Postischemic Changes Research Articles

Sodium Loading Does Not Induce Oxidative Stress-Mediated Reductions in Vascular Function in Young Adults

Short-term, high sodium diets decrease dilation responses in conduit arteries and the microvasculature when compared to low sodium diets (e.g., 7000 vs. 500 mg/day). Supraphysiological antioxidant treatment mitigates these effects supporting a role for oxidative stress in sodium-induced vascular impairments. It is unclear whether these effects are present when high sodium conditions are compared to the sodium level of a typical American diet (~3400 mg/day). Therefore, we tested the hypotheses that sodium added to the habitual diet of young adults would reduce flow mediated dilation (FMD) and post-ischemic reactive hyperemia (RH) and that an acute infusion of the antioxidant ascorbic acid (AA) would attenuate the vascular consequences of excess sodium. Methods: Young adults (6M / 8F; age: 26 ± 4 y; BMI: 23.6 ± 2.5 kg/m2) were studied following 10 days of sodium loading (SL) via table salt-filled capsules (3900 mg sodium/day) and 10 days of placebo capsules in addition to their normal diet, in random order. Total sodium intake was estimated via 24-hour urinary sodium content on day 10. On day 11, brachial artery diameter and blood velocity were continuously measured via duplex ultrasound at baseline and after 5 min of forearm ischemia. FMD, the post-ischemic change in brachial artery diameter relative to baseline diameter, provided an index of conduit artery endothelial function. The total RH in the 2 min following ischemia was measured for an index of microvascular function. Within each condition, testing was performed before (pre-AA) and after (post-AA) a 20 min intravenous infusion of 0.06 g of AA/kg lean body mass. Results: Urinary sodium content was increased by SL compared to the placebo (285 ± 94 vs. 160 ± 75 mmol/24 h, p<0.001) indicating approximate sodium intakes of 6600 and 3700 mg/day, respectively. Mean arterial pressure did not differ across conditions pre-AA (SL: 77 ± 7; placebo: 75 ± 5 mmHg, P=0.40) or post-AA (SL: 79 ± 8; placebo: 76 ± 5 mmHg, P=0.17). Brachial artery FMD was not different across time or condition (SL pre-AA: 8.7 ± 3.6, post-AA: 8.8 ± 4.2% vs. placebo pre-AA: 8.8 ± 3.2, post-AA: 8.1 ± 3.5%, time x condition interaction P=0.48). RH was similar following SL and placebo (condition effect: P=0.38) but was reduced in both conditions post AA (SL: Δ-45 ± 44 ml, P=0.01; placebo: Δ-72 ± 59ml, p<0.001). Conclusion: Contrary to our hypothesis, 10 days of sodium loading did not decrease FMD or post- ischemic RH in young adults compared to their habitual diet. Likewise, acute antioxidant treatment did not augment FMD in either condition and paradoxically decreased total RH independent of sodium intake. These data suggest that a short-term increase in dietary sodium intake in healthy young adults does not elicit oxidative stress-induced reductions in vascular function. NIH 5R01HL104106 and 5P20GM113125; AHA 20POST35080171. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

THE INFLUENCE OF ACUTE CEREBRAL BLOOD CIRCULATION DISORDERS IN THE POOL OF CAROTID ARTERIES ON THE RNA CONTENT IN THE CELLS OF THE LYMPHOID POPULATION OF THE RATS’ THYMUS OF DIFFERENT AGE GROUPS

The aim of the work – to find out the age-related features of the response of RNA cells ofthe lymphoid population of the thymus to an acute disturbance of cerebral blood flow inthe pool of carotid arteries in six- and nine-month-old rats.Materials and methods. Acute cerebrovascular accident was simulated in 6- and9-month-old white non-linear laboratory rats by bilateral carotid artery clamping for 20min. followed by reperfusion. The thymus was taken on the 12th day of the postischemicperiod, fixed in Buen’s solution, after standard histological processing it was embedded inparaffin, and serial sections with a thickness of 5 μm were made. After deparaffinization,rehydration, and staining with hallocyanine- chromium alum according to Einarson,histological sections were analyzed in a digital image analysis system VIDAS-386(Kontron Electronik, Germany) with a fluorescent microscope AXIOSKOP (Zeiss,Germany). Total RNA content was expressed in units of optical density (EOP per 1 mm2). The results. In the cells of the lymphoid population of all structural and functional zones ofthe thymus of control rats of both age groups, an increase in RNA content was establishedin the direction from immature to more mature classes (p<0.05). This regularity persistsin the post-ischemic period. In the cells of the lymphoid population of the subcapsular anddeep cortical zones of the thymus, the RNA content significantly prevails in six-month-oldrats, in intralobular perivascular spaces – in nine-month-old rats, and in the medullaryzone there are no age differences. Postischemic changes in RNA content in six-month-oldrats in the subcapsular zone and intralobular perivascular spaces of the thymus consistin its decrease in immature cell classes and its increase in mature small thymocytes(р<0.05); in the deep cortex – in growth in all classes of thymocytes (p<0.05). In ninemonth-old animals, the differences were in the increase in RNA content in the subcapsularzone and in less mature middle thymocytes, in the deep cortex – in a decrease in RNAcontent in all classes, except small thymocytes, in intralobular perivascular spaces – ina decrease in RNA content in all classes of thymocytes (p<0.05 for all cases). In themedullary zone of animals of both age groups, changes are unidirectional (decrease inRNA content, p<0.05).Conclusion. Age differences in the nature of postischemic changes in the content of RNAin thymocytes are present in all structural and functional zones of the gland, with theexception of the medullary, in which the changes were unidirectional in both age groups.

Coronary artery disease in cardiac amyloidosis

Abstract Background Cardiac amyloidosis is an important disease causing significant morbidity and mortality. Due to the ageing society as well as better diagnostic tools such as 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy (DPD scan), cardiac amyloidosis has increased in prevalence, however, the coexistence, as well as the differences in presentation with coronary artery disease (CAD), has not yet been discovered. Purpose The purpose of the study is to evaluate the prevalence of CAD in patients with cardiac amyloidosis, to assess differences in late gadolinium enhancement (LGE) in cardiac MRI, and to assess differences in symptoms such as dyspnea. Materials and Methods We retrospectively assessed all patients with cardiac amyloidosis at our center and screened for an evaluation of coronary artery disease with coronary angiography, coronary CT, or myocardial scintigraphy. In all patients, who underwent cardiac MRI we assessed the pattern of LGE using the cardiac left ventricular segmentation model published by the AHA [1]. Results 295 patients (27% female, 74 ± 11 years) with cardiac amyloidosis (26% AL-amyloidosis, 74% ATTR-amyloidosis) were retrospectively assessed. Of those, 205 (69%) had a CAD evaluation. In 69 patients (34%), significant CAD was present, 10 patients (5%) had undergone CABG and 48 patients (23%) had received a PCI in the past. In patients with CAD, 3 patients (4%) suffered from NYHA IV and 51 patients (74%) were symptomatic with NYHA II or NYHA III. There were no significant differences to patients without CAD (p=0.252). In 153 patients (75%), cardiac MRI was performed. In 7% of the patients, no LGE was obvious, in 84%, a diffuse circular subendocardial to transmural LGE with basoapical gradient, typical for cardiac amyloidosis, could be observed. In 6% of the cases, a subendocardial pattern typical for post-ischemic changes could be observed; in 56% of the patients, a previous myocardial infarction was known. In the remaining 3%, LGE in the insertion points could be observed. Conclusion With 34%, CAD is highly prevalent in patients with cardiac amyloidosis. In 28%, a coronary intervention (surgical or interventional) was performed, making coronary interventions in patients with cardiac amyloidosis a feasible option. Cardiac MRI in patients with concomitant CAD and cardiac amyloidosis often shows the typical diffuse LGE, therefore, visualization of postischemic changes in these patients is difficult. Furthermore, symptoms do not differ between patients with CAD and no CAD.

Age features of the thymocite RNA response in the thymus structural and functional areas to blood circulation disorders in the pool of carotic arteries in rats

Introduction. Ischemic-reperfusion injuries of the brain are accompanied by immunological disorders, which in their turn can extend post-ischemic changes in the brain. The studies of structural and functional changes in the thymus cells caused byischemia-reperfusion of the brain can supplement the existing understanding of the mechanism of the above interaction.
 The aim of the study. To investigate the reaction of thymocyte RNA in the structural and functional areas of the thymus gland to blood circulation disturbances in the carotid artery pool.
 Results. In rats of both age groups, cerebral ischemia-reperfusion reduces the content of RNA in the thymus cells in all the structural and functional areas of the thymus except the deep cortical one in one-month rats and the sub-capsular one in three-month rats. 
 Conclusions. Acute circulatory disorders in the pool of the carotid arteries result in certain changes in RNA content in all the structural and functional areas of the thymus with age-related and structural features available.

КЛИНИЧЕСКИЙ СЛУЧАЙ КОАРКТАЦИИ АОРТЫ У РЕБЕНКА, ОСЛОЖНИВШЕЙСЯ ИШЕМИЧЕСКИМ ИНСУЛЬТОМ

Introduction. Aortic coarctation is a congenital defect of the cardiovascular system characterized by narrowing in the isthmus of the aorta, in which blood flow through the narrowed area is obstructed, blood pressure in the aorta increases significantly above the narrowing site, arterial hypertension syndrome develops, which can lead to a stroke. Aim. To analyze a clinical case of aortic coarctation, first detected in a 4.5-year-old child, and late- diagnosed arterial hypertension led to an ischemic stroke. Material and methods. The boy D., at the age of 4.5 years, was admitted to the hospital at the place of residence with symptoms of a stroke on the background of complete well-being. Echocardiography, electrocardiography, magnetic resonance and computed tomography of the brain, computed tomography of the chest organs with contrast, aortography, and manometry were performed. Results and discussion. The crisis course of arterial hypertension resistant to therapy was objectively noted. Echocardiography revealed coarctation of the aorta in a typical place, the defect was confirmed on computed tomography of the chest organs with contrast, on magnetic resonance imaging of the brain – extensive ischemic stroke of the right hemisphere. The early post-stroke period, post-ischemic changes in the brain made it difficult to choose cardiac surgery tactics, but given the lack of response to hypotensive therapy, it was decided to operate, resection of the narrowed aortic area with the formation of an end-to-end anastomosis was performed. Observation in the postoperative period (after 2 years) revealed hypoplasia of the distal part of the aortic arch, repeated surgery was not performed, since angiography with manometry showed a sufficient pressure gradient between the ascending and descending aorta. Currently, the child is on constant hypotensive therapy, is disabled due to neurological pathology. Conclusion. The lack of alertness of doctors regarding aortic coarctation and blood pressure monitoring did not allow early suspicion of this pathology and led to the appearance of ischemic stroke in the child, irreversible changes in the nervous system, made it difficult to choose cardiac surgery tactics.

Apitherapy in Post-Ischemic Brain Neurodegeneration of Alzheimer's Disease Proteinopathy: Focus on Honey and Its Flavonoids and Phenolic Acids.

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood-brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, β-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer's disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey's potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration.

Possibilities and features of zero-ischemia nephron-sparing surgery in localized kidney cancer

Kidney cancer (KCa) is one of the greatest challenges in oncological urology due to the increase in morbidity and mortality rates annually. In the treatment of KCa, preservation of renal function is an important objective, in addition to achieving oncological results. The article presents the experience of treatment of 175 KCa-patients of pT1a – T2aN0M0 stages, who underwent nephron-saving surgery (NSS) with preventive hemostatic sutures. Functional outcomes of NSS were studied in the groups without cross-linking (group 1; n = 150) and with cross-linking of the renal pedicle (group 2; n = 25). Kidney resection with prophylactic suturing has been shown to allow removal of a tumour of almost any localisation. By avoiding cross-linking of the renal pedicle during surgery, post-ischemic changes in the renal parenchyma are minimised. Thus, one month after surgery, the perfusion indexes in groups 1 & 2 were 45.2 ± 3.0% vs 35.5 ± 3.3%; renal indexes were 44.8 ± 2.4% vs 39.1 ± 1.4%; areas of the functioning parenchyma were 52.0 ± 10.0% vs 35.0 ± 9.0%, respectively.

Ischemic stroke in a pediatric patient: complication of the course of COVID-19 (clinical case and literature review)

Recently, there is a growing number of publications about the complicated course of the COVID-19 in children. The literature describes only a few cases of acute cerebrovascular diseases. In the case described in this paper, an 11‑year-old boy presented with COVID-19 complicated by an ischemic stroke. Moderate ischemic stroke (pedNIHSS 14 points) occurred on the 7th day after infection with the SARS-CoV-2 and the background of the multisystem inflammatory syndrome. It has started with the left hemiplegia, hemianesthesia, central-type facial moderate palsy, and pseudobulbar palsy. Focal brain ischemia in the right hemisphere brain and occlusion of the right middle cerebral artery was confirmed by neuroimaging data. The treatment observed regression of neurological symptoms: there were minimal movements in his left arm and leg, facial muscles, also improved gulping and speech. After 1.5 months, the stroke was provided clinical examination: no markers predisposing to hypercoagulability or a prothrombotic state, as well as markers of systemic diseases. According to neuroimaging data, was occurred recanalization of occluded middle cerebral artery, was postischemic changes. This case shows the possibility of stroke against the background of COVID-19 in children without somatic problems and makes the doctor more vigilant during the treatment of COVID-19.

Correction of Postischemic Changes in the Microcirculation of Rat Cerebral Cortex with Mesenchymal Stem Cells

Correction of Postischemic Changes in the Microcirculation of Rat Cerebral Cortex with Mesenchymal Stem Cells

A case of successful treatment of complete atrioventricular block complicated by sudden arrhythmic death in an elderly patient with post COVID-19 thrombocytopenia

As established today by a number of studies, transferred COVID-19 (even mild) is associated with a high risk of delayed heart damage. Although human coronaviruses are a minor cause of all cases of viral myocarditis, they have been associated with myocarditis in patients of all age groups. Post-COVID-19 myocarditis can be manifested by heart failure, heart rhythm and conduction disorders. A case report of 14-day hospitalization of an 89 y.o. man for a life-threatening myocardial conduction disorder – complete AV block – on the background of a permanent form of Arial fibrillation, accompanied by clinical death of the patient, coagulopathy, nosocomial pneumonia, heart failure and impaired consciousness. During the treatment, which included cardiopulmonary resuscitation, the use of temporary and then permanent pacemaker, antibiotics, levocarnitine, Fondaparinux, blood clot transfusions for profound thrombocytopenia, led to the restoration of heart rhythm and conduction, reduction of heart failure, cure of nosocomial pneumonia and restoration of exercise tolerance. Post- COVID-19 complications are currently still weakly understood and poorly predicted, but their treatment according to the general rules gives positive results. In patients with heparin-induced thrombocytopenia, as in patients with initial thrombocytopenia (including after COVID-19 conditions), it is advisable to use the drug Fondaparinux, which has proven itself in the prevention and treatment of arterial and venous thromboembolism. In the treatment of posthypoxic complications, it is appropriate to use Levocarnitine to correct post-ischemic changes in the myocardium and brain.

Global Cerebral Ischemia in Male Long Evans Rats Impairs Dopaminergic/ΔFosB Signalling in the Mesocorticolimbic Pathway Without Altering Delay Discounting Rates.

Global cerebral ischemia (GCI) in rats has been shown to promote exploration of anxiogenic zones of the Elevated-Plus Maze (EPM) and Open Field Test (OFT). This study investigated changes in impulsive choice and/or defensive responses as possible contributors of heightened anxiogenic exploration observed after ischemia. Impulsivity was assessed using delay discounting (DD) paradigms, while the Predator Odour Test (PO) served to assess changes in defensive responses towards a naturally aversive stimulus. Male Long Evans rats underwent 9 days of autoshaping training and 24 days of DD training prior to GCI or sham surgery (n = 9/group). Post-surgery, rats completed the OFT, EPM, and PO, followed by 6 days of DD sessions. Blood droplets served to evaluate corticosterone secretion associated with PO exposure. With impulsivity being regulated through mesocorticolimbic monoaminergic pathways, we also characterised post-ischemic changes in the expression of dopamine D2 receptors (DRD2), dopamine transporters (DAT), and 1FosB in the basolateral amygdala (BLA), nucleus accumbens core (NAcC) and shell (NAcS), and ventromedial prefrontal cortex (vmPFC) using immunohistofluorescence. Our findings revealed no impact of GCI on delay discounting rates, while PO approach behaviours were minimally affected. Nonetheless, GCI significantly reduced DRD2 and ΔFosB-ir in the NAcS and NAcC, respectively, while DAT-ir was diminished in both NAc subregions. Collectively, our findings refine the understanding of cognitive-behavioural and biochemical responses following stroke or cardiac arrest. They support significant alterations to the dopaminergic mesocorticolimbic pathway after ischemia, which are not associated with altered impulsive choice in a DD task but may influence locomotor exploration of the OFT and EPM.

The Many Faces of Post-Ischemic Tau Protein in Brain Neurodegeneration of the Alzheimer's Disease Type.

Recent data suggest that post-ischemic brain neurodegeneration in humans and animals is associated with the modified tau protein in a manner typical of Alzheimer’s disease neuropathology. Pathological changes in the tau protein, at the gene and protein level due to cerebral ischemia, can lead to the development of Alzheimer’s disease-type neuropathology and dementia. Some studies have shown increased tau protein staining and gene expression in neurons following ischemia-reperfusion brain injury. Recent studies have found the tau protein to be associated with oxidative stress, apoptosis, autophagy, excitotoxicity, neuroinflammation, blood-brain barrier permeability, mitochondrial dysfunction, and impaired neuronal function. In this review, we discuss the interrelationship of these phenomena with post-ischemic changes in the tau protein in the brain. The tau protein may be at the intersection of many pathological mechanisms due to severe neuropathological changes in the brain following ischemia. The data indicate that an episode of cerebral ischemia activates the damage and death of neurons in the hippocampus in a tau protein-dependent manner, thus determining a novel and important mechanism for the survival and/or death of neuronal cells following ischemia. In this review, we update our understanding of proteomic and genomic changes in the tau protein in post-ischemic brain injury and present the relationship between the modified tau protein and post-ischemic neuropathology and present a positive correlation between the modified tau protein and a post-ischemic neuropathology that has characteristics of Alzheimer’s disease-type neurodegeneration.

EARLY AND REMOTE RESPONSE OF HIF-1Α PROTEIN IN THE HIPPOCAMPUS FIELDS TO ISCHEMIA-REPERFUSION IN RATS WITH DIABETES MELLITUS

The role of the transcription factor Hif-1α in pathogenesis of hypoxic lesions and diabetes mellitus (DM) has been confirmed, though molecular mechanisms underlying dysfunctions of the factor in the association of DM with ischemic-reperfusion lesion of the brain remain unknown. Objective: the investigation of Hif-1α protein content in the neurons of the hippocampus fields of rats with experimental DM in the dynamics of ischemic-reperfusion lesion of the brain. The study was conducted on 60 6-month rats with DM simulated at the age of 2 months by means of a single administration of streptozotocin (60 mg/kg of the body weight) (Sigma, USA). Disorders of the cerebral circulation were simulated by means of occlusion of both carotid arteries for 20 minutes. The content of Hif1-α protein was determined by means of fluoroimmunoassay after 20-minute ischemia with one hour reperfusion, and on the 12th day of the post-ischemic period in the hippocampus fields: СА1, СА2, СА3, СА4. In rats without DM 20-minute ischemia with one hour reperfusion increases the content of Hif-1α protein in all the hippocampus fields. On the 12th day of ischemic-reperfusion period in СА2-СА4 hippocampus fields the values of certain examined activity indices of the transcription factor Hif-1α continue to increase, and in СА1 field they are normalized or come closer to the values of animals from the control group. In rats with DM at the early post-ischemic period changes of Hif-1α protein content are lacking in СА1 field, the signs of its reduced activity are found in СА2 field, in СА3 field they are limited by the response of one index, and in СА4 field they are similar to those of the control rats under the experimental conditions. On the 12th day of ischemic-reperfusion period all the activity indices of the transcription factor Hif-1α increase in СА1 filed. They are higher than the corresponding indices in animals from the control group by absolute values under similar experimental conditions; changes of the examined parameters are limited in СА2 and СА3 fields in comparison with those from the control group; the parameters, which increased in the control group of animals, decreased in СА4 field. DM restricts Hif-1α protein response to ischemia-reperfusion in the neurons of СА1-СА3 field at the early ischemic-reperfusion period and in the neurons of СА2-СА4 fields — on the 12th day of the observation.

Активность фактора Виллебранда у крыс после кратковременной ишемии головного мозга

The von Willebrand factor (vWF) is a recognized marker of endothelial dysfunction associated with an imbalance in endothelial production of substances with procoagulant activity. vWF activity and hematocrit index in Wistar rats after 12 min occlusion of both carotid arteries with simultaneous controlled hypotension to 45±3 mm Hg, was investigated. Post-ischemic changes were evaluated in 5 groups of rats: 1 hour and 3, 7, 14 and 21 days after ischemia. An increase in the activity of vWF was manifested as early as 1 hour after ischemia. By the 3rd day of the post-ischemic time, the concentration of vWF in the blood plasma decreased as a result of hemodilution, as evidenced by hematocrit decrease. After 7 days there was a sharp increase in the activity of the marker. In the future, the activity of vWF decreased and by 21 days after ischemia, the values of the vWF activity reached values in control rats. It was established that cerebral ischemia led to the development of vascular endothelial dysfunction associated with an imbalance of endothelial production of substances with procoagulant activity, which persists for 14 days after ischemia.

Dynamics of Postischemic Changes in the Microcirculation in the Rat Cerebral Cortex

Postischemic changes in the circulation appear primarily in the microcirculatory system. There are few studies of the cerebral microcirculation after ischemia and these are scattered and fragmentary. The aim of the present work was to conduct a complex study of the dynamics of the main parameters of the microcirculation (tissue perfusion with blood, blood saturation, and tissue oxygen consumption) in the cerebral cortex of rats 1 h and 2, 7, 14, and 21 days after ischemia induced by occlusion of both carotid arteries for 12 min with simultaneous controlled hypotension to a level of 45 ± 3 mmHg. The hyperperfusion seen 1 h after ischemia was found to be replaced by degradation of the microcirculation in rat brain tissue lasting the next three weeks, due to suppression of the active mechanisms controlling blood flow and decreases in vessel tone. These features were accompanied by stagnation of the blood, decreases in cortical tissue oxygen consumption, and decreases in blood oxygen saturation.

Molecular Alterations and Effects of Acute Dehydroepiandrosterone Treatment Following Brief Bilateral Common Carotid Artery Occlusion: Relevance to Transient Ischemic Attack

Transient ischemic attack (TIA) represents brief neurological dysfunction of vascular origin without detectable infarction. Despite major clinical relevance characterization of post-TIA molecular changes using appropriate experimental model is lacking and no therapeutic agent has been established yet. Neurosteroid dehydroepiandrosterone (DHEA) arose as one of the candidates for cerebral ischemia treatment but its effects on TIA-like condition remain unknown. Seeking an animal model applicable for investigation of molecular alterations in mild ischemic conditions such as TIA, 15-min bilateral common carotid artery occlusion with 24-h reperfusion was performed to induce ischemia/ reperfusion (I/R) injury in adult male Wistar rats. Additionally, effects of 4-h post-operative DHEA treatment (20 mg/kg) were investigated in physiological and I/R conditions in hippocampus (HIP) and prefrontal cortex (PFC). The study revealed absence of sensorimotor deficits, cerebral infarcts and neurodegeneration along with preserved HIP and PFC overall neuronal morphology and unaltered malondialdehyde and reduced glutathione level following I/R and/or DHEA treatment. I/R induced nitric oxide burst in HIP and PFC was accompanied with increased neuronal nitric oxide synthase protein level exclusively in HIP. DHEA had no effects in physiological conditions, while increase of Bax/Bcl2 ratio and dissipation of mitochondrial membrane potential in treated I/R group suggested DHEA-mediated exacerbation of post-ischemic changes that might lead to pro-apoptotic events in HIP. Interestingly, DHEA restored I/R-induced NO to the control level in PFC. Obtained results indicated that I/R may serve as an appropriate model for investigation of molecular changes and treatment outcome following mild ischemic conditions such as TIA.

The coagulation hemostasis dynamics in rats in the post-ischemic time

Introduction. Ischemic injury to the endothelium influences on a coagulation hemostasis, worsening hemodynamics of cerebral microcirculation as a result of rheological occlusion. The long-term post-ischemic blood clotting system changes are not studied well by now.The work purpose – to study a coagulation hemostasis and endothelial prostacyclin – synthetic activity of pial vessels within 21 days after single short-term transient cerebral ischemia in rat.Material and Methods. Ischemia was reproduced by means of 12-minute time occlusion of both carotids with the simultaneous arterial hypotension. Post-ischemic changes were investigated in 4 groups of rats: on the 3rd, 7th, 14th and 21st day after ischemia. The state of blood clotting system was estimated on time of clot formation in the blood plasma by an automatic optical method with use of screening tests of definition of prothrombin and thrombin clotting time and concentration of fibrinogen. Endothelial prostacyclin – synthetic activity was estimated by pial vessel reaction to indometacin.Results. On the 3rd day after ischemia the increase in prothrombin time was observed. Level of fibrinogen increased on the 3rd and the 14th days of the post-ischemic time. On the 21st day after ischemia thrombin time decreased. The inverse correlation of pial vessel endothelial prostacyclin – synthetic activity with the fibrinogen level and direct correlation with vessel cross-sectional area of these vessels is established.Conclusions. Short-time global cerebral ischemia causes changes of blood clotting system mechanisms lasting for 21 days of the post-ischemic time. Post-ischemic abnormalities in hemostasis system are connected with changes in endothelial prostacyclin – synthetic activity of cerebral vessels that, along with decreased anti-aggregation ability of vascular system, is also the reason of narrowing of the lumen in pial vessels.

Ventricular Tachycardia (VT) Substrate Characteristics: Insights from Multimodality Structural and Functional Imaging of the VT Substrate Using Cardiac MRI Scar, 123I-Metaiodobenzylguanidine SPECT Innervation, and Bipolar Voltage.

Postischemic adaptation results in characteristic myocardial structural and functional changes in the ventricular tachycardia (VT) substrate. The aim of this study was to compare myocardial structural and functional adaptations (late gadolinium enhancement/abnormal innervation) with detailed VT mapping data to identify regional heterogeneities in postischemic changes. Methods: Fifteen patients with ischemic cardiomyopathy and drug-refractory VT underwent late gadolinium enhancement cardiac MRI (CMR), 123I-metaiodobenzylguanidine SPECT, and high-resolution bipolar voltage mapping to assess fibrosis (>3 SDs), abnormal innervation (<50% tracer uptake), and low-voltage area (<1.5 mV), respectively. Three-dimensional reconstructed CMR/123I-metaiodobenzylguanidine models were coregistered for further comparison. Results: Postischemic structural and functional adaptations in all 3 categories were similar in size (reported as median [quartile 1-quartile 3]: CMR scar, 46.1 cm2 [33.1-86.9 cm2]; abnormal innervation, 47.8 cm2 [40.5-68.1 cm2]; and low-voltage area, 29.5 cm2 [24.5-102.6 cm2]; P > 0.05). However, any single modality underestimated the total VT substrate area defined as abnormal in at least 1 of the 3 modalities (76.0 cm2 [57.9-143.2 cm2]; P < 0.001). Within the total VT substrate area, regions abnormal in all 3 modalities were most common (25.2%). However, significant parts of the VT substrate had undergone heterogeneous adaptation (abnormal in <3 modalities); the most common categories were "abnormal innervation only" (18.2%), "CMR scar plus abnormal innervation only" (14.9%), and "CMR scar only" (14.6%). All 14 VT channel/exit sites (0.88 ± 0.74 mV) were localized to myocardium demonstrating CMR scar and abnormal innervation. This specific tissue category accounted for 68.3% of the CMR scar and 31.2% of the total abnormal postischemic VT substrate area. Conclusion: Structural and functional imaging demonstrated regional heterogeneities in the postischemic VT substrate not appreciated by any single modality alone. The coexistence of abnormal innervation and CMR scar may identify a particularly "proarrhythmic" adaptation and may represent a potential novel target for VT ablation.

Regional-specific effects of cerebral ischemia/reperfusion and dehydroepiandrosterone on synaptic NMDAR/PSD-95 complex in male Wistar rats

Excessive glutamate efflux and N-methyl-D-aspartate receptor (NMDAR) over-activation represent well-known hallmarks of cerebral ischemia/reperfusion (I/R) injury, still, expression of proteins involved in this aspect of I/R pathophysiology show inconsistent data. Neurosteroid dehydroepiandrosterone (DHEA) has been proposed as potent NMDAR modulator, but its influence on I/R-induced changes up to date remains questionable. Therefore, I/R-governed alteration of vesicular glutamate transporter 1 (vGluT1), synaptic NMDAR subunit composition, postsynaptic density protein 95 (PSD-95) and neuronal morphology alone or following DHEA treatment were examined. For that purpose, adult male Wistar rats were treated with a single dose of vehicle or DHEA (20 mg/kg i.p.) 4 h following sham operation or 15 min bilateral common carotid artery occlusion. Western blot was used for analyses of synaptic protein expressions in hippocampus and prefrontal cortex, while neuronal morphology was assessed using Nissl staining. Regional-specific postischemic changes were detected on protein level i.e. signs of neuronal damage in CA1 area was accompanied with hippocampal vGluT1, NR1, NR2B enhancement and PSD-95 decrement, while histological changes observed in layer III were associated with decreased NR1 subunit in prefrontal cortex. Under physiological conditions DHEA had no effect on protein and histological appearance, while in ischemic milieu it restored hippocampal PSD-95 and NR1 in prefrontal cortex to the control level. Along with intact neurons, ones characterized by morphology observed in I/R group were also present. Future studies involving NMDAR-related intracellular signaling and immunohistochemical analysis will reveal precise effects of I/R and DHEA treatment in selected brain regions.

Enhanced pyruvate dehydrogenase activity improves cardiac outcomes in a murine model of cardiac arrest.

RationalePost-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown. We hypothesized that therapeutic hypothermia (TH) following CA is associated with the inhibition of PDK activity and increased PDH activity. We further hypothesized that an inhibitor of PDK activity, dichloroacetate (DCA), would improve PDH activity and post-CA outcomes.Methods and resultsAnesthetized and ventilated adult female C57BL/6 wild-type mice underwent a 12-minute KCl-induced CA followed by cardiopulmonary resuscitation. Compared to normothermic (37°C) CA controls, administering TH (30°C) improved overall survival (72-hour survival rate: 62.5% vs. 28.6%, P<0.001), post-resuscitation myocardial function (ejection fraction: 50.9±3.1% vs. 27.2±2.0%, P<0.001; aorta systolic pressure: 132.7±7.3 vs. 72.3±3.0 mmHg, P<0.001), and neurological scores at 72-hour post CA (9.5±1.3 vs. 5.4±1.3, P<0.05). In both heart and brain, CA increased lactate concentrations (1.9-fold and 3.1-fold increase, respectively, P<0.01), decreased PDH enzyme activity (24% and 50% reduction, respectively, P<0.01), and increased PDK protein expressions (1.2-fold and 1.9-fold, respectively, P<0.01). In contrast, post-CA treatment with TH normalized lactate concentrations (P<0.01 and P<0.05) and PDK expressions (P<0.001 and P<0.05), while increasing PDH activity (P<0.01 and P<0.01) in both the heart and brain. Additionally, treatment with DCA (0.2 mg/g body weight) 30 min prior to CA improved both myocardial hemodynamics 2 hours post-CA (aortic systolic pressure: 123±3 vs. 96±4 mmHg, P<0.001) and 72-hour survival rates (50% vs. 19%, P<0.05) in normothermic animals.ConclusionsEnhanced PDH activity in the setting of TH or DCA administration is associated with improved post-CA resuscitation outcomes. PDH is a promising therapeutic target for improving post-CA outcomes.