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.

Neuroinflammation in Cerebral Ischemia and Ischemia/Reperfusion Injuries: From Pathophysiology to Therapeutic Strategies

“…Resting NLRP3 is situated at the endoplasmic reticulum. In step two, an effector domain (pyrin domain, or PYD) is oligomerized in the NLRP3 central domain, serving as a girder for ADC adaptor protein (apoptosis-associated speck-like protein containing a carboxy-terminal CARD), which combines with procaspase-1 and forms the NLRP3 inflammasome [ 146 ]. This, in turn, by using the CARD (caspase activation and recruitment domain), activates procaspase-1 to caspase-1 and splits pro-IL-1β into its active form [ 147 ], leading to pyroptosis, a specific type of cell death [ 141 ].…”

Pathogenetic Mechanisms of Hypertension–Brain-Induced Complications: Focus on Molecular Mediators

“…They include tumour necrosis factor-alfa (TNF-α), interleukin (IL) 1α, IL-1β, chemokine (C-X-C motif) ligand 7 (CXCL7), chemokine (C-C motif), ligand 5 (CCL5), chemokine (C-X-C motif) ligand 4 (CXCL4), chemokine (C-X3-C motif) ligand 1 (CX3CL1), adhesion molecules, proteases, prostanoids and leukotrienes, while IL-1, IL-10, TNF-α, IL-6, IL-20, IL-17, NADPH oxidase, chemokine (C-X-C motif) ligand 8 (CXCL8), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are involved in the enhancement phase of this process. In addition, other molecules, including transforming growth factor β (TGF-β), IL-17, IL-10 and IL-23, mediate the resolution phase [ 18 , 19 , 88 , 89 , 90 , 91 , 92 , 93 ].…”

“…Finally, some molecules such as the neutrophil-to-lymphocyte ratio family pyrin domain-containing 3 (NLRP3) inflammasome, Dickkopf WNT Signalling Pathway Inhibitor 3 (DKK-3), dectin-1, MKEY and microRNAs (miRNAs), as well as being implicated in the course of neuroinflammation [ 18 , 19 , 86 , 88 , 89 , 90 , 91 , 92 , 93 ], have shown to have interesting characteristics that can attribute a target role in the management of brain damage, and they are summarized as follows: The NLRP3 inflammasome is responsible for the activation of IL-1β and the release of IL-18, which phosphorylate insulin receptor substrate 1 (IRS-1), worsening insulin resistance and causing neuronal death. The NLRP3 inflammasome is one of the primary mediators contributing to the neuroinflammation process and consequent brain damage [ 88 ].…”

“…A series of changes occur in the cardiovascular system during this long period, including cerebral circulation. These changes, such as vascular remodelling, inflammation, oxidative stress, baroreflex dysfunction, etc., may contribute to the pathogenesis of stroke in hypertension [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ] ( Figure 1 ).…”

Toll-Like Receptor Signaling Pathways: Novel Therapeutic Targets for Cerebrovascular Disorders

“…Numerous amounts of evidence revealed that hypoxic-ischemic insults and neuroinflammation attribute to the pathogenic mechanisms of CVDs [ 22 , 23 ]. Increasing evidence suggests the crucial role of TLRs in the pathogenesis of AIS [ 24 , 25 ], ICH [ 26 , 27 ], and SAH [ 28 ].…”