Search for: All records

Acute stroke causes complex, pathological, and systemic responses that have not been treatable by any single medication. In this study, using a murine transient middle cerebral artery occlusion stroke model, a novel therapeutic strategy is proposed, where blood replacement (BR) robustly reduces infarctions and improves neurological deficits in mice. Our analyses of immune cell subsets suggest that BR therapy substantially decreases neutrophils in blood following a stroke. Electrochemiluminescence detection demonstrates that BR therapy reduces cytokine storm in plasma and ELISA demonstrates reduced levels of matrix metalloproteinase-9 (MMP-9) in the plasma and brains at different time points post-stroke. Further, we have demonstrated that the addition of MMP-9 to the blood diminishes the protective effect of the BR therapy. Our study is the first to show that BR therapy leads to profoundly improved stroke outcomes in mice and that the improved outcomes are mediated via MMP-9. These results offer new insights into the mechanisms of stroke damage.

 

Abstract Cell specific-targeted therapy (CSTT) for acute ischemic stroke remains underdeveloped. Cerebrovascular endothelial cells (CECs) are key components of the blood–brain barrier and are the first brain cells affected by ischemic stroke. After stroke, CEC injury causes insufficient energy supply to neurons and leads to cytotoxic and vasogenic brain edema. Aptamers are short single-stranded RNA or DNA molecules that can bind to specific ligands for cell specific delivery. The expression of vascular cell adhesion molecule-1 (VCAM-1) is increased on CECs after stroke. Herein, we report that an RNA-based VCAM-1-aptamer can specifically target CECs in stroke brains following transient middle cerebral artery occlusion in mice. Our data demonstrate the potential of an RNA-based aptamer as an effective delivery platform to target CECs after stroke. We believe this method will allow for the development of CSTT for treatment of patients with stroke. 

Abstract Background Cerebral edema (CE) at admission is a surrogate marker of ‘early brain injury’ (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH. Methods Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0–4 ‘subarachnoid hemorrhage early brain edema score’ (SEBES). SEBES ≤ 2 and SEBES ≥ 3 were considered good and poor grade, respectively. Serum samples from the same subject cohort were collected at 4 time periods (at < 24 h [T1], at 24 to 48 h [T2]. 3–5 days [T3] and 6–8 days [T4] post-admission) and concentration levels of 17 cytokines (implicated in peripheral inflammatory processes) were measured by multiplex immunoassay. Multivariable logistic regression analyses were step-wisely performed to identify cytokines independently associated with persistent CE adjusting for covariables including age, sex and past medical history (model 1), and additional inclusion of clinical and radiographic severity of SAH and treatment modality (model 2). Results Of the 135 patients enrolled in the study, 21 of 135 subjects (15.6%) showed a persistently poor SEBES grade. In multivariate model 1, higher Eotaxin (at T1 and T4), sCD40L (at T4), IL-6 (at T1 and T3) and TNF-α (at T4) were independently associated with persistent CE. In multivariate model 2, Eotaxin (at T4: odds ratio [OR] = 1.019, 95% confidence interval [CI] = 1.002–1.035) and possibly PDGF-AA (at T4), sCD40L (at T4), and TNF-α (at T4) was associated with persistent CE. Conclusions We identified serum cytokines at different time points that were independently associated with persistent CE. Specifically, persistent elevations of Eotaxin is associated with persistent CE after SAH. 

Ischemic stroke is a serious cerebrovascular event that results in cell death, blood-brain barrier dysfunction, tissue degradation, and inflammation, often leading to permanent disability or death. As the incidence of ischemic stroke continues to rise globally, it is crucial to examine the mechanisms of the various proteins and molecules contributing to worsened patient outcome and recovery. Cathepsin L, a cysteine protease known for degrading tissues in lysosomes and elsewhere, may play a role in brain tissue loss and inflammation after stroke. Studies have suggested that cathepsin L appears in the ischemic core shortly after stroke is induced. Using immunohistochemical staining, mass spectrometry, and other assays, the increase of cathepsin L in the brain was correlated with extracellular matrix and perlecan degradation after ischemic stroke. Additionally, injection of a cathepsin L inhibitor significantly reduced brain infarct size and improved functional scores. More research is needed to elucidate cathepsin L's role in post-stroke inflammation and brain damage, in order to further explore the factors contributing to worsened patient outcome after ischemic stroke and work toward finding better therapeutic interventions. 

Stroke is an overwhelming neurological disease with very limited treatment options. As blood-brain barrier (BBB) integrity is well-implicated in the prevention of brain injury, its regulation may prove beneficial for stroke patients. BBB cerebro-vascular endothelial cells primarily utilize mitochondria as their energy-producing source, and mitochondrial function has revealed importance in outcomes for tissue post-stroke. In this review, bioenergetics in relation to BBB permeability in stroke is discussed. Moreover, what causes mitochondrial dysfunction following stroke is explored. 

Chronic brain hypoperfusion is the primary cause of vascular dementia and has been implicated in the development of white matter disease and lacunar infarcts. Cerebral hypoperfusion leads to a chronic state of brain inflammation with immune cell activation and production of pro-inflammatory cytokines, including IL-1β. In the present study, we induced chronic, progressive brain hypoperfusion in mice using ameroid constrictor, arterial stenosis (ACAS) surgery and tested the efficacy of an IL-1β antibody on the resulting brain damage. We observed that ACAS surgery causes a reduction in cerebral blood flow (CBF) of about 30% and grey and white matter damage in and around the hippocampus. The IL-1β antibody treatment did not significantly affect CBF but largely eliminated grey matter damage and reduced white matter damage caused by ACAS surgery. Over the course of hypoperfusion/injury, grip strength, coordination, and memory-related behavior were not significantly affected by ACAS surgery or antibody treatment. We conclude that antibody neutralization of IL-1β is protective from the brain damage caused by chronic, progressive brain hypoperfusion.