Development Of Cerebral Ischemia Research Articles

Analysis of differentially expressed genes related to cerebral ischaemia in young rats based on the Gene Expression Omnibus database.

The incidence rate of cerebral infarction in young people is increasing day by day, the age of onset tends to be younger, and its internal pathogenesis and mechanism are very complicated, which leads to greater difficulties in treatment. Therefore, it is essential to analyze the key pathway that affects the onset of cerebral infarction in young people from the perspective of genetics. To compare the differentially expressed genes in the brain tissue of young and aged rats with middle cerebral artery occlusion and to analyse their effect on the key signalling pathway involved in the development of cerebral ischaemia in young rats. The Gene Expression Omnibus 2R online analysis tool was used to analyse the differentially expressed genes in the GSE166162 dataset regarding the development of cerebral ischaemia in young and aged groups of rats. DAVID 6.8 software was further used to filter the differentially expressed genes. These genes were subjected to Gene Ontology (GO) function analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the key gene pathway that affects the occurrence of cerebral ischaemia in young rats. Thirty-five differentially expressed genes (such as Igf2, Col1a2, and Sfrp1) were obtained; 73 GO enrichment analysis pathways are mainly involved in biological processes such as drug response, amino acid stimulation response, blood vessel development, various signalling pathways, and enzyme regulation. They are involved in molecular functions such as drug binding, protein binding, dopamine binding, metal ion binding, and dopamine neurotransmitter receptor activity. KEGG pathway enrichment analysis showed a significantly enriched pathway: The cyclic adenosine monophosphate (c-AMP) signalling pathway. The c-AMP signalling pathway might be the key pathway in the intervention of cerebral infarction in young people.

ОЦЕНКА ЦЕРЕБРАЛЬНОЙ ОКСИГЕНАЦИИ ПРИ РАЗВИТИИ ТРАНЗИТОРНОГО ТАХИПНОЭ У НОВОРОЖДЕННЫХ

One of the most common respiratory diseases in term and late preterm infants is the Transient tachypnea of the newborn (TTN). The clinical picture of TTN is characterized by respiratory disorders with the development of hypoxemia, which is especially important for the functioning of the central nervous system and may cause its damage. One of the methods for functional assessment of the supply of oxygen to the brain is the determination of cerebral oxygenation (CO) using the Near-infrared spectroscopy (NIRS). The purpose of this research was to assess the CO in TTN using the NIRS technology. Materials and methods used: a single-center prospective cohort study was conducted from June 01 till Dec. 31, 2021. The study group consisted of 75 full-term newborns with the development of a clinical picture of TTN and a Downes score of ≥3 pts within 60 minutes after birth. Exclusion criteria: other causes of respiratory disorders. The control group consisted of 20 full-term healthy newborns after the C-section recruited by continuous sampling within 3 days from Dec. 21 to 23, 2021. The study of CO was performed only at the stage of the delivery room using the SenSmart™ Model X-100 device; the single-channel monitoring was performed with an SenSmart™ 8004CB-NA sensor (both - by Nonin Medical, Inc., USA). Results: based on the results of the analysis of the data obtained, an increase in the CO indicators in the study group was demonstrated from 72% at the 10th minute to 81% at the 60th minute of life with a further decrease to 80% to 79%. In contrast to healthy newborns, who’ve also showed an increase in CO from 75% at the 5th minute, and reaching a plateau level of 80% already at the 15th minute with a further decrease in indicators to 79% to 77%, a statistically significant difference between the groups was found at the 10th minute with a higher CO level in the group of healthy children (79 (78-82)% vs. 72 (70-73)%, p=0.007). Despite the fact that there was no statistically significant correlation between the severity of respiratory disorders, the development of cerebral ischemia and the CO indicators, there is a general trend towards a decrease and a slow increase in the CO level in full-term patients with TTN. Conclusion: the study showed that in the process of developing TTN, not only the respiratory function suffers, but also the processes of oxygenation of the brain. A prolonged period of low CO levels may have adverse outcomes for the CNS, the life and health of the child in general, this therefore requires further research.

Research progress on astrocyte autophagy in ischemic stroke

Ischemic stroke is a highly disabling and potentially fatal disease. After ischemic stroke, autophagy plays a key regulatory role as an intracellular catabolic pathway for misfolded proteins and damaged organelles. Mounting evidence indicates that astrocytes are strongly linked to the occurrence and development of cerebral ischemia. In recent years, great progress has been made in the investigation of astrocyte autophagy during ischemic stroke. This article summarizes the roles and potential mechanisms of astrocyte autophagy in ischemic stroke, briefly expounds on the crosstalk of astrocyte autophagy with pathological mechanisms and its potential protective effect on neurons, and reviews astrocytic autophagy-targeted therapeutic methods for cerebral ischemia. The broader aim of the report is to provide new perspectives and strategies for the treatment of cerebral ischemia and a reference for future research on cerebral ischemia.

Management of In-Stent Stenosis with Dual Antiplatelet Therapy Following Pipeline Embolization of Intracranial Aneurysms

Flow diversion of intracranial aneurysms with the pipeline embolization device (PED) may produce angiographically apparent stenosis within the PED, which can lead to secondary ischemic complications. In-stent stenosis can be treated medically with dual antiplatelet therapy (DAPT), but the safety and efficacy of this approach are unknown. In this work, we review the safety and efficacy of DAPT to prevent progression of in-stent stenosis or development of cerebral ischemia. Clinical and angiographic data from eligible patients were assessed from a prospectively maintained neurointerventional database. Details surrounding in-stent stenosis and DAPT were extracted. Patients were included in this study if in-stent stenosis was detected at any angiographic follow-up and managed with DAPT. The primary efficacy endpoint was lack of angiographic progression of in-stent stenosis or new ipsilateral infarct following initiation of medical therapy. In total, 23 PED constructs developed in-stent stenosis and were managed with DAPT. Follow-up angiography was available for 19 constructs. Eighty-nine percent (17/19) of PED constructs achieved the primary endpoint of lack of stenosis progression and lack of new ipsilateral ischemic events. Of the 2 PED constructs that failed to achieve the primary endpoint of this study, one demonstrated worsening of in-stent stenosis from 55% to 76% over 16months, while the other developed ipsilateral ischemic stroke 4months after detection of in-stent stenosis. In addition, one patient experienced intracranial hemorrhage 9months after the initiation of DAPT. Progression of in-stent stenosis and new ipsilateral ischemic events are limited in the presence of DAPT. However, hemorrhagic events related to DAPT may occasionally occur.

Фактори ризику лакунарних ішемічних мозкових інсультів

Гострий мозковий інсульт є однією з основних причин інвалідності та смертності у світі. Щорічно близько 16 млн людей уперше переносять мозковий інсульт, а близько 7 млн помирають унаслідок нього. В Україні 100–110 тисяч жителів щороку переносять мозковий інсульт, вмирає приблизно 40 тисяч жителів України. Стратегія профілактики інсульту базується на виявленні та корекції факторів ризику мозкового інсульту. Існує 5 підтипів ішемічного інсульту (атеротромботичний, кардіоемболічний, лакунарний, гемодинамічний, гемореологічний). На сьогодні ще не вирішено багато питань, пов’язаних з етіологією, патогенезом, особливостями клінічного перебігу лакунарного інсульту. Аналіз патогенезу лакунарного інсульту показав, що провідними внутрішніми факторами ризику є артеріальна гіпертензія, цукровий діабет, вік, гіперхолестеринемія та кардіальна патологія. Проте зовнішні (або соціальні) фактори ризику, що модифікуються, є недостатньо вивченими, хоча вони відіграють значну роль у формуванні авторегуляції мозкового кровообігу. Метою дослідження було вивчення спектра та оцінка впливів соціальних факторів ризику на частоту виникнення лакунарного мозкового ішемічного інсульту. Було обстежено 140 пацієнтів, які перенесли ішемічний інсульт, віком від 42 до 84 років (середній вік — 65,2 ± 8,7 року), використовувалися клініко-інструментальні методи, зокрема нейровізуалізація (комп’ютерна та магнітно-резонансна томографія), ультразвукова допплерографія магістральних артерій голови, електрокардіографія, лабораторне підтвердження цукрового діабету та детальне клініко-анамнестичне опитування. Оцінка зовнішніх факторів ризику здійснювалася за допомогою спеціалізованої шкали соціального ризику інсульту. Проведена статистична обробка матеріалу. У результаті дослідження встановлено, що найбільш значимими внутрішніми факторами з високим ступенем вірогідності виникнення лакунарного інсульту була артеріальна гіпертензія (100 %) та атеросклероз судин (96,1 %), хоча ступінь стенозу судин був гемодинамічно незначимим. Серед соціальних факторів ризику основними предикторами, що впливають на розвиток церебральної ішемії за механізмом лакунарного інсульту, були надмірна стресогенність оточення (100 %), надмірна нічна активність (73,1 %), тривала робота з моніторами (76,9 %) та нерегулярне харчування (65,3 %). Отримана комбінація зовнішніх та внутрішніх факторів ризику ішемії головного мозку дозволить клініцистам своєчасно виявити пацієнтів, які знаходяться в групі ризику щодо виникнення лакунарного інсульту, та розробити відповідну індивідуальну стратегію профілактики.

HIF‑1α in cerebral ischemia (Review).

Cerebral ischemic injury may lead to a series of serious brain diseases, death or different degrees of disability. Hypoxia-inducible factor-1α (HIF-1α) is an oxygen-sensitive transcription factor, which mediates the adaptive metabolic response to hypoxia and serves a key role in cerebral ischemia. HIF-1α is the main molecule that responds to hypoxia. HIF-1α serves an important role in the development of cerebral ischemia by participating in numerous processes, including metabolism, proliferation and angiogenesis. The present review focuses on the endogenous protective mechanism of cerebral ischemia and elaborates on the role of HIF-1α in cerebral ischemia. In addition, it focuses on cerebral ischemia interventions that act on the HIF-1α target, including biological factors, non-coding RNA, hypoxic-ischemic preconditioning and drugs, and expands upon the measures to strengthen the endogenous compensatory response to support HIF-1α as a therapeutic target, thus providing novel suggestions for the treatment of cerebral ischemia.

Features of monitoring the bispectral index in young children with hydrocephalus

Background. Millions of children with neurological diseases are subjected to general anesthesia every year. The conditions under which surgeries are done in these patients depend on a number of interrelated factors that arise in conditions of neurological deficiency and are often the cause of anesthetic complications. The possibility of using the monitoring of bispectral index in pediatric patients with neurological disorders is of particular interest, specifically in those with hydrocephalus against the background of ventriculomegaly. The purpose was to evaluate of the dynamics of bispectral index monitoring in young children with hydrocephalus during ventriculoperitoneal shunting. Materials and methods. The study included 109 children: 59 with acquired form of hydrocephalus who underwent ventriculoperitoneal shunting and 50 without neurological disorders who underwent reconstructive surgery. The study had 5 stages: initial, induction into anesthesia, tracheal intubation, traumatic stage of the operation, awakening. Results. Electroencephalographic analysis in children with hydrocephalus showed the homogeneity of the rearrangements of the bioelectric pattern, which reflected the wide and stable involvement in the pathological process of various cerebral systems with dysfunction of mesencephalic-diencephalic formations, including hypothalamic ones, in combination with impaired cortical-subcortical-brainstem interrelations. When analyzing the baseline bispectral index in patients with hydrocephalus, significantly lower values were found compared to neurologically healthy children (89.25 ± 2.52 and 94.80 ± 1.55, respectively). Analysis of changes in the intraoperative bispectral index showed that in the group with hydrocephalus using propofol, during induction upon reaching the first surgical stage of anesthesia according to clinical indications, the bispectral index significantly decreased to 36.00 ± 2.74, which is 30 % less than in children without neurological disorders and 29 % less when using sevoflurane. The groups where propofol was used showed a significant difference in bispectral index between patients with hydrocephalus and neurologically healthy children at all stages of the operation. This indicated that the intraoperative sleep pattern in individuals with hydrocephalus is at abnormal low levels. Conclusions. Hypoperfusion of the medulla, together with impaired cortical-subcortical relationships, affect the value of the bispectral index. The use of propofol in children with hydrocephalus can lead to the development of cerebral ischemia with a decrease in the electrical activity of the brain.

ОСОБЕННОСТИ ТЕЧЕНИЯ БЕРЕМЕННОСТИ, РОДОВ И ПЕРИНАТАЛЬНЫЕ ИСХОДЫ У ЖЕНЩИН С ВИРУСНЫМ ГЕПАТИТОМ С

This article presents data from a review of literature sources on the peculiarities of the course of pregnancy, childbirth and perinatal outcomes in women with viral hepatitis C. The current problem is due to the high prevalence of hepatitis C virus infection among the population, the possibility of a clinically asymptomatic course of the disease, the possibility of a transplacental route of transmission of the virus to the fetus. So, viral hepatitis C can be diagnosed during pregnancy as a result of the determination of immunoglobulins of classes M and G to the antigen of viral hepatitis C three times - in each trimester of pregnancy. Viral hepatitis C can have an adverse effect on the course of the gestational period, childbirth, and the neonatal period. Viral hepatitis C provokes the following complications: the threat of termination of pregnancy, preeclampsia of moderate severity and severe, fetoplacental insufficiency, which leads to chronic fetal hypoxia, intrauterine growth retardation of I and II degrees, and in the early neonatal period the development of cerebral ischemia of I and II degrees, moderate asphyxia or severe, impaired course of the adaptive reactions of the newborn, impaired neurological status of the newborn. This proves that the problem of the course of pregnancy against the background of viral hepatitis in a woman has not only important medical, but also social significance. The teratogenic effect of drugs used in the treatment of viral hepatitis C and the lack of drugs that are safe for use during pregnancy emphasize the integral role of pregravidar preparation to exclude or minimize the risk of complications during the gravidar period, childbirth, and unfavorable perinatal outcomes.

Prognostic value of CT perfusion and permeability imaging in traumatic brain injury.

Currently established prognostic models in traumatic brain injury (TBI) include noncontrast computed tomography (CT) which is insensitive to early perfusion alterations associated with secondary brain injury. Perfusion CT (PCT) on the other hand offers insight into early perfusion abnormalities. We hypothesized that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model. A prospective cohort study of consecutive 50 adult patients with head injury and Glasgow Coma Scale score of 12 or less was performed at a single Level 1 Trauma Centre. Perfusion CT was added to routine control CT 12 hours to 24 hours after admission. Region of interest analysis was performed in six major vascular territories on perfusion and permeability parametric maps. Glasgow Outcome Scale (GOS) was used 6 months later to categorize patients' functional outcomes to favorable (GOS score > 3) or unfavorable (GOS score ≤ 3). We defined core prognostic model, consisting of age, motor Glasgow Coma Scale score, pupillary reactivity, and CT Rotterdam Score. Next, we added perfusion and permeability data as predictors and compared updated models to the core model using cross-validated areas under the receiver operator curves (cv-AUC). Significant advantage over core model was shown by the model, containing both mean cerebral extravascular-extracellular volume per unit of tissue volume and cerebral blood volume of the least perfused arterial territory in addition to core predictors (cv-AUC, 0.75; 95% confidence interval, 0.51-0.84 vs. 0.6; 95% confidence interval, 0.37-0.74). The development of cerebral ischemia and traumatic cerebral edema constitutes the secondary brain injury and represents the target for therapeutic interventions. Our results suggest that adding CT perfusion and permeability data to the established outcome predictors improves the performance of the prognostic model in the setting of moderate and severe TBI. Prognostic study, level III.

Cerebral Hemodynamics Are Not Affected by the Size of the Patent Ductus Arteriosus

Introduction: Although patent ductus arteriosus (PDA) has been implicated to play a role in the development of cerebral ischemia and intraventricular hemorrhage (IVH) through a cerebral steal phenomenon, there is conflicting data on the impact of PDA size on cerebral blood flow (CBF). Cerebral autoregulation is the brain’s innate protective mechanism to maintain constant CBF despite changes in blood pressure, and it is unclear if it is influenced by PDA hemodynamics. Objective: To delineate the relationship between PDA size and CBF velocity (CBFv) in premature infants. Methods: 113 premature infants born at 23–29 weeks’ gestation had echocardiograms performed during the first week after birth to evaluate for PDA. The infants were divided into 3 groups according to PDA size: none-to-small, moderate, or large. All infants had continuous recordings of umbilical artery blood pressure (ABP) and CBFv during the first week after birth. Critical closing pressure (CrCP) was calculated from ABP and CBFv tracings. Diastolic closing margin (DCM), defined as diastolic blood pressure minus CrCP, was calculated as a marker for the risk of developing IVH. Results: Infants with a large PDA (n = 16) had the lowest ABP across all phases of the cardiac cycle (systole [p = 0.003], mean [p = 0.005], and diastole [p = 0.012]) compared to infants with a moderate (n = 19) or none-to-small PDA (n = 78). Despite blood pressure being different, systolic, mean, and diastolic CBFv were not different across groups. Cerebral autoregulation, as measured during systole, was intact regardless of the PDA size. CrCP and DCM were also not different across groups. Conclusions: In this cohort, CBFv and cerebral autoregulation during systole were not influenced by PDA size. Intact cerebral autoregulation may play a role in maintaining CBFv regardless of PDA size and differences in ABP.

MicroRNA-579-3p Exerts Neuroprotective Effects Against Ischemic Stroke via Anti-Inflammation and Anti-Apoptosis.

Background/AimsMultiple studies have found that microRNAs (miRNAs) are involved in the development of cerebral ischemia. MiR-579-3p can inhibit inflammatory responses and apoptosis, leading to ischemia/reperfusion (I/R) damage. However, the mechanism of how miR-579-3p actions in brain I/R injury remains unclear. This study aimed to investigate the mechanism of the role of miR-579-3p in brain I/R injury.MethodsA rat model of cerebral ischemia–reperfusion injury was established by suture method. The effects of miR-579-3p on cerebral infarction size, brain water content, and neurological symptoms were evaluated. Flow cytometry was used to detect apoptosis. ELISA was used to detect the level of inflammatory factors. Western blot was used to detect the expression of P65, NCOA1, Bcl-2 and Bax. The relationship between miR-579-3p and NCOA1 was analyzed by bioinformatics analysis and luciferase assay.ResultsOverexpression of miR-579-3p reduced infarct volume, brain water content and neurological deficits. Overexpression of miR-579-3p inhibited the expression level of the inflammatory cytokines, such as TNF-α, IL-6, COX-2 and iNOS, and increased the expression level of IL-10. MiR-579-3p overexpression inhibited NF-кB activity by reducing NRIP1. In addition, miR-579-3p could reduce the apoptotic rate of cortical neurons. Overexpression of miR-579-3p inhibited the activity of caspase-3, increased the expression level of anti-apoptotic gene Bcl-2 in neurons, and decreased the expression level of apoptotic gene Bax.ConclusionmiR-579-3p can be used to treat brain I/R injury, and its neuroprotective effect may be ascribed to the reduction of inflammation and apoptosis.

Involvement of d-amino acid oxidase in cerebral ischaemia induced by transient occlusion of the middle cerebral artery in mice.

d-Amino acid oxidase (DAAO) is a flavine adenine dinucleotide-containing flavoenzyme and specifically catalyses oxidative deamination of d-amino acids. This study aimed to explore the association between increased cerebral DAAO expression or enzymic activity and the development of cerebral ischaemia. A mouse model of transient (90 min) middle cerebral artery occlusion (MCAO) was established, and western blotting, enzymic activity assay, and fluorescent immunostaining techniques were used. The expression and enzymic activity of DAAO increased over time in the cortical peri-infarct area of the mice subjected to transient MCAO. The DAAO was specifically expressed in astrocytes, and its double immunostaining with the astrocytic intracellular marker, glial fibrillary acidic protein, in the cortical peri-infarct area was up-regulated following ischaemic insult, with peak increase on Day 5 after MCAO. Single intravenous injection of the specific and potent DAAO inhibitor Compound SUN reduced the cerebral DAAO enzymic activity and attenuated neuronal infarction and neurobehavioural deficits with optimal improvement apparent immediately after the MCAO procedure. The neuroprotective effect was dose dependent, with ED50 values of 3.9-4.5mg·kg-1 . Intracerebroventricular injection of the DAAO gene silencer siRNA/DAAO significantly reduced cerebral DAAO expression and attenuated MCAO-induced neuronal infarction and behavioural deficits. Our results, for the first time, demonstrated that increased cerebral astrocytic DAAO expression and enzymic activity were causally associated with the development of neuronal destruction following ischaemic insults, suggesting that targeting cerebral DAAO could be a potential approach for treatment of neurological conditions following cerebral ischaemia.

Telmisartan regulates the development of cerebral ischemia by alleviating endoplasmic reticulum stress.

Recent studies have shown that telmisartan (TMS) is effective for the protection against ischemia/brain damage in rat models. However, the specific underlying mechanism is poorly understood. In line with previous results, our data showed that TMS improves CBF and physiological variables, including pH, pCO2, pO2. Through CD31 immunofluorescence staining, reduction of blood vessel density was found in MCAO group, but TMS treatment could enhance the cerebral vascular density in the ischemic area. Meanwhile, TMS treatment could enhance the number of BrdU/lectin double-positive cells. Furthermore, the reduction of nestin-positive cells was identified in the brain of MCAO rats, while the number of nestin-positive cells was significantly increased after TMS administration. Furthermore, the expression of ERS-related proteins, including GRP78, CHOP/GADD153, Caspase12 was increased after MCAO, but was decreased after administration of TMS, thereby enhancing angiogenesis and neuron regeneration.

Surgical treatment and perioperative management of intracranial aneurysms in Chinese patients with ischemic cerebrovascular diseases: a case series

BackgroundPatients with ischemic cerebrovascular diseases are more likely to suffer from intracranial aneurysms, and their surgical treatment has a growing controversy in this condition. The current case series was aimed at exploring surgical treatment and perioperative management of intracranial aneurysms in Chinese patients with ischemic cerebrovascular diseases.MethodsMinimally invasive surgical approach through small pterion or inferolateral forehead was applied in 31 patients. Anti-platelet drugs were withdrawn 1 week before surgical operation. Systolic blood pressure was controlled to be more than 110 mmHg and increased by 20% after the clipping of intracranial aneurysms. Branches of external carotid artery were spared to ensure collateral circulation. Temporary blocking was minimized and ischemic time was shortened during surgical operation.ResultsPatients had an average age of 66 (46–78) years, and proportion of males was 39% (12 males). There were 35 unruptured intracranial aneurysms with a diameter more than 5 mm. There were 20 posterior communicating and anterior choroidal aneurysms (57%), seveb middle cerebral aneurysms (20%), and eight anterior communicating aneurysms (23%), with 21 lobular aneurysms (60%). Twenty-nine patients had normal neurological function (Glasgow Outcome Scale [GOS] 5), one patient with mild neurological defect (GOS 4), and one patient with severe neurological defect (GOS 3) at discharge. Meanwhile, there were 26 patients with modified Rankin Scale (MRS) 0–1, 4 patient with MRS 2, and one patient with MRS 3 at discharge. There were four patients lost during the follow-up. During the follow-up, 26 patients had normal neurological function (GOS 5), and one patient with severe neurological defect (GOS 3). Meanwhile, there were 25 patients with MRS 0–1, one patient with MRS 2, and one patient with MRS 3. All patients had no recurrence of intracranial aneurysms after operation.ConclusionsThe current case series found that minimally invasive surgical approach and intraoperative monitoring, supplemented by effective management of cerebrovascular perfusion, circulation and coagulation, can promote the treatment of intracranial aneurysms and prevent the development of cerebral ischemia and aneurysm rupture in Chinese patients with ischemic cerebrovascular diseases. Future studies with large sample size will be needed to confirm the results from the current case series.

Risk factors of cerebral ischemia in infants born to mothers with gestational diabetes

Objectives: Gestational diabetes mellitus (GDM) is carbohydrate intolerance that occurs during pregnancy. The present study was arranged to determine the risk of cerebral ischemia (CI) in infants born to mothers with gestational diabetes mellitus and MTHFR gene polymorphism.Material and methods: The study includes 70 pregnant women with GDM, divided into two groups depending on existence of cerebral ischemia (CI) in newborn infants. All patients were tested for coagulation cascade components, polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene and assessed by thromboelastography (TEG).Results: We observed that there was an increased frequency (74.2%) of 1298С MTHFR genotype carriers among women with CI newborns. The state of hypercoagulation according to both coagulation cascade tests and TEG data was diagnosed in women of this group.Conclusions: The results of this study suggest that hyperglycemia may program the development of cerebral ischemia in infants born to women with 1298С MTHFR gene polymorphism.

Characteristic of the cerebral cortex microcirculation after ischemia

Introduction. The outcome of ischemia is depending on a condition of microcirculatory bed. The important factor in development of cerebral ischemia is regulation of microvascular function, influencing both perfusion and oxygenation of cerebral tissue. The aim of the current study was to examine the time course of micirculatory changes in rat cerebral cortex, as well as to assess the changes in oscillatory components of myogenic, neurogenic and endothelial levels of cortical microvessel tone within 21 days after ischemia. Methods. Transient global cerebral ischemia was induced in anesthetized Wistar rats by clamping of both common carotid arteries for 12 min with simultaneous controlled hypotension to 45±3 mm Hg, followed by blood reinfusion and recovering from anesthesia. Five different groups of rats were re-anesthetized at 1 hour and 2, 7, 14 or 21 days after ischemia and subjected to studies using continuous wavelet transform analysis of laser Doppler flowmetry. Results. In the first 7 days of the post-ischemic period, peripheral resistance was reduced in the cerebral cortex, which was associated with domination of nutritive blood flow. By 14th day after ischemia it resulted in the blood stagnation connected with development of endothelial dysfunction. From 14th to 21st day post-ischemia, the increase of shunt blood flow was noted. It was possibly a consequence of blood shunting processes happening in a cerebral cortex bypassing a nutritive level that prevents microcirculation from congestion. Conclusions. It is established that transient global cerebral ischemia results in significant changes of microcirculation in cerebral cortex lasting at least 3 weeks after ischemia. Initial dominant nutritive blood flow is probably due to blood congestion because of endothelial dysfunction. Three weeks post-ischemia, it is followed by increase in shunt blood flow that can prevent blood congestion in microcirculatory vascular bed.

Dynamic Changes in the Renin-Angiotensin-Aldosterone System and the Beneficial Effects of Renin-Angiotensin-Aldosterone Inhibitors on Spatial Learning and Memory in a Rat Model of Chronic Cerebral Ischemia.

Renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and brain function. Therefore, we studied the dynamic changes in the RAAS in the blood, cerebral cortex, and hippocampus and the effects of RAAS inhibitors on spatial learning and memory and hippocampal apoptosis in a rat model of chronic cerebral ischemia (CCI) established by bilateral ligation of the common carotid arteries of rats. The levels of renin, angiotensin II (Ang II), and aldosterone (ALD) in the plasma, and the homogenates of the left side of cerebral cortex and whole hippocampus of rats were detected on day 1, 3, 7, 14, 21, and 30 by radioimmunoassay. Spatial learning and memory and hippocampal apoptosis were evaluated on day 30 by Morris water maze test (navigation and space exploration tests) and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively, after rats were orally administered with distilled water (DW), renin inhibitor aliskiren (30 mg/kg), Ang converting enzyme inhibitor enalapril (4 mg/kg), or Ang II receptor antagonist candesartan (2 mg/kg) daily for 30 days. The results showed that the levels of renin and Ang II were significantly higher but ALD fluctuated in the blood, cerebral cortex, and hippocampus in CCI rats compared to normal rats. However, aliskiren and enalapril could significantly decrease (p < 0.05) the levels of renin, Ang II and ALD in the blood, cerebral cortex, and hippocampus compared to DW treatment; while candesartan had similar effect on renin and ALD but no effect on Ang II in CCI rats. Furthermore, spatial learning and memory were significantly decreased but apoptosis in the hippocampus was obviously increased in CCI rats compared to normal rats (p < 0.05). However, aliskiren, enalapril, and candesartan were equally effective to improve spatial learning and memory and decrease apoptosis in the hippocampus. Therefore, RAAS plays an important role in the development of cerebral ischemia and RAAS inhibitors aliskiren, enalapril, and candesartan improve spatial learning and memory and protect brain injury by inhibiting hippocampal apoptosis in CCI rats.

Terminalia methanol extracts inhibit the amidolytic activity of human activated factor XII (Hageman factor)

The long‐term goal of this study is to develop the selective inhibitors of FXIIa based on traditional medicine, which might be safe, and effective. There are positive correlations between increased plasma FXIIa levels with coronary heart disease as well as increased risk of recurrent coronary events. Although they maintain a normal hemostasis, FXII knockout mice (FXII−/−) display defective arterial thrombus formation. In addition, FXII−/− mice are protected from development of cerebral ischemia and pulmonary embolism. Thus, inhibition of FXIIa would help prevent cardiovascular diseases. The present study examines the effects of different but related herbal medicines that impact on the plasma blood coagulation FXII. While it initiates the activation of blood coagulation to stop any bleeding, FXII helps the remaining blood clotting factors and platelets to keep certain circulating pathogenic microorganism close to the phagocytes. The negative charge on the microorganism surface or platelet polyphosphate (poly P) binds readily to zymogen FXII, resulting in the activation of FXII. Evidence indicates that poly P containing pathogens promote FXII‐mediated blood coagulation independent of factor XI, reflecting a novel poly P‐induced thrombus formation. The methanol extracts of T. chebula fruit, T. bellirica fruit, T. arjuna fruit, and T. arjuna bark blocked FXIIa activity with IC50 values of 30, 50, 190, 190 and 27 mg/ml, respectively. Two isolated compounds from Terminalia, Arjunoglucoside II and arjunic acid blocked FXIIa activity with IC50 values of 370 and 780 μM, respectively. T. chebula fruit, T. and arjuna fruit extracts at 50 mg/ml did not affect endothelial cells viability. Overall, T. chebula fruit and T. arjuna fruit extracts might be useful to improve symptoms of FXIIa‐dependent inflammation and thrombosis.

Association of frequent genetic variants in platelet activation pathway genes with large-vessel ischemic stroke in Polish population

Platelets are critically involved in the development of cerebral ischemia. Our study aimed to establish an association between frequent (minor allele frequency (MAF) > 5%) genetic polymorphisms in 84 candidate genetic loci previously linked to platelet reactivity by the use of next-generation sequencing of exons from pooled DNA samples in Polish patients with a history of large-vessel ischemic stroke. Genetic analysis was performed on blood samples obtained from 500 patients (diagnosed with acute non-cardioembolic ischemic stroke with coexisting large-artery atherosclerosis) and age/sex/history of smoking matching 500 controls of Polish origin with high risk of cardiovascular disease. Sequencing of 10 pools (five for each ischemic and control groups) was performed on the Ilumina HiSeq2500 sequencer which generated an average of 36.1 (22.7–45.9 range) million pair-end 101 bp reads and 5.3 (3–7 range) Gbp per pooled sample consisting of 100 subjects. In total, we observed 789 frequent polymorphisms in the sequenced 84 genes (703 of single-nucleotide polymorphism (SNP) type and 86 indels). When the MAF between control and stroke groups was compared, only two intronic polymorphisms (1 SNP and 1 indel) in RGS7 (rs127445 36) and ANKS1B (rs398098426) genes, respectively, show statistically significant differences, which persisted after individual genotyping of the variants and adjustment for potential confounding factors. From the remaining variants, 35 polymorphisms displayed various degrees of nominal significance (from 0.6.3 × 10−5 to 5 × 10−2) and 754 polymorphisms did not show any statistical significance when comparison was evaluated for differences in MAF between the study groups. In conclusion, the results of the study demonstrate statistically significant differences in two frequent intronic genetic variants (in RGS7 and ANKS1B) that could be associated with the platelet function between ischemic stroke patients with coexisting large-vessel atherosclerosis and control patients having high vascular risk.

The role of Na+, K+-ATPase in the hypoxic vasoconstriction in isolated rat basilar artery

Hypoxia-induced cerebrovascular dysfunction is a key factor in the occurrence and the development of cerebral ischemia. Na+, K+-ATPase affects the regulation of intracellular Ca2+ concentration and plays an important role in vascular smooth muscle function. However, the potential role of Na+, K+-ATPase in hypoxia-induced cerebrovascular dysfunction is unknown. In this study, we found that the KCl-induced contraction under hypoxia in rat endothelium-intact basilar arteries is similar to that of denuded arteries, suggesting that hypoxia may cause smooth muscle cell (SMC)-dependent vasoconstriction in the basilar artery. The Na+, K+–ATPase activity of the isolated basilar artery with or without endothelium significantly reduced with prolonged hypoxia. Blocking the Na+–Ca2+ exchanger with Ni2+ (10−3M) or the L-type Ca2+ channel with nimodipine (10−8M) dramatically attenuated KCl-induced contraction under hypoxia. Furthermore, prolonged hypoxia significantly reduced Na+, K+-ATPase activity and increased [Ca2+]i in cultured rat basilar artery SMCs. Hypoxia reduced the protein and mRNA expression of the α2 isoform of Na+, K+-ATPase in SMCs in vitro. We used a low concentration of the Na+, K+-ATPase inhibitor ouabain, which possesses a high affinity for the α2 isoform. The contractile response in the rat basilar artery under hypoxia was partly inhibited by ouabain pretreatment. The decreased Na+, K+-ATPase activity in isolated basilar artery and the increased [Ca2+]i in SMCs induced by hypoxia were partly inhibited by pretreatment with a low concentration of ouabain. These results suggest that hypoxia may educe Na+, K+-ATPase activity in SMCs through the α2 isoform contributing to vasoconstriction in the rat basilar artery.