta. The effectiveness of intravenous transplantation of neural progenitor cells in the model of occlusion of the middle cerebral artery is shown by us for the first time, although the therapeutic effect of their direct transplantation into the brain has already been described.

The mathematical model of group of neurons and astrocytes in the ischemic stroke is discussed. The model includes the description of synaptic signal transmission between the neurons, calcium signaling in astrocytes, ionic currents between the cells and extracellular space and the diffusion through extracellular space. The new modeling approach, based on the creation of appropriate graph, is developed to describe the structure of the system. Using the model, we have analyze the influence of inhibitory synapses on system functioning. We also have shown how the use of medications supporting the activity of inhibitory synapses affects the system behavior in ischemic stroke.

Today the systemic thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) is the most effective treatment of ischemic stroke. We included 116 patients with stroke, 82 received rt-PA, 34 were enrolled to the control group. Median NIHSS score was 16,2 +/- 5,4 in the main group and 16,2 +/- 5,4 in the control group. The trial revealed the prognostic significance of some early CT sings of ischemic brain damage for the hemorrhagic transformation and functional outcomes to the 90th day. It was shown that hyperfibrinogenemia (over 450 mg/dl) might be a risk factor of the hemorrhagic transformation. The excess of segmental leukocytes over 78% might be a predictor of the lethal outcome. The initial activity of tissue plasminogen inhibitor (first type) over 11,65 IU/L might be a risk factor of the vascular reocclusion after successful thrombolysis. The analysis of characteristic curves of leukocyte elastase revealed the informativeness of its initial values in the prognosis of reocclusion and hemorrhagic transformation.

Modern data on molecular mechanisms underlying intracerebral pleutropic action ofgestagens (progesterone, its metabolites, and synthetic gestagens) are reviewed. Properties of classical and membrane-bound progesterone receptors involved in regulation of gene expression, modulation of neurotransmitter systems, and activation of signal cascades in neurons are described along with data of regional distribution of progesterone receptor subtypes in brain, metabolism, functional activity, and mechanisms of action of progesterone metabolites. Special attention is given to analysis of progesterone and metabolite neuroprotective activity in CNS, such as anti-inflammatory and antiapoptotic effects, and participation in neurogenesis regulation. Clinical application of progesterone-based drugs is discussed with reference to the treatment of brain injuries and prospects for extension of indications for their use in neurologic practice.

The aim of this study was to examine Taftsin derivates--macrophage inhibitory factor (MIF, Thr-Lys-Pro) and heptapeptide selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) in the model of experimental intracerebral hemorrhage in rats. The double autologous blood injection in the basal nucleus was used as a model of intracerebral hemorrhage. Animals ware randomly divided into three groups--the control group (n = 5) was treated with saline, the second group (n = 5) was injected with MIF in dose 150 mkg/ kg/day, the third group (n = 5) received Selank in dose 300 mkg/kg/day. Intraperitoneal injection of peptides was used. Body weight assessment, neurological examination and brain MRI were performed in 24, 72 hours and 10 days after the hematoma formation. The effect of neuropeptides on the functional restoration in animals, in the absence of the effect on hematoma volume and perifocal edema, was found. The significant reduction of perifocal edema and hematoma volume was observed in the 10th day after the hematoma formation in all experimental groups (p < 0.05). Only the control group of animals showed the significant (p < 0.05) weight loss in the 3rd day after the operation. The rate of neurological deficit was different: the significant improvement assessed with Menzes and limb placing test scales was seen only in the groups treated with neuropeptides in the 10th day.