Translational stroke research
-
Stroke, resulting from limited blood flow to the brain, is one of the most important causes of morbidity and mortality worldwide. Stroke is classified as ischemic, due to lack of blood flow, or hemorrhagic, due to bleeding. Because 87 % of strokes are classified as ischemic, this type will be the predominant focus of this review. ⋯ However, these approaches have not led to successful clinical outcomes. This review addresses the pathophysiology of stroke, neurogenesis after stroke, and how to stimulate these processes based on the current literature. Finally, ongoing clinical trials to improve neurological functions after stroke by enhancing neurogenesis are discussed in this review.
-
Oxidative stress plays an important role in cerebral ischemia-reperfusion injury. Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) are antioxidant agents that can activate the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and induce the expression of antioxidant proteins. Here, we evaluated the impact of DMF and MMF on ischemia-induced brain injury and whether the Nrf2 pathway mediates the effects provided by DMF and MMF in cerebral ischemia-reperfusion injury. ⋯ Further, DMF and MMF suppress glial activation following brain ischemia. Importantly, the protection of DMF and MMF was mostly evident during the subacute stage and was abolished in Nrf2-/- mice, indicating that the Nrf2 pathway is required for the beneficial effects of DMF and MMF. Together, our data indicate that DMF and MMF have therapeutic potential in cerebral ischemia-reperfusion injury and their protective role is likely mediated by the Nrf2 pathway.
-
Anesthetics have enabled major advances in development of experimental models of human stroke. Yet, their profound pharmacologic effects on neural function can confound the interpretation of experimental stroke research. Anesthetics have species-, drug-, and dose-specific effects on cerebral blood flow and metabolism, neurovascular coupling, autoregulation, ischemic depolarizations, excitotoxicity, inflammation, neural networks, and numerous molecular pathways relevant for stroke outcome. ⋯ Anesthetics also modulate systemic arterial blood pressure, lung ventilation, and thermoregulation, all of which may interact with the ischemic insult as well as the therapeutic interventions. These confounds present a dilemma. Here, we provide an overview of the anesthetic mechanisms of action and molecular and physiologic effects on factors relevant to stroke outcomes that can guide the choice and optimization of the anesthetic regimen in experimental stroke.
-
The present study investigates the association between hour-to-hour blood pressure (BP) variability and severe hemorrhagic transformation (HT) after intravenous thrombolysis (IVT) during hyperacute stage. We analyzed hour-to-hour BP measurement within 24 h after IVT in patients with acute ischemic stroke. We calculated the maximum, minimum, and average (mean) of 24-h BP values, and BP variability profiles including standard deviation (SD), average squared difference between successive measurements (SV), average squared difference between rise and drop successive measurements (SV rise and SV drop), and maximum of SV rise and SV drop (SVrisemax and SVdropmax) after quartering 0-to-24 h BP course. ⋯ Binary logistic regression indicated that SBPSD and SBPSV within the first 24 h were associated with sICH (OR, 4.538; 95 % CI, 1.834-11.230; p = 0.001 and OR, 6.117; 95 % CI, 2.000-18.711; p = 0.002) and PH (OR, 2.146; 95 % CI, 1.106-4.165; p = 0.024 and OR, 2.202; 95 % CI, 1.046-4.633; p = 0.038). For the SBP SV parameters among four periods of the initial 24 h, only SV, SVrise, and SVrisemax during the first 6 h were significantly associated with sICH (OR, 2.785; 95 % CI, 1.294-5.994; p = 0.009; OR, 1.825; 95 % CI, 1.110-3.002; p = 0.018 and OR, 1.495; 95 % CI, 1.039-2.149; p = 0.030) and PH (OR, 2.088; 95 % CI, 1.287-3.387; p = 0.003; OR, 1.501; 95 % CI, 1.044-2.156; p = 0.028 and OR, 1.334; 95 % CI, 1.023-1.739; p = 0.033). High systolic BP variability during the first 6 h after IVT was related with severe HTs, which highlights the potential predictability to severe HTs.
-
Partial MHC Constructs Treat Thromboembolic Ischemic Stroke Characterized by Early Immune Expansion.
Inflammation and thrombosis are tightly linked, with inflammation contributing to thromboembolism and to stroke outcome. Thromboembolism is a frequent cause of ischemic stroke; yet, the most used occlusion mouse models of experimental stroke do not effectively replicate thromboembolism. Our group recently described a novel thromboembolic mouse model of stroke that successfully occludes the middle cerebral artery with high reproducibility. ⋯ Brain and spleen tissues were harvested 24 h after thromboembolic stroke and cells immunophenotyped by flow cytometry. We observed a significant increase in neutrophils and early activated T cells in the spleen and an increase in neutrophils and activated monocytes/microglia in the ischemic cortex after thromboembolic stroke. Moreover, as was shown previously for transient MCAO models, treatment of thromboembolic stroke with partial MHC constructs significantly reduced ischemic damage indicating an equivalent effect of this immune-based therapy in the thromboembolic model that better mimics the pathophysiology of human stroke.