Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies

蛛网膜下腔出血后脑脊液室中的红细胞: 意义和新兴治疗策略

Subarachnoid haemorrhage (SAH) is a subtype of stroke that predominantly impacts younger individuals. It is associated with high mortality rates and can cause long-term disabilities. This review examines the contribution of the initial blood load and the dynamics of clot clearance to the pathophysiology of SAH and the risk of adverse outcomes. These outcomes include hydrocephalus and delayed cerebral ischaemia (DCI), with a particular focus on the impact of blood located in the cisternal spaces, as opposed to ventricular blood, in the development of DCI. The literature described underscores the prognostic value of haematoma characteristics, such as volume, density, and anatomical location. The limitations of traditional radiographic grading systems are discussed, compared with the more accurate volumetric quantification techniques for predicting patient prognosis. Further, the significance of red blood cells (RBCs) and their breakdown products in secondary brain injury after SAH is explored. The review presents novel interventions designed to accelerate clot clearance or mitigate the effects of toxic byproducts released from erythrolysis in the cerebrospinal fluid following SAH. In conclusion, this review offers deeper insights into the complex dynamics of SAH and discusses the potential pathways available for advancing its management.

蛛网膜下腔出血 (SAH) 是中风的一种亚型，主要影响年轻人。它与高死亡率相关，并可能导致长期残疾。这篇综述研究了初始血液负荷和凝块清除动力学对SAH病理生理学的贡献以及不良结局的风险。这些结果包括脑积水和迟发性脑缺血 (DCI)，特别关注位于脑池空间的血液而不是脑室血液在DCI发展中的影响。所描述的文献强调了血肿特征的预后价值，例如体积，密度和解剖位置。与用于预测患者预后的更准确的体积量化技术相比，讨论了传统射线照相分级系统的局限性。此外，探讨了SAH后继发性脑损伤中红细胞 (rbc) 及其分解产物的重要性。该综述提出了旨在加速凝块清除或减轻SAH后脑脊液中红细胞裂解释放的有毒副产物的影响的新型干预措施。总之，本综述对SAH的复杂动力学提供了更深入的见解，并讨论了可用于推进其管理的潜在途径。

REF: Bandyopadhyay S, Schwendinger N, Jahromi BR, et al. Red Blood Cells in the Cerebrospinal Fluid Compartment After Subarachnoid Haemorrhage: Significance and Emerging Therapeutic Strategies. Transl Stroke Res. Published online February 29, 2024. doi:10.1007/s12975-024-01238-9 PMID: 38418755

Similarities in the Electrographic Patterns of Delayed Cerebral Infarction and Brain Death After Aneurysmal and Traumatic Subarachnoid Hemorrhage

动脉瘤和外伤性蛛网膜下腔出血后迟发性脑梗死和脑死亡的电图模式的相似性

While subarachnoid hemorrhage is the second most common hemorrhagic stroke in epidemiologic studies, the recent DISCHARGE-1 trial has shown that in reality, three-quarters of focal brain damage after subarachnoid hemorrhage is ischemic. Two-fifths of these ischemic infarctions occur early and three-fifths are delayed. The vast majority are cortical infarcts whose pathomorphology corresponds to anemic infarcts. Therefore, we propose in this review that subarachnoid hemorrhage as an ischemic-hemorrhagic stroke is rather a third, separate entity in addition to purely ischemic or hemorrhagic strokes. Cumulative focal brain damage, determined by neuroimaging after the first 2 weeks, is the strongest known predictor of patient outcome half a year after the initial hemorrhage. Because of the unique ability to implant neuromonitoring probes at the brain surface before stroke onset and to perform longitudinal MRI scans before and after stroke, delayed cerebral ischemia is currently the stroke variant in humans whose pathophysiological details are by far the best characterized. Optoelectrodes located directly over newly developing delayed infarcts have shown that, as mechanistic correlates of infarct development, spreading depolarizations trigger (1) spreading ischemia, (2) severe hypoxia, (3) persistent activity depression, and (4) transition from clustered spreading depolarizations to a negative ultraslow potential. Furthermore, traumatic brain injury and subarachnoid hemorrhage are the second and third most common etiologies of brain death during continued systemic circulation. Here, we use examples to illustrate that although the pathophysiological cascades associated with brain death are global, they closely resemble the local cascades associated with the development of delayed cerebral infarcts.

虽然蛛网膜下腔出血是流行病学研究中第二常见的出血性中风，但最近的DISCHARGE-1试验表明，实际上，蛛网膜下腔出血后四分之三的局灶性脑损伤是缺血性的。这些缺血性梗塞中有五分之二发生在早期，5分之3发生延迟。绝大多数是皮质梗塞，其病理形态学对应于贫血性梗塞。因此，我们在这篇综述中建议，除了纯粹的缺血性或出血性中风之外，蛛网膜下腔出血作为缺血性出血性中风是第三个独立的实体。最初2周后通过神经影像学确定的累积性局灶性脑损伤是初次出血后半年患者预后的最强已知预测指标。由于具有在中风发作之前在脑表面植入神经监测探针并在中风之前和之后进行纵向MRI扫描的独特能力，因此延迟的脑缺血目前是人类的中风变体，其病理生理学细节是迄今为止最好的特征。直接位于新发生的延迟梗塞上方的光电极表明，作为梗塞发展的机械相关性，扩散的去极化触发 (1) 扩散的缺血，(2) 严重的缺氧，(3) 持续的活动抑制以及 (4) 从成簇的扩散去极化过渡到负的超低电位。此外，创伤性脑损伤和蛛网膜下腔出血是持续体循环期间脑死亡的第二和第三常见病因。在这里，我们使用示例来说明，尽管与脑死亡相关的病理生理级联是全球性的，但它们与与迟发性脑梗塞的发展相关的局部级联非常相似。

REF: Dreier JP, Lemale CL, Horst V, et al. Similarities in the Electrographic Patterns of Delayed Cerebral Infarction and Brain Death After Aneurysmal and Traumatic Subarachnoid Hemorrhage. Transl Stroke Res. Published online February 23, 2024. doi:10.1007/s12975-024-01237-w PMID: 38396252

Remote Ischemic Post-conditioning Reduces Cognitive Impairment in Rats Following Subarachnoid Hemorrhage: Possible Involvement in STAT3/STAT5 Phosphorylation and Th17/Treg Cell Homeostasis

远端缺血后处理减轻大鼠蛛网膜下腔出血后的认知障碍: 可能参与STAT3/STAT5磷酸化和Th17/Treg细胞稳态

The inflammatory response following subarachnoid hemorrhage (SAH) may lead to Early Brain Injury and subsequently contribute to poor prognosis such as cognitive impairment in patients. Currently, there is a lack of effective strategies for SAH to ameliorate inflammation and improve cognitive impairment in clinical. This study aims to examine the inhibitory impact of remote ischemic post-conditioning (RIPostC) on the body's inflammatory response by regulating Th17/Treg cell homeostasis after SAH. The ultimate goal is to search for potential early treatment targets for SAH. The rat SAH models were made by intravascular puncture of the internal carotid artery. The intervention of RIPostC was administered for three consecutive days immediately after successful modeling. Behavioral experiments including the Morris water maze and Y-maze tests were conducted to assess cognitive functions such as spatial memory, working memory, and learning abilities 2 weeks after successful modeling. The ratio of Th17 cells and Treg cells in the blood was detected using flow cytometry. Immunofluorescence was used to observe the infiltration of neutrophils into the brain. Signal transducers and activators of transcription 5 (STAT5) and signal transducers and activators of transcription 3 (STAT3) phosphorylation levels, receptor-related orphan receptor gamma-t (RORγt), and forkhead box protein P3 (Foxp3) levels were detected by Western blot. The levels of anti-inflammatory factors (IL-2, IL-10, IL-5, etc.) and pro-inflammatory factors (IL-6, IL-17, IL-18, TNF-α, IL-14, etc.) in blood were detected using Luminex Liquid Suspension Chip Assay. RIPostC significantly improved the cognitive impairment caused by SAH in rats. The results showed that infiltration of Th17 cells and neutrophils into brain tissue increased after SAH, leading to the release of pro-inflammatory factors (IL-6, IL-17, IL-18, and TNF-α). This response can be inhibited by RIPostC. Additionally, RIPostC facilitates the transfer of Treg from blood to the brain and triggers the release of anti-inflammatory (IL-2, IL-10, and IL-5) factors to suppress the inflammation following SAH. Finally, it was found that RIPostC increased the phosphorylation of STAT5 while decreasing the phosphorylation of STAT3. RIPostC reduces inflammation after SAH by partially balancing Th17/Treg cell homeostasis, which may be related to downregulation of STAT3 and upregulation of STAT5 phosphorylation, which ultimately alleviates cognitive impairment in rats. Targeting Th17/Treg cell homeostasis may be a promising strategy for early SAH treatment.

蛛网膜下腔出血 (SAH) 后的炎症反应可能导致早期脑损伤，并随后导致预后不良，例如患者的认知障碍。目前，临床上缺乏SAH改善炎症和改善认知障碍的有效策略。本研究旨在探讨远端缺血后适应 (RIPostC) 通过调节SAH后Th17/Treg细胞稳态对机体炎症反应的抑制作用。最终目标是寻找SAH的潜在早期治疗目标。通过颈内动脉血管内穿刺制作大鼠SAH模型。成功建模后立即连续三天给予RIPostC干预。成功建模后2周，进行了包括Morris水迷宫和Y迷宫测试在内的行为实验，以评估认知功能，例如空间记忆，工作记忆和学习能力。流式细胞术检测血液中Th17细胞和Treg细胞的比例。免疫荧光用于观察中性粒细胞向脑内的浸润。通过蛋白质印迹检测信号转导和转录激活因子5 (STAT5) 和信号转导和转录激活因子3 (STAT3) 的磷酸化水平、受体相关孤儿受体 γ-t (ror γ t) 和叉头框蛋白P3 (Foxp3) 水平。使用Luminex液体悬浮芯片法检测血液中抗炎因子 (IL-2、IL-10、IL-5等) 和促炎因子 (IL-6、IL-17、IL-18、tnf-α 、IL-14等) 的水平。RIPostC能明显改善SAH引起的大鼠认知功能障碍。结果表明，SAH后Th17细胞和中性粒细胞向脑组织的浸润增加，导致促炎因子 (IL-6，IL-17，IL-18和tnf-α) 的释放。RIPostC可以抑制这种反应。此外，RIPostC促进Treg从血液转移到大脑，并触发抗炎 (IL-2，IL-10和IL-5) 因子的释放，以抑制SAH后的炎症。最后，发现RIPostC增加了STAT5的磷酸化，同时降低了stat3的磷酸化。RIPostC通过部分平衡Th17/Treg细胞稳态来减轻SAH后的炎症，这可能与STAT3的下调和STAT5磷酸化的上调有关，从而最终减轻大鼠的认知障碍。靶向Th17/Treg细胞稳态可能是早期SAH治疗的有希望的策略。

REF: Zhu Y, Li X, Wen D, et al. Remote Ischemic Post-conditioning Reduces Cognitive Impairment in Rats Following Subarachnoid Hemorrhage: Possible Involvement in STAT3/STAT5 Phosphorylation and Th17/Treg Cell Homeostasis. Transl Stroke Res. Published online February 15, 2024. doi:10.1007/s12975-024-01235-y PMID: 38356020

Switching Off Vascular MAPK Signaling: A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage

关闭血管MAPK信号: 预防蛛网膜下腔出血后迟发性脑缺血的新策略

Patients who initially survive the rupture and repair of a brain aneurysm often take a devastating turn for the worse some days later and die or suffer permanent neurologic deficits. This catastrophic sequela is attributed to a delayed phase of global cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH), but we lack effective treatment. Here we present our view, based on 20 years of research, that the initial drop in blood flow at the time of rupture triggers genomic responses throughout the brain vasculature that manifest days later as increased vasoconstriction and decreased cerebral blood flow. We propose a novel treatment strategy to prevent DCI by early inhibition of the vascular mitogen-activated protein kinase (MAPK) pathway that triggers expression of vasoconstrictor and inflammatory mediators. We summarize evidence from experimental SAH models showing early treatment with MAPK inhibitors "switches off" these detrimental responses, maintains flow, and improves neurological outcome. This promising therapy is currently being evaluated in clinical trials.

最初在脑动脉瘤破裂和修复中幸存下来的患者通常会在几天后发生毁灭性的转折，并死亡或遭受永久性神经系统缺陷。这种灾难性的后遗症归因于动脉瘤性蛛网膜下腔出血 (aSAH) 后全脑缺血 (DCI) 的延迟期，但我们缺乏有效的治疗方法。在这里，我们根据20年的研究提出了我们的观点，即破裂时血流的初始下降触发了整个大脑血管系统的基因组反应，几天后表现为血管收缩增加和脑血流量减少。我们提出了一种新的治疗策略，通过早期抑制触发血管收缩剂和炎症介质表达的血管丝裂原活化蛋白激酶 (MAPK) 途径来预防DCI。我们总结了来自实验性SAH模型的证据，这些证据显示MAPK抑制剂的早期治疗 “关闭” 了这些有害反应，维持了血流并改善了神经系统结果。这种有希望的疗法目前正在临床试验中进行评估。

REF: Edvinsson L, Krause DN. Switching Off Vascular MAPK Signaling: A Novel Strategy to Prevent Delayed Cerebral Ischemia Following Subarachnoid Hemorrhage. Transl Stroke Res. Published online February 9, 2024. doi:10.1007/s12975-024-01234-z PMID: 38334872

Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke

蛋白酶激活受体 (PARs): 围手术期卒中的生物学和治疗潜力

Perioperative stroke is a devastating complication that occurs during surgery or within 30 days following the surgical procedure. Its prevalence ranges from 0.08 to 10% although it is most likely an underestimation, as sedatives and narcotics can substantially mask symptomatology and clinical presentation. Understanding the underlying pathophysiology and identifying potential therapeutic targets are of paramount importance. Protease-activated receptors (PARs), a unique family of G-protein-coupled receptors, are widely expressed throughout the human body and play essential roles in various physiological and pathological processes. This review elucidates the biology and significance of PARs, outlining their diverse functions in health and disease, and their intricate involvement in cerebrovascular (patho)physiology and neuroprotection. PARs exhibit a dual role in cerebral ischemia, which underscores their potential as therapeutic targets to mitigate the devastating effects of stroke in surgical patients.

围手术期中风是在手术期间或手术后30天内发生的毁灭性并发症。它的患病率从0.08到10% 不等，尽管很可能被低估了，因为镇静剂和麻醉药可以大大掩盖症状和临床表现。了解潜在的病理生理学并确定潜在的治疗靶标至关重要。蛋白酶激活受体 (par) 是一个独特的g蛋白偶联受体家族，在人体内广泛表达，并在各种生理和病理过程中发挥重要作用。这篇综述阐明了PARs的生物学和意义，概述了它们在健康和疾病中的多种功能，以及它们在脑血管 (病理) 生理学和神经保护中的复杂参与。PARs在脑缺血中表现出双重作用，这强调了它们作为减轻手术患者中风的破坏性影响的治疗靶标的潜力。

REF: Mavridis T, Choratta T, Papadopoulou A, et al. Protease-Activated Receptors (PARs): Biology and Therapeutic Potential in Perioperative Stroke. Transl Stroke Res. Published online February 7, 2024. doi:10.1007/s12975-024-01233-0 PMID: 38326662

Angiotensin II Type 2 Receptor Agonism Alleviates Progressive Post-stroke Cognitive Impairment in Aged Spontaneously Hypertensive Rats

血管紧张素 ⅱ 2型受体激动作用减轻老年自发性高血压大鼠卒中后进行性认知障碍

Hypertension and aging are leading risk factors for stroke and vascular contributions to cognitive impairment and dementia (VCID). Most animal models fail to capture the complex interplay between these pathophysiological processes. In the current study, we examined the development of cognitive impairment in 18-month-old spontaneously hypertensive rats (SHR) before and following ischemic stroke. Sixty SHRs were housed for 18 months with cognitive assessments every 6 months and post-surgery. MRI scans were performed at baseline and throughout the study. On day 3 post-stroke, rats were randomized to receive either angiotensin II type 2 receptor (AT2R) agonist Compound 21 (C21) or plain water for 8 weeks. SHRs demonstrated a progressive cognitive decline and significant MRI abnormalities before stroke. Perioperative mortality within 72 h of stroke was low. Stroke resulted in significant acute brain swelling, chronic brain atrophy, and sustained sensorimotor and behavioral deficits. There was no evidence of anhedonia at week 8. C21 enhanced sensorimotor recovery and ischemic lesion resolution at week 8. SHRs represent a clinically relevant animal model to study aging and stroke-associated VCID. This study underscores the importance of translational disease modeling and provides evidence that modulation of the AT2R signaling via C21 may be a useful therapeutic option to improve sensorimotor and cognitive outcomes even in aged animals.

高血压和衰老是中风和血管性认知障碍和痴呆 (VCID) 的主要危险因素。大多数动物模型未能捕捉到这些病理生理过程之间复杂的相互作用。在当前的研究中，我们检查了缺血性中风前后18个月大的自发性高血压大鼠 (SHR) 认知障碍的发展。60个shr被安置18个月，每6个月和手术后进行认知评估。在基线和整个研究期间进行MRI扫描。在中风后第3天，将大鼠随机接受血管紧张素ii2型受体 (AT2R) 激动剂化合物21 (C21) 或普通水8周。Shr在中风前表现出进行性认知下降和明显的MRI异常。卒中72小时内的围手术期死亡率较低。中风导致严重的急性脑肿胀，慢性脑萎缩以及持续的感觉运动和行为缺陷。在第8周时，没有证据表明缺乏性障碍。在第8周时，C21增强了感觉运动恢复和缺血性病变消退。SHRs代表了研究衰老和中风相关VCID的临床相关动物模型。这项研究强调了转化疾病建模的重要性，并提供了证据表明，通过C21调节AT2R信号可能是一种有用的治疗选择，即使在老年动物中也能改善感觉运动和认知结果。

REF: Alshammari A, Pillai B, Kamat P, et al. Angiotensin II Type 2 Receptor Agonism Alleviates Progressive Post-stroke Cognitive Impairment in Aged Spontaneously Hypertensive Rats. Transl Stroke Res. Published online February 2, 2024. doi:10.1007/s12975-024-01232-1 PMID: 38302738