The precise regulation of blood-brain barrier (BBB) permeability for immune cells and blood-borne substances is essential to maintain brain homeostasis. Sphingosine-1-phosphate (S1P), a lipid signaling molecule enriched in plasma, is known to affect BBB permeability. Previous studies focused on endothelial S1P receptors 1 and 2, reporting a barrier-protective effect of S1P1 and a barrier-disruptive effect of S1P2. Here, we present novel data characterizing the expression, localization, and function of the S1P receptor 4 (S1P4) on primary brain microvascular endothelial cells (BMECs). Hitherto, the receptor was deemed to be exclusively immune cell associated. We detected a robust expression of S1P4 in homeostatic murine BMECs (MBMECs), bovine BMECs (BBMECs), and porcine BMECs (PBMECs) and pinpointed its localization to abluminal endothelial membranes via immunoblotting of fractionated brain endothelial membrane fragments. Apical S1P treatment of BMECs tightened the endothelial barrierin vitro, whereas basolateral S1P treatment led to an increased permeability that correlated with S1P4 downregulation. Likewise, downregulation of S1P4 was observed in mouse brain microvessels (MBMVs) after stroke, a neurologic disease associated with BBB impairment. RNA sequencing and qPCR analysis of BMECs suggested the involvement of S1P4 in endothelial homeostasis and barrier function. Using S1P4 knock-out (KO) mice and S1P4 siRNA as well as pharmacological agonists and antagonists of S1P4 bothin vitroandin vivo, we demonstrate an overall barrier-protective function of S1P4. We therefore suggest S1P4 as a novel target regulating BBB permeability and propose its therapeutic potential in CNS diseases associated with BBB dysfunction.SIGNIFICANCE STATEMENTMany neurologic diseases including multiple sclerosis and stroke are associated with blood-brain barrier (BBB) impairment and disturbed brain homeostasis. Sphingosine-1-phosphate receptors (S1PRs) are potent regulators of endothelial permeability and pharmacological S1PR modulators are already in clinical use. However, the precise role of S1P for BBB permeability regulation and the function of receptors other than S1P1 and S1P2 therein are still unclear. Our study shows both barrier-disruptive and barrier-protective effects of S1P at the BBB that depend on receptor polarization. We demonstrate the expression and novel barrier-protective function of S1P4 in brain endothelial cells and pinpoint its localization to abluminal membranes. Our work may contribute to the development of novel specific S1PR modulators for the treatment of neurologic diseases associated with BBB impairment.

Aneurysmal subarachnoid hemorrhage (SAH) involves a significant influx of blood into the cerebrospinal fluid, representing a severe form of stroke. Despite advancements in aneurysm closure and neuro-intensive care, outcomes remain impaired due to cerebral vasospasm and delayed cerebral ischemia (DCI). Previous pharmacological therapies have not successfully reduced DCI while improving overall outcomes. As a result, significant efforts are underway to better understand the cellular and molecular mechanisms involved. This review focuses on the activation and effects of immune cells after SAH and their interactions with neurotoxic and vasoactive substances as well as inflammatory mediators. Particular attention is given to clinical studies highlighting the roles of natural killer (NK) cells and regulatory T cells (Treg) cells. Alongside microglia, astrocytes, and oligodendrocytes, NK cells and Treg cells are key contributors to the inflammatory cascade following SAH. Their involvement in modulating the neuro-inflammatory response, vasospasm, and DCI underscores their potential as therapeutic targets and prognostic markers in the post-SAH recovery process. We conducted a systematic review on T cell- and natural killer cell-mediated inflammation and their roles in cerebral vasospasm and delayed cerebral ischemia. We conducted a meta-analysis to evaluate outcomes and mortality in studies focused on NK cell- and T cell-mediated mechanisms.

Local anesthetics are commonly administered by nuchal infiltration to provide a temporary interscalene brachial plexus block (ISB) in a surgical setting. Although less commonly reported, local anesthetics can induce central nervous system toxicity. In this case study, we present three patients with acute central nervous system toxicity induced by local anesthetics applied during ISB with emphasis on neurological symptoms, key neuroradiological findings and functional outcome. Medical history, clinical and imaging findings, and outcome of three patients with local anesthetic-induced toxic left hemisphere syndrome during left ISB were analyzed. All patients were admitted to our neurological intensive care unit between November 2016 and September 2019. All three patients presented in poor clinical condition with impaired consciousness and left hemisphere syndrome. Electroencephalography revealed slow wave activity in the affected hemisphere of all patients. Seizure activity with progression to status epilepticus was observed in one patient. In two out of three patients, cortical FLAIR hyperintensities and restricted diffusion in the territory of the left internal carotid artery were observed in magnetic resonance imaging. Assessment of neurological severity scores revealed spontaneous partial reversibility of neurological symptoms. Local anesthetic-induced CNS toxicity during ISB can lead to severe neurological impairment and anatomically variable cerebral lesions.

Background: The burden of stroke weighs heavily in developing countries where recurrence rates clearly exceed that of developed countries. The impact of nonadherence to antithrombotic treatment within this context has been poorly investigated. Objective: The objective of this study was to evaluate patients with recurrent ischemic stroke in Egypt and Germany with focus on stroke subtype distribution and adherence to antithrombotic therapy. Methods: We conducted a comparative cross-sectional retrospective cohort study enrolling consecutive patients hospitalized for recurrent ischemic stroke in 2017 in 2 academic centers. Data were collected on demographics, risk factors, stroke subtypes, and medication adherence. Nonadherence to antithrombotic agents was analyzed at the time point of index stroke (recurrent stroke). Predictors of nonadherence were analyzed using logistic regression. Results: A total of 373 Egyptian and 468 German patients with ischemic stroke were included. The proportion of recurrent ischemic stroke among all patients was higher in the Egyptian cohort compared to the German cohort (33 vs. 10%, p < 0.05). Small-vessel occlusion stroke was the most frequent subtype in Egyptians, with a significantly greater proportion than in Germans (45 vs. 26%, p < 0.05). Nonadherence to antiplatelets at the time point of the recurrent stroke was higher in Egyptians than in Germans (82 vs. 19%, p < 0.001). Low educational attainment among Egyptians (OR 0.14, 95% CI [0.00–0.19], p < 0.01) and high comorbidity scores among Germans (OR 2.45, 95% CI [1.06–5.66], p < 0.05) were found to be predictors of nonadherence to antithrombotic treatment. Conclusions: The large stroke recurrence burden in Egypt may be partly explained by differing adherence to secondary preventative antithrombotic pharmacotherapy. Predictors of medication nonadherence have to be addressed to reduce stroke recurrence disparities.

Despite the enormous health burden of lacunar stroke, data from low- and middle-income countries on lacunar stroke characteristics and its comparison with that of high-income countries are scarce. Thus, we aimed to investigate and compare the variable characteristics and vascular status in patients from Egypt and Germany suffering lacunar stroke. Two cohorts of lacunar stroke patients from Ain Shams University Hospital, Egypt and Goethe University Hospital Frankfurt, Germany were retrospectively collected between January 2019 and December 2020 and analyzed for demographics, risk factors, mode of presentation, neuroimaging features, treatment protocols and outcomes. MRI showed a different distribution pattern of lacunar strokes between cohorts, detecting posterior circulation lacunar infarctions preponderantly in patients from Egypt and anterior circulation lacunar infarctions preponderantly in patients from Germany. Complementary MR/CT angiography revealed a significantly higher proportion of intracranial and combined intracranial and extracranial arterial stenosis in patients from Egypt than in patients from Germany, suggesting differences in pathological processes. Younger age, higher NIHSS on admission, and posterior circulation lacunar infarction were predictors of Egyptian origin, whereas hypertension was a predictor of German origin. Our results support the idea of clinical and neuroimaging phenotype variations in lacunar stroke, including different sources of lacunar stroke in patients of different populations and geographical regions. This implies that guidelines for management of lacunar stroke might be tailored to these differences accordingly.