Molecular Biology of Atherosclerotic Ischemic Strokes

Abstract

Among the causes of global death and disability, ischemic stroke (also known as cerebral ischemia) plays a pivotal role, by determining the highest number of worldwide mortality, behind cardiomyopathies, affecting 30 million people. The etiopathogenetic burden of a cerebrovascular accident could be brain ischemia (~80%) or intracranial hemorrhage (~20%). The most common site when ischemia occurs is the one is perfused by middle cerebral arteries. Worse prognosis and disablement consequent to brain damage occur in elderly patients or affected by neurological impairment, hypertension, dyslipidemia, and diabetes. Since, in the coming years, estimates predict an exponential increase of people who have diabetes, the disease mentioned above constitutes together with stroke a severe social and economic burden. In diabetic patients after an ischemic stroke, an exorbitant activation of inflammatory molecular pathways and ongoing inflammation is responsible for more severe brain injury and impairment, promoting the advancement of ischemic stroke and diabetes. Considering that the ominous prognosis of ischemic brain damage could by partially clarified by way of already known risk factors the auspice would be modifying poor outcome in the post-stroke phase detecting novel biomolecules associated with poor prognosis and targeting them for revolutionary therapeutic strategies.

Keywords: AF; BBB; CD200-CD200R; DKK-3; Dectin-1; MKEY; NLRP3 inflammasome; atherosclerosis; ischemic stroke; microRNAs; microglia; neuroinflammation.

Figure 1

The NLRP3 inflammasome plays a fundamental part in the process of neuroinflammation consequent to a cerebrovascular accident, particularly in diabetic patients in which enhances the progression of metabolic disorder. The figure above illustrates three hypothetic etiopathogenetic factors such as lysosomal rupture, ROS and cellular potassium efflux, which are co-responsible of the activation of caspase 1, triggering the release of mediators of inflammation like cytokines IL-18 and IL-1β. In the macrophages of adipose tissue, the activation of NLRP3 inflammasome is determined by the release of DNA and the production of ROS in mitochondria, through the desegregation of TRX-TXNIP complex. After its triggering, NLRP3 inflammasome provokes the cleavage of pro-IL-1β into IL1-1β, the active form, and the release of IL-18. These cytokines phosphorylate IRS-1, as known as the insulin receptor substrate-1, worsening insulin- resistance and causing neuronal death.

Figure 2

Dectin-1, also known as Dendritic cell-associated C-type lectin-1, a receptor activated by the interaction with DAMPs (damage-associated molecular patterns), is responsible for an innate immune response when brain damage such cerebral ischemia occurs. The crosstalk between Dectin-1 and DAMPs determines phosphorylation of ITAM and, subsequently, of Syk, a kinase which mediates a cascade of neuroinflammation and the release of several cytokines. Some antagonist molecules of Dectin-1 like Syk inhibitor piceatannol and laminarin can underregulate this process, reducing the detrimental effects of neuroinflammation on brain damage after a stroke.