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

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.

Keywords: adhesion molecules; cerebral ischemia/reperfusion; inflammation; neurovascular unit; stroke comorbidities.

Figure 1

The diagram showing the hypothetical links between common stroke comorbidities (arterial hypertension, diabetes mellitus and hyperlipidemia), inflammatory processes and the course of cerebral ischemia/reperfusion cascade. The comorbid risk factors enhance the influence of the inflammatory processes on the course of the ischemia/reperfusion cascade, contributing to the processes leading to the damage and dysfunction of the neurovascular unit in the penumbra. Inflammatory processes, together with the primary outcomes of the ischemic cascade, form a vicious cycle – where they constitute an amplifying point, and the connecting bridge point, between risk factors and the ischemic cascade. The detailed description is provided in the text. ROS, reactive oxygen species; RNS, reactive nitrogen species; DAMPs, danger associated molecular patterns; TLR4, toll like receptor 4; RAGE, receptor for advanced glycation end products; CD36, platelet glycoprotein 4; MyD88, myeloid differentiation primary response protein (innate immune signal transduction adaptor); NF-κB, nuclear factor kappa B; AP-1, activator protein 1; MMP-9, matrix metalloproteinase-9; GFAP, glial fibrillary acidic protein; AQP4, aquaporin-4; BBB, blood-brain barrier; ↑, upregulation; ↓, downregulation.