Understanding the Connection Between Common Stroke Comorbidities, Their Associated Inflammation, and the Course of the Cerebral Ischemia/Reperfusion Cascade.

Łukasz Przykaza

doi:10.3389/fimmu.2021.782569

Abstract

Despite the enormous progress in the understanding of the course of the ischemic stroke over the last few decades, a therapy that effectively protects neurovascular units (NVUs) and significantly improves neurological functions in stroke patients has still not been achieved. The reasons for this state are unclear, but it is obvious that the cerebral ischemia and reperfusion cascade is a highly complex phenomenon, which includes the intense neuroinflammatory processes, and comorbid stroke risk factors strongly worsen stroke outcomes and likely make a substantial contribution to the pathophysiology of the ischemia/reperfusion, enhancing difficulties in searching of successful treatment. Common concomitant stroke risk factors (arterial hypertension, diabetes mellitus and hyperlipidemia) strongly drive inflammatory processes during cerebral ischemia/reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of NVUs. Broad consideration of this situation in basic research may prove to be crucial for the success of future clinical trials of neuroprotection, vasculoprotection and immunomodulation in stroke. This review focuses on the mechanism by which coexisting common risk factors for stroke intertwine in cerebral ischemic/reperfusion cascade and the dysfunction and disintegration of NVUs through inflammatory processes, principally activation of pattern recognition receptors, alterations in the expression of adhesion molecules and the subsequent pathophysiological consequences.

Highlights

Ischemic stroke is a serious clinical and socioeconomic problem, especially among the aging populations of industrialized countries
Common concomitant stroke risk factors strongly drive inflammatory processes during cerebral ischemia/ reperfusion; because these factors are often present for a long time before a stroke, causing low-grade background inflammation in the brain, and already initially disrupting the proper functions of neurovascular units (NVUs)
Harmful factors such as glutamic acid and potassium ions, released in excessive concentrations from the infarct core, reach the surrounding penumbral area and cause gradual recruitment of the penumbra to the infarct core through excitotoxicity processes and recurrent peri-infarct depolarizations, which cause the production of reactive oxygen species (ROS) and RNS, increased expression MMP-9 and MMP-2, disturbances in communication between components of the neurovascular units, and further hemodynamic disturbances during reperfusion

Summary

INTRODUCTION

Ischemic stroke is a serious clinical and socioeconomic problem, especially among the aging populations of industrialized countries. Chronically elevated blood cholesterol levels result in endothelial disturbances and increased adhesion of leukocytes and platelets during ischemia/reperfusion [12,13,14] These observations constitute important clinical indications for research in the field of ischemic stroke neuroprotection, vasculoprotection and immunomodulation, and for widespread preclinical studies with animal models with modeled risk factors for stroke in humans. It is commonly accepted that damage to NVUs in the penumbra occurs as a consequence of a combination of numerous factors of a diverse nature – such as excitotoxicity, peri-infarct depolarizations (PIDs), free radical stress, apoptosis, inflammatory processes, cerebral blood vessel damage, and microcirculatory disturbances during ischemia and reperfusion. Inflammatory processes begin; activated peripheral leukocytes migrate to brain tissues, contributing to brain tissue damage, the aggravation of BBB disruption and vasogenic edema, as well as hemorrhagic transformation (HT); and blood cellular elements create intravascular conglomerates that impair microcirculation [42, 43]

Inflammatory Processes in the Course of Ischemic Stroke

Findings

SUMMARY