Prevention of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage—Summary of Existing Clinical Evidence

动脉瘤性蛛网膜下腔出血后迟发性脑缺血的预防 -- 现有临床证据总结

The 2023 International Subarachnoid Hemorrhage Conference identified a need to provide an up-to-date review on prevention methods for delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage and highlight areas for future research. A PubMed search was conducted for key factors contributing to development of delayed cerebral ischemia: anesthetics, antithrombotics, cerebrospinal fluid (CSF) diversion, hemodynamic, endovascular, and medical management. It was found that there is still a need for prospective studies analyzing the best methods for anesthetics and antithrombotics, though inhaled anesthetics and antiplatelets were found to have some advantages. Lumbar drains should increasingly be considered the first line of CSF diversion when applicable. Finally, maintaining euvolemia before and during vasospasm is recommended as there is no evidence supporting prophylactic spasmolysis or angioplasty. There is accumulating observational evidence, however, that intra-arterial spasmolysis with refractory DCI might be beneficial in patients not responding to induced hypertension. Nimodipine remains the medical therapy with the most support for prevention.

2023国际蛛网膜下腔出血会议确定需要对动脉瘤性蛛网膜下腔出血后迟发性脑缺血 (DCI) 的预防方法进行最新综述，并强调未来研究的领域。PubMed搜索了导致迟发性脑缺血发展的关键因素: 麻醉药，抗血栓药，脑脊液 (CSF) 转移，血液动力学，血管内和药物管理。研究发现，尽管吸入麻醉药和抗血小板药物具有一些优势，但仍需要进行前瞻性研究来分析麻醉药和抗血栓药物的最佳方法。在适用的情况下，应越来越多地将腰部排水沟视为CSF改道的第一线。最后，建议在血管痉挛之前和期间保持真血容量，因为没有证据支持预防性痉挛或血管成形术。然而，越来越多的观察证据表明，难治性DCI的动脉内痉挛可能对对无诱发性高血压反应的患者有益。尼莫地平仍然是最支持预防的药物治疗。

REF: Miller M, Thappa P, Bhagat H, Veldeman M, Rahmani R. Prevention of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage-Summary of Existing Clinical Evidence. Transl Stroke Res. Published online August 30, 2024. doi:10.1007/s12975-024-01292-3 PMID: 39212835

RNF213 Mutation Associated with the Progression from Middle Cerebral Artery Steno-Occlusive Disease to Moyamoya Disease

RNF213突变与大脑中动脉狭窄闭塞性疾病进展为烟雾病相关

Middle cerebral artery steno-occlusive disease (MCAD) has been recognized as a different clinical entity from moyamoya disease (MMD). Although MCAD can progress to MMD, the extent to which patients actually progress and the risk factors for this progression have not been fully elucidated. We retrospectively reviewed patients with MCAD who underwent RNF213 genotyping. Demographic features, RNF213 p.R4810K mutation, medical history, and longitudinal changes in angiography were analyzed. Sixty patients with 81 affected hemispheres were enrolled. During the follow-up period, 17 patients developed MMD, and the RNF213 p.R4810K mutation was the only factor significantly associated with progression to MMD (odds ratio, 16.1; 95% CI, 2.13-731; P = 0.001). The log-rank test demonstrated that patients with the mutation had a higher risk of progression to MMD (P = 0.007), stenosis progression (P = 0.010), and symptomatic cerebral infarction or hemorrhage (P = 0.026). In Cox regression analysis the p.R4810K mutation remained a significant factor after adjusting for age group (childhood or adult onset) at diagnosis (hazard ratio, 8.42; 95% CI, 1.10-64.4). Hemisphere-based analysis also showed that the mutation was associated with a higher risk of progression to the MMD hemisphere (P = 0.002), stenosis progression (P = 0.005), and cerebral infarction or hemorrhage (P = 0.012). The RNF213 p.R4810K mutation was identified as a risk factor for progression from MCAD to MMD. Genotyping for this mutation may contribute to risk stratification in MCAD.

大脑中动脉狭窄闭塞性疾病 (MCAD) 已被认为是与烟雾病 (MMD) 不同的临床实体。尽管MCAD可以进展为MMD，但患者实际进展的程度以及这种进展的风险因素尚未完全阐明。我们回顾性分析了接受RNF213基因分型的MCAD患者。分析了人口统计学特征，RNF213 p.R4810K突变，病史和血管造影的纵向变化。纳入了60例81个受影响半球的患者。在随访期间，17例患者发生MMD，RNF213 p.R4810K突变是与MMD进展显著相关的唯一因素 (比值比，16.1; 95% CI，2.13-731; P = 0.001)。log-rank检验表明，具有突变的患者进展为MMD (P = 0.007)，狭窄进展 (P = 0.010) 和症状性脑梗死或出血 (P = 0.026) 的风险更高。在Cox回归分析中，在诊断时调整年龄组 (儿童期或成人发病) 后，p.R4810K突变仍然是一个重要因素 (风险比，8.42; 95% CI，1.10-64.4)。基于半球的分析还显示，该突变与MMD半球进展 (P = 0.002)，狭窄进展 (P = 0.005) 以及脑梗死或出血 (P = 0.012) 的风险较高相关。RNF213 p.R4810K突变被鉴定为从MCAD发展为MMD的风险因素。该突变的基因分型可能有助于MCAD的风险分层。

REF: Sasagasako T, Mineharu Y, Funaki T, et al. RNF213 Mutation Associated with the Progression from Middle Cerebral Artery Steno-Occlusive Disease to Moyamoya Disease. Transl Stroke Res. Published online August 27, 2024. doi:10.1007/s12975-024-01293-2 PMID: 39191959

Progesterone Receptor Agonist, Nestorone, Exerts Long-Term Neuroprotective Effects Against Permanent Focal Cerebral Ischemia in Adult and Aged Male Rats

孕酮受体激动剂Nestorone对成年和老年雄性大鼠永久性局灶性脑缺血的长期神经保护作用

Stroke is a leading cause of death and disability worldwide. Tissue plasminogen activator (tPA) is currently the most effective medicine for stroke; however, it has a narrow therapeutic time window (4.5 h after symptom onset). We demonstrated that nestorone, a progesterone (P4) receptor agonist, exerted neuroprotective effects against transient focal cerebral ischemia 6 h post-ischemic administration in adult male rats. This study examines its effects on permanent focal cerebral ischemia in adult and aged male rats, which are better models for evaluating treatment outcomes in typical stroke patients. Adult (6-month-old) or aged (18-month-old) male rats subjected to permanent middle cerebral artery occlusion (pMCAO) were continuously administered nestorone (10µg/day) or its vehicle (30% hydroxypropyl-β-cyclodextrin) for 7 days via an osmotic pump subcutaneously implanted, starting at 18 h post-pMCAO. Nestorone-treated adult male rats showed marked improvements in behavioral outcomes in the adhesive removal and rotarod tests and a significant reduction in infarct size compared to vehicle-treated rats 9 and 30 days post-pMCAO. The same administration of nestorone resulted in apparently comparable neuroprotective effects in aged male rats. The inflammatory mediator NF-κB/p65 was increased in Iba-1 positive cells 24 h post-pMCAO, but was significantly suppressed by subcutaneous injection of nestorone. These results suggested that nestorone exerts long-term neuroprotective effects against permanent focal cerebral ischemia in adult and aged male rats. Nestorone is thus a promising agent for post-stroke treatment owing to its wide age-independent therapeutic time window (18 h after symptom onset), which is longer than that of tPA therapy.

卒中是全球死亡和残疾的主要原因。组织型纤溶酶原激活物 (tPA) 是目前治疗卒中最有效的药物; 然而，它具有狭窄的治疗时间窗 (症状发作后4.5 h)。我们证明了孕酮 (P4) 受体激动剂nestorone对成年雄性大鼠缺血后6小时的短暂性局灶性脑缺血具有神经保护作用。这项研究检查了其对成年和老年雄性大鼠永久性局灶性脑缺血的影响，这是评估典型卒中患者治疗结果的更好模型。接受永久性大脑中动脉闭塞 (pMCAO) 的成年 (6个月大) 或老年 (18个月大) 雄性大鼠通过皮下植入的渗透泵连续给药nestorone (10 µ g/天) 或其载体 (30% 羟丙基-β-环糊精) 7天，从pMCAO后18小时开始。与pMCAO后9天和30天的媒介物处理的大鼠相比，Nestorone处理的成年雄性大鼠在粘合剂去除和旋转杆测试中的行为结果显着改善，并且梗塞面积显着减小。相同的nestorone给药在老年雄性大鼠中产生了明显相当的神经保护作用。pMCAO后24小时，Iba-1阳性细胞中的炎症介质nf-κb/p65增加，但皮下注射nestorone可显着抑制。这些结果表明，nestorone对成年和老年雄性大鼠的永久性局灶性脑缺血具有长期的神经保护作用。由于其与年龄无关的治疗时间窗 (症状发作后18小时) 比tPA疗法更长，因此，Nestorone是卒中后治疗的有前途的药物。

REF: Tanaka M, Sokabe M, Asai M. Progesterone Receptor Agonist, Nestorone, Exerts Long-Term Neuroprotective Effects Against Permanent Focal Cerebral Ischemia in Adult and Aged Male Rats. Transl Stroke Res. Published online August 22, 2024. doi:10.1007/s12975-024-01288-z PMID: 39172309

Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: The Role of the Complement and Innate Immune System

动脉瘤性蛛网膜下腔出血后迟发性脑缺血: 补体和先天免疫系统的作用

Specific inflammatory pathways are important in the development of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Understanding the specific pathways of inflammation may be critical for finding new treatments. Evidence is accumulating that innate inflammatory cells and proteins play a more important role than cells of the adaptive inflammatory system. In this work, we review the evidence from clinical and preclinical data regarding which cells of the immune system play a role in DCI with particular emphasis on the bone-marrow-derived cells monocytes and neutrophils and the brain parenchymal microglia. In addition, we will review the evidence that complement proteins, a non-cellular part of the innate immune system, play a role in the development of DCI.

特定的炎症途径在动脉瘤性蛛网膜下腔出血后迟发性脑缺血的发展中起重要作用。了解炎症的特定途径对于寻找新的治疗方法可能至关重要。越来越多的证据表明，先天炎症细胞和蛋白质比适应性炎症系统的细胞起着更重要的作用。在这项工作中，我们回顾了来自临床和临床前数据的证据，这些证据涉及免疫系统的哪些细胞在DCI中起作用，特别强调了骨髓来源的细胞单核细胞和中性粒细胞以及脑实质小胶质细胞。此外，我们将回顾补体蛋白 (先天免疫系统的非细胞部分) 在DCI的发展中发挥作用的证据。

REF: Provencio JJ, Inkelas S, Vergouwen MDI. Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: The Role of the Complement and Innate Immune System. Transl Stroke Res. Published online August 21, 2024. doi:10.1007/s12975-024-01290-5 PMID: 39168941

Changes in Neuroimmunological Synapses During Cerebral Ischemia

脑缺血期间神经免疫突触的变化

The direct interplay between the immune and nervous systems is now well established. Within the brain, these interactions take place between neurons and resident glial cells, i.e., microglia and astrocytes, or infiltrating immune cells, influenced by systemic factors. A special form of physical cell-cell interactions is the so-called "neuroimmunological (NI) synapse." There is compelling evidence that the same signaling pathways that regulate inflammatory responses to injury or ischemia also play potent roles in brain development, plasticity, and function. Proper synaptic wiring is as important during development as it is during disease states, as it is necessary for activity-dependent refinement of neuronal circuits. Since the process of forming synaptic connections in the brain is highly dynamic, with constant changes in strength and connectivity, the immune component is perfectly suited for the regulatory task as it is in constant turnover. Many cellular and molecular players in this interaction remain to be uncovered, especially in pathological states. In this review, we discuss and propose possible communication hubs between components of the adaptive and innate immune systems and the synaptic element in ischemic stroke pathology.

免疫系统和神经系统之间的直接相互作用现已确立。在大脑中，这些相互作用发生在受系统因素影响的神经元和常驻神经胶质细胞之间，即小胶质细胞和星形胶质细胞，或浸润免疫细胞。物理细胞-细胞相互作用的一种特殊形式是所谓的 “神经免疫 (NI) 突触”。有令人信服的证据表明，调节对损伤或缺血的炎症反应的相同信号通路在大脑发育，可塑性和功能中也起着重要作用。正确的突触连接在发育过程中与在疾病状态中一样重要，因为它对于神经元回路的活动依赖性细化是必需的。由于在大脑中形成突触连接的过程是高度动态的，强度和连接性不断变化，因此免疫成分非常适合调节任务，因为它处于不断的周转中。这种相互作用中的许多细胞和分子参与者仍有待发现，尤其是在病理状态下。在这篇综述中，我们讨论并提出了适应性和先天免疫系统的组成部分与缺血性卒中病理学中的突触元件之间可能的通讯枢纽。

REF: Bitar L, Puig B, Oertner TG, Dénes Á, Magnus T. Changes in Neuroimmunological Synapses During Cerebral Ischemia. Transl Stroke Res. Published online August 5, 2024. doi:10.1007/s12975-024-01286-1 PMID: 39103660

Deacetylase SIRT2 Inhibition Promotes Microglial M2 Polarization Through Axl/PI3K/AKT to Alleviate White Matter Injury After Subarachnoid Hemorrhage

抑制去乙酰化酶SIRT2通过Axl/PI3K/AKT促进小胶质细胞M2极化减轻蛛网膜下腔出血后脑白质损伤

White matter injury (WMI) subsequent to subarachnoid hemorrhage (SAH) frequently leads to an unfavorable patient prognosis. Previous studies have indicated that microglial M1 polarization following SAH results in the accumulation of amyloid precursor protein (APP) and degradation of myelin basic protein (MBP), thereby catalyzing the exacerbation of WMI. Consequently, transitioning microglial polarization towards the M2 phenotype (neuroprotective state) represents a potential therapeutic approach for reversing WMI. The SIRT2 gene is pivotal in neurological disorders such as neurodegeneration and ischemic stroke. However, its function and underlying mechanisms in SAH, particularly how it influences microglial function to ameliorate WMI, remain unclear. Our investigations revealed that in post-SAH, there was a temporal increase in SIRT2 expression, predominantly in the cerebral corpus callosum area, with notable colocalization with microglia. However, following the administration of the SIRT2 inhibitor AK-7, a shift in microglial polarization towards the M2 phenotype and an improvement in both short-term and long-term neuronal functions in rats were observed. Mechanistically, CO-IP experiments confirmed that SIRT2 can interact with the receptor tyrosine kinase Axl within the TAM receptor family and act as a deacetylase to regulate the deacetylation of Axl. Concurrently, the inhibition of SIRT2 by AK-7 can lead to increased expression of Axl and activation of the anti-inflammatory pathway PI3K/Akt signaling pathway, which regulates microglial M2 polarization and consequently reduces WMI. However, when Axl expression was inhibited by the injection of the shAxl virus into the lateral ventricles, the downstream signaling pathways were significantly suppressed. Rescue experiments also confirmed that the neuroprotective effects of AK-7 can be reversed by PI3K inhibitors. These data suggest that SIRT2 influences WMI by affecting microglial polarization through the Axl/PI3K/AKT pathway, and that AK-7 could serve as an effective therapeutic drug for improving neurological functions in SAH patients.

蛛网膜下腔出血 (SAH) 后的白质损伤 (WMI) 经常导致患者预后不良。先前的研究表明，SAH后小胶质细胞M1极化会导致淀粉样前体蛋白 (APP) 的积累和髓鞘碱性蛋白 (MBP) 的降解，从而催化WMI的恶化。因此，将小胶质细胞极化转变为M2表型 (神经保护状态) 代表了逆转WMI的潜在治疗方法。SIRT2基因在神经系统疾病如神经变性和缺血性卒中中起关键作用。然而，它在SAH中的功能和潜在机制，特别是它如何影响小胶质细胞功能以改善WMI，仍不清楚。我们的研究表明，在SAH后，SIRT2表达随时间增加，主要在大脑call体区域，与小胶质细胞有明显的共定位。然而，在施用SIRT2抑制剂AK-7后，观察到大鼠中小胶质细胞极化向M2表型的转变以及短期和长期神经元功能的改善。从机制上讲，co-ip实验证实SIRT2可以与TAM受体家族内的受体酪氨酸激酶Axl相互作用，并作为脱乙酰基酶来调节Axl的脱乙酰作用。同时，AK-7对SIRT2的抑制可导致Axl的表达增加和抗炎途径PI3K/Akt信号传导途径的激活，其调节小胶质细胞M2极化并因此降低WMI。然而，当通过向侧脑室注射shAxl病毒来抑制Axl表达时，下游信号传导途径被显著抑制。救援实验还证实，AK-7的神经保护作用可以被PI3K抑制剂逆转。这些数据表明，SIRT2通过Axl/PI3K/AKT途径影响小胶质细胞极化来影响WMI，并且AK-7可以作为改善SAH患者神经功能的有效治疗药物。

REF: Yuan K, Wu Q, Yao Y, et al. Deacetylase SIRT2 Inhibition Promotes Microglial M2 Polarization Through Axl/PI3K/AKT to Alleviate White Matter Injury After Subarachnoid Hemorrhage. Transl Stroke Res. Published online August 5, 2024. doi:10.1007/s12975-024-01282-5 PMID: 39103659

Plasma Levels of Neuron/Glia-Derived Apoptotic Bodies, an In Vivo Biomarker of Apoptosis, Predicts Infarct Growth and Functional Outcome in Patients with Ischemic Stroke

神经元/神经胶质细胞凋亡小体的血浆水平是凋亡的体内生物标志物，可预测缺血性卒中患者的梗塞生长和功能结局

Evidence demonstrating the involvement of apoptosis in the death of the potentially salvageable area (penumbra zone) in patients during stroke remains limited. Our aim was to investigate whether apoptotic processes occur in penumbral brain tissue by analyzing circulating neuron- and glia-derived apoptotic bodies (CNS-ApBs), which are vesicles released into the bloodstream during the late stage of apoptosis. We have also assessed the clinical utility of plasma neuronal and glial apoptotic bodies in predicting early neurological evolution and functional outcome. The study included a total of 71 patients with acute hemispheric ischemic stroke (73 ± 10 years; 30 women). Blood samples were collected from these patients immediately upon arrival at the hospital (within 9 h) and at 24 and 72 h after symptom onset. Subsequently, isolation, quantification, and phenotypic characterization of CNS-ApBs during the first 72 h post-stroke were performed using centrifugation and flow cytometry techniques. We found a correlation between infarct growth and final infarct size with the amount of plasma CNS-ApBs detected in the first 72 h after stroke. In addition, patients with neurological worsening (progressive ischemic stroke) had higher plasma levels of CNS-ApBs at 24 h after symptom onset than those with a stable or improving course. Circulating CNS-ApB concentration was further associated with patients' functional prognosis. In conclusion, apoptosis may play an important role in the growth of the cerebral infarct area and plasma CNS-ApB quantification could be used as a predictive marker of penumbra death, neurological deterioration, and functional outcome in patients with ischemic stroke.

证明细胞凋亡参与卒中期间患者潜在可挽救区域 (半影区) 死亡的证据仍然有限。我们的目的是通过分析循环中的神经元和神经胶质衍生的凋亡小体 (cns-apb) 来研究半影脑组织中是否发生凋亡过程，这些凋亡小体是在凋亡后期释放到血液中的囊泡。我们还评估了血浆神经元和神经胶质凋亡体在预测早期神经系统演变和功能结果中的临床效用。该研究共纳入71例急性半球缺血性卒中患者 (73 ± 10岁; 30名女性)。在到达医院后 (9小时内) 以及症状发作后24和72小时从这些患者中收集血液样本。随后，使用离心和流式细胞术技术进行卒中后第一个72小时期间的cns-apb的隔离、定量和表型表征。我们发现梗死生长和最终梗死面积与卒中后前72小时检测到的血浆cns-apb量之间存在相关性。此外，症状发作后24小时，神经系统恶化 (进行性缺血性卒中) 的患者血浆cns-apb水平高于病程稳定或改善的患者。循环中枢神经系统-ApB浓度进一步与患者的功能预后相关。总之，细胞凋亡可能在脑梗死区域的生长中起重要作用，血浆cns-apb定量可作为缺血性卒中患者半影死亡，神经系统恶化和功能预后的预测指标。

REF: Díaz-Maroto I, Castro-Robles B, Villar M, et al. Plasma Levels of Neuron/Glia-Derived Apoptotic Bodies, an In Vivo Biomarker of Apoptosis, Predicts Infarct Growth and Functional Outcome in Patients with Ischemic Stroke. Transl Stroke Res. Published online August 2, 2024. doi:10.1007/s12975-024-01283-4 PMID: 39090486