Possibilities of pharmacological correction of reperfusion injury of ischemic myocardium (review)

Timely and effective reperfusion in ischemia and reoxygenation in hypoxia of the heart muscle prevent myocardial infarction. Delayed reperfusion and reoxygenation in myocardial ischemia and hypoxia can cause reversible damage in it, which, with a favorable outcome, disappear without a trace. Excessively late reperfusion and reoxygenation inevitably ends with irreversible damage to the myocardium, which is widely known as a myocardial infarction, and which, together with other complications of cardiac ischemia, can cause disability and death of the patient. In recent years, reperfusion injury of the ischemic heart muscle has been recognized as an independent link in the pathogenesis of myocardial infarction. The mechanisms of this link of pathogenesis have been partially studied in experimental conditions. The phenomena of preconditioning and post-conditioning have been discovered, the effects of which are currently determined fairly reliably. After determining the mechanisms of reperfusion injury of the ischemic myocardium, the search and development of pharmacological agents capable of inducing such a phenomenon as cardioprotection began. In parallel, studies of specific microRNAs that claim to be diagnostic markers are being conducted, as well as the search for drugs that affect the level of their expression is being conducted. The information about the achieved successes in this direction is given.

Cardioprotective Effect of Nec-1 in Rats Subjected to MI/R: Downregulation of Autophagy-Like Cell Death

Objective. Necrostatin-1 (Nec-1), an inhibitor of necroptosis, has been reported to protect against myocardial ischemia-reperfusion (MI/R) injury. However, the contribution of the potential antinecroptotic effect of Nec-1 on its infarct limitation and cardiac function improvement effects after MI/R has not been investigated. Methods. The present study investigated the effect of Nec-1 on myocardial infarct size, necroptosis, and cardiac functional recovery in rats subjected to myocardial ischemia-reperfusion (MI/R 30 min/12, 24, 48, and 72 h). Results. The study showed that Nec-1 might reduce myocardial cell death and maintain myoarchitectonic integrity, consequently inhibiting the reactive fibrosis process in rats in myocardial ischemia/late reperfusion. Moreover, the administration of Nec-1 (0.6 mg/kg) at the onset of reperfusion significantly reduced the release of creatine kinase and downregulation of autophagy within 24 h after reperfusion, and there was a significantly positive correlation between them. Conclusion. These results suggest that antinecroptosis treatment may improve the clinical outcomes of patients with ischemic heart disease.

Crosstalk between Inflammation and the BBB in Stroke

The blood-brain barrier (BBB), which is located at the interface between the central nervous system (CNS) and the circulatory system, is instrumental in establishing and maintaining the microenvironmental homeostasis of the CNS. BBB disruption following stroke promotes inflammation by enabling leukocytes, T cells and other immune cells to migrate via both the paracellular and transcellular routes across the BBB and to infiltrate the CNS parenchyma. Leukocytes promote the removal of necrotic tissues and neuronal recovery, but they also aggravate BBB injury and exacerbate stroke outcomes, especially after late reperfusion. Moreover, the swelling of astrocyte endfeet is thought to contribute to the ‘no-reflow’ phenomenon observed after cerebral ischemia, that is, blood flow cannot return to capillaries after recanalization of large blood vessels. Pericyte recruitment and subsequent coverage of endothelial cells (ECs) alleviate BBB disruption, which causes the transmigration of inflammatory cells across the BBB to be a dynamic process. Furthermore, interneurons and perivascular microglia also make contacts with ECs, astrocytes and pericytes to establish the neurovascular unit. BBB-derived factors after cerebral ischemia triggered microglial activation. During the later stage of injury, microglia remain associated with brain ECs and contribute to repair mechanisms, including postinjury angiogenesis, by acquiring a protective phenotype, which possibly occurs through the release of microglia-derived soluble factors. Taken together, we reviewed dynamic and bidirectional crosstalk between inflammation and the BBB during stroke and revealed targeted interventions based on the crosstalk between inflammation and the BBB, which will provide novel insights for developing new therapeutic strategies.

Effect of Ischemic Postconditioining on Change of Immunoreactivity Level to PECAM-1/CD31 in Rat Neocortex Structures after Global Brain Ischemia

Introduction. Ischemic postconditioning (IPostC) of the brain can be considered as a promising approach to limit reperfusion injury in the ischemic area of the brain. Objective – to study the effect of IPostC after global cerebral ischemia on the level of immunoreactivity to PECAM-1/CD31 in the structures of layers II, III and V of the neocortex of rats at different periods of the reperfusion period.Material and methods. In male Wistar rats, a 10-minute global cerebral ischemia was modeled followed by IPostC in the form of reperfusion-ischemia at 15sec/15sec. In the early (2 days) and late (7 days) reperfusion periods after damaging ischemia, the number of morphologically unchanged neurons and the level of immunoreactivity to PECAM-1/CD31 in the structures of layers II, III and V of the neocortex were estimated.Results. It is shown that the use of IPostC by 2 days of reperfusion contributed to the increase in the number of unchanged neurons in layers II and III of 25.8 and 28.2 % (P<0.05), which was not accompanied by changes in the level of immunoreactivity to PECAM-1/CD31, to 7 days of reperfusion there was an increase in the number of unchanged neurons in layers II, III and V of 19.2, 22,1, 21,4 % (P<0.05) was observed a decrease in the level of immunoreactivity to PECAM-1/CD31 in the structures of these layers of 27.4, 39.4, and 16.7 % (P<0.05), respectively, when compared with similar indicators in groups without the use of IPostC.Conlusions. In the mechanisms of physiological reaction formed in the application of ischemic postconditioning after cerebral ischemia and leading to the preservation of the number of unchanged neurons in the late reperfusion period involved PECAM-1/CD31, which suggests that the protective potential of the phenomenon is realized by possible inhibiting the migration of neutrophils, monocytes and lymphocytes and extravasation of leukocytes from the systemic blood flow into the damaged area of the brain, i.e. through suppression of inflammatory response.

Influence of cerebral global ischemia-reperfusion on succinate dehydrogenase activity in neurons of different neocortical layers

The aim of the study was to investigate changes in activity of succinate dehydrogenase (SDH) in cytoplasm of neurons of different cortical layers in early and late reperfusion period after global cerebral ischemia in rats. Reversible global cerebral ischemia was modeled by occlusion of the brachiocephalic trunk, left subclavian artery and left common carotid artery for 10 minutes and following reperfusion during 2 or 7 days. The SDH activity in cytoplasm of neurons of II, III and V cortical layers was determined histoenzymatically. It is shown that the SDH activity in neurons of the studied cortical layers was characterized by the increased reperfusion period to the 2 days with a subsequent increased activity of the reperfusion period to the 7 days. The change in the SDH activity in cytoplasm of cortical neurons depends on the particular cerebral layer and duration of postischemic reperfusion.