Potential Role of Soluble Toll-like Receptors 2 and 4 as Therapeutic Agents in Stroke and Brain Hemorrhage.

Hemolysis is a physiological condition in which red blood cells (RBCs) lyse, releasing their contents into the extracellular environment. Hemolysis can be a manifestation of several diseases and conditions, such as sickle cell disease, hemorrhagic stroke, and trauma. Heme and hemoglobin are among the unique contents of RBCs that are released into the environment. Although these contents can cause oxidative stress, especially when oxidized in the extracellular environment, they can also initiate a proinflammatory response because they bind to receptors such as the Toll-like receptor (TLR) family. This review seeks to clarify the mechanism by which TLRs initiate a proinflammatory response to heme, hemoglobin, and their oxidized derivatives, as well as the possibility of using soluble TLRs (sTLRs) as therapeutic agents. Furthermore, this review explores the possibility of using sTLRs in hemorrhagic disorders in which mitigating inflammation is essential for clinical outcomes, including hemorrhagic stroke and its subtypes, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH).

Soluble Receptors Affecting Stroke Outcomes: Potential Biomarkers and Therapeutic Tools.

Soluble receptors are widely understood to be freestanding moieties formed via cleavage from their membrane-bound counterparts. They have unique structures, are found among various receptor families, and have intriguing mechanisms of generation and release. Soluble receptors' ability to exhibit pleiotropic action by receptor modulation or by exhibiting a dual role in cytoprotection and neuroinflammation is concentration dependent and has continually mystified researchers. Here, we have compiled findings from preclinical and clinical studies to provide insights into the role of soluble/decoy receptors, focusing on the soluble cluster of differentiation 36, the soluble cluster of differentiation 163, and soluble lipoprotein-related protein 1 (sCD36, sCD163, and sLRP1, respectively) and the functions they could likely serve in the management of stroke, as they would notably regulate the bioavailability of the hemoglobin and heme after red blood cell lysis. The key roles that these soluble receptors play in inflammation, oxidative stress, and the related pharmacotherapeutic potential in improving stroke outcomes are described. The precise pleiotropic physiological functions of soluble receptors remain unclear, and further scientific investigation/validation is required to establish their respective role in diagnosis and therapy.

Critical Role of Hemopexin Mediated Cytoprotection in the Pathophysiology of Sickle Cell Disease.

Circulating hemopexin is the primary protein responsible for the clearance of heme; therefore, it is a systemic combatant against deleterious inflammation and oxidative stress induced by the presence of free heme. This role of hemopexin is critical in hemolytic pathophysiology. In this review, we outline the current research regarding how the dynamic activity of hemopexin is implicated in sickle cell disease, which is characterized by a pathological aggregation of red blood cells and excessive hemolysis. This pathophysiology leads to symptoms such as acute kidney injury, vaso-occlusion, ischemic stroke, pain crises, and pulmonary hypertension exacerbated by the presence of free heme and hemoglobin. This review includes in vivo studies in mouse, rat, and guinea pig models of sickle cell disease, as well as studies in human samples. In summary, the current research indicates that hemopexin is likely protective against these symptoms and that rectifying depleted hemopexin in patients with sickle cell disease could improve or prevent the symptoms. The data compiled in this review suggest that further preclinical and clinical research should be conducted to uncover pathways of hemopexin in pathological states to evaluate its potential clinical function as both a biomarker and therapy for sickle cell disease and related hemoglobinopathies.

Contribution of Various Types of Transfusion to Acute and Delayed Intracerebral Hemorrhage Injury.

Intracerebral hemorrhage (ICH) is the second most prevalent type of stroke, after ischemic stroke, and has exceptionally high morbidity and mortality rates. After spontaneous ICH, one primary goal is to restrict hematoma expansion, and the second is to limit brain edema and secondary injury. Various types of transfusion therapies have been studied as treatment options to alleviate the adverse effects of ICH etiopathology. The objective of this work is to review transfusions with platelets, fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and red blood cells (RBCs) in patients with ICH. Furthermore, tranexamic acid infusion studies have been included due to its connection to ICH and hematoma expansion. As stated, the first line of therapy is limiting bleeding in the brain and hematoma expansion. Platelet transfusion is used to promote recovery and mitigate brain damage, notably in patients with severe thrombocytopenia. Additionally, tranexamic acid infusion, FFP, and PCC transfusion have been shown to affect hematoma expansion rate and volume. Although there is limited available research, RBC transfusions have been shown to cause higher tissue oxygenation and lower mortality, notably after brain edema, increases in intracranial pressure, and hypoxia. However, these types of transfusion have varied results depending on the patient, hemostasis status/blood thinner, hemolysis, anemia, and complications, among other variables. Inconsistencies in published results on various transfusion therapies led us to review the data and discuss issues that need to be considered when establishing future guidelines for patients with ICH.

Nutritional Supplementation of Naturally Occurring Vitamin D to Improve Hemorrhagic Stroke Outcomes.

Vitamin D deficiency, if left untreated, is associated with bone disorders, cardiovascular damage, and an increased risk of ischemic stroke. While there are various nutritional options for the natural intake of vitamin D, we hope to elucidate the potential mechanisms dietary vitamin D may play in hemorrhagic stroke pathology. This scoping review outlines findings from studies relevant to the biochemical activity of vitamin D, the impact of vitamin D deficiency on hemorrhagic stroke outcomes, and the potential benefit of nutritional vitamin D on hemorrhagic stroke outcomes. Here, we analyze the relevant factors that can lead to vitamin D deficiency, and subsequently, a higher risk of hemorrhagic stroke incidence with worsened subsequent outcomes. The neuroprotective mechanisms through which vitamin D works to attenuate hemorrhagic stroke onset and post-stroke outcomes have not yet been thoroughly examined. However, researchers have proposed several potential protective mechanisms, including reduction of blood brain barrier disturbance by inhibiting the production of reactive oxygen species, mitigation of inflammation through a reduction of levels of proinflammatory cytokines, and prevention of cerebral vasospasm and delayed cerebral ischemia following subarachnoid hemorrhage and intracerebral hemorrhage. While more research is needed and there are limitations to vitamin D supplementation, vitamin D as a whole may play a significant role in the dynamics of hemorrhagic stroke. Further research should focus on expanding our understanding of the neuroprotective capacity and mechanisms of vitamin D, as well as how vitamin D supplementation could serve as an effective course of treatment of hemorrhagic strokes.