Sirtuins as Potential Targets for Neuroprotection: Mechanisms of Early Brain Injury Induced by Subarachnoid Hemorrhage

Sirtuins作为神经保护的潜在靶点：蛛网膜下腔出血所致早期脑损伤的机制

Subarachnoid hemorrhage (SAH) is a prevalent cerebrovascular disease with significant global mortality and morbidity rates. Despite advancements in pharmacological and surgical approaches, the quality of life for SAH survivors has not shown substantial improvement. Traditionally, vasospasm has been considered a primary contributor to death and disability following SAH, but anti-vasospastic therapies have not demonstrated significant benefits for SAH patients' prognosis. Emerging studies suggest that early brain injury (EBI) may play a crucial role in influencing SAH prognosis. Sirtuins (SIRTs), a group of NAD + -dependent deacylases comprising seven mammalian family members (SIRT1 to SIRT7), have been found to be involved in neural tissue development, plasticity, and aging. They also exhibit vital functions in various central nervous system (CNS) processes, including cognition, pain perception, mood, behavior, sleep, and circadian rhythms. Extensive research has uncovered the multifaceted roles of SIRTs in CNS disorders, offering insights into potential markers for pathological processes and promising therapeutic targets (such as SIRT1 activators and SIRT2 inhibitors). In this article, we provide an overview of recent research progress on the application of SIRTs in subarachnoid hemorrhage and explore their underlying mechanisms of action.

蛛网膜下腔出血(SAH)是一种常见的脑血管疾病，在全球范围内具有显著的死亡率和发病率。尽管在药理学和外科方法方面取得了进步，但SAH幸存者的生活质量并没有显示出实质性的改善。传统上，血管痉挛被认为是SAH后死亡和残疾的主要因素，但抗血管痉挛治疗并未显示出对SAH患者预后的显著好处。新出现的研究表明，早期脑损伤(EBI)可能在影响SAH预后中发挥关键作用。Sirtuins(SIRTs)是一组依赖NAD+的脱酰基酶，由七个哺乳动物家族成员(SIRT1至SIRT7)组成，已被发现参与神经组织的发育、可塑性和衰老。它们还在各种中枢神经系统(CNS)过程中发挥重要作用，包括认知、痛觉、情绪、行为、睡眠和昼夜节律。广泛的研究揭示了SIRT在中枢神经系统疾病中的多方面作用，为病理过程的潜在标记物和有前景的治疗靶点(如SIRT1激活剂和SIRT2抑制剂)提供了见解。本文就SIRT在蛛网膜下腔出血中应用的最新研究进展进行综述，并探讨其潜在的作用机制。

REF: Lei K, Wu R, Wang J, et al. Sirtuins as Potential Targets for Neuroprotection: Mechanisms of Early Brain Injury Induced by Subarachnoid Hemorrhage. Transl Stroke Res. Published online October 2, 2023. doi:10.1007/s12975-023-01191-z PMID: 37779164

Mesenchymal Stem Cells Overexpressing FGF21 Preserve Blood-Brain Barrier Integrity in Experimental Ischemic Stroke

高表达FGF21的间充质干细胞在实验性缺血性卒中中保护血脑屏障完整性

Blood-brain barrier (BBB) disruption is a prominent pathophysiological mechanism in stroke. Transplantation of mesenchymal stem cells (MSCs) preserves BBB integrity following ischemic stroke. Fibroblast growth factor 21 (FGF21) has been shown to be a potent neuroprotective agent that reduces neuroinflammation and protects against BBB leakage. In this study, we assessed the effects of transplantation of MSCs overexpressing FGF21 (MSCs-FGF21) on ischemia-induced neurological deficits and BBB breakdown. MSCs-FGF21 was injected into the rat brain via the intracerebroventricular route 24 h after middle cerebral artery occlusion (MCAO) surgery. The behavioral performance was assessed using modified neurological severity scores and Y-maze tests. BBB disruption was measured using Evans blue staining, IgG extravasation, and brain water content. The levels of tight junction proteins, aquaporin 4, and neuroinflammatory markers were analyzed by western blotting and immunohistochemistry. The activity of matrix metalloproteinase-9 (MMP-9) was determined using gelatin zymography. At day-5 after MCAO surgery, intraventricular injection of MSCs-FGF21 was found to significantly mitigate the neurological deficits and BBB disruption. The MCAO-induced loss of tight junction proteins, including ZO-1, occludin, and claudin-5, and upregulation of the edema inducer, aquaporin 4, were also remarkably inhibited. In addition, brain infarct volume, pro-inflammatory protein expression, and MMP-9 activation were effectively suppressed. These MCAO-induced changes were only marginally improved by treatment with MSCs-mCherry, which did not overexpress FGF21. Overexpression of FGF21 dramatically improved the therapeutic efficacy of MSCs in treating ischemic stroke. Given its multiple benefits and long therapeutic window, MSC-FGF21 therapy may be a promising treatment strategy for ischemic stroke.

血脑屏障(BBB)破坏是卒中的重要病理生理机制。间充质干细胞(MSCs)移植可保护缺血性卒中后血脑屏障的完整性。成纤维细胞生长因子21(FGF21)已被证明是一种有效的神经保护剂，可以减少神经炎症和防止血脑屏障渗漏。在这项研究中，我们评估了移植过表达FGF21的MSCs(MSCs-FGF21)对缺血诱导的神经功能障碍和血脑屏障破坏的影响。大鼠大脑中动脉闭塞(MCAO)后24 h经侧脑室注射MSCs-FGF21。用改良的神经严重度评分和Y-迷宫测试评估行为表现。用伊文思蓝染色、免疫球蛋白渗出量和脑含水量测量血脑屏障的破坏程度。Western blotting和免疫组织化学分析紧密连接蛋白、水通道蛋白4和神经炎性标志物的水平。明胶酶谱法检测基质金属蛋白酶-9(MMP9)活性。在MCAO术后第5天，脑室内注射MSCs-FGF21可显著减轻神经功能缺失和血脑屏障破坏。MCAO诱导的紧密连接蛋白ZO-1、occludin和claudin-5的丢失以及水通道蛋白4的上调也明显受到抑制。此外，还能有效抑制脑梗塞体积、促炎性蛋白表达和基质金属蛋白酶-9的激活。MCAO诱导的这些变化仅通过MSCs-mCherry治疗略有改善，MSCs-mCherry不过度表达FGF21。FGF21过表达可显著提高MSCs治疗缺血性卒中的疗效。鉴于其多重益处和较长的治疗窗口，MSC-FGF21疗法可能是一种有前途的缺血性卒中的治疗策略。

REF: Do PT, Chuang DM, Wu CC, et al. Mesenchymal Stem Cells Overexpressing FGF21 Preserve Blood-Brain Barrier Integrity in Experimental Ischemic Stroke. Transl Stroke Res. Published online October 3, 2023. doi:10.1007/s12975-023-01196-8 PMID: 37783839

Intracerebral Administration of a Novel Self-Assembling Peptide Hydrogel Is Safe and Supports Cell Proliferation in Experimental Intracerebral Haemorrhage

脑内注射新型自组装肽水凝胶安全并支持实验性脑出血的细胞增殖

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, but current treatment options are limited, meaning ICH survivors are often left with life-changing disabilities. The significant unmet clinical need and socioeconomic burden of ICH mean novel regenerative medicine approaches are gaining interest. To facilitate the regeneration of the ICH lesion, injectable biomimetic hydrogels are proposed as both scaffolds for endogenous repair and delivery platforms for pro-regenerative therapies. In this paper, the objective was to explore whether injection of a novel self-assembling peptide hydrogel (SAPH) Alpha2 was feasible, safe and could stimulate brain tissue regeneration, in a collagenase-induced ICH model in rats. Alpha2 was administered intracerebrally at 7 days post ICH and functional outcome measures, histological markers of damage and repair and RNA-sequencing were investigated for up to 8 weeks. The hydrogel Alpha2 was safe, well-tolerated and was retained in the lesion for several weeks, where it allowed infiltration of host cells. The hydrogel had a largely neutral effect on functional outcomes and expression of angiogenic and neurogenic markers but led to increased numbers of proliferating cells. RNAseq and pathway analysis showed that ICH altered genes related to inflammatory and phagocytic pathways, and these changes were also observed after administration of hydrogel. Overall, the results show that the novel hydrogel was safe when injected intracerebrally and had no negative effects on functional outcomes but increased cell proliferation. To elicit a regenerative effect, future studies could use a functionalised hydrogel or combine it with an adjunct therapy.

脑出血(ICH)是最致命的中风形式，但目前的治疗选择有限，这意味着ICH幸存者往往会留下改变生活的残疾。重要的未得到满足的临床需求和脑出血的社会经济负担意味着新的再生医学方法正受到越来越多的关注。为了促进脑出血损伤的再生，建议将可注射仿生水凝胶作为内源性修复的支架和促进再生治疗的输送平台。本文旨在探讨在胶原酶诱导的大鼠脑出血模型中注射新型自组装多肽水凝胶α2是否可行、安全并能刺激脑组织再生。在脑出血后7天给予α2脑内注射，观察8周后的功能结果、损伤和修复的组织学标志和RNA测序。水凝胶Alpha2是安全的，耐受性良好，在病变中保留了几个星期，允许宿主细胞渗透。水凝胶对功能结果以及血管和神经源性标记物的表达有很大程度的中性影响，但导致增殖细胞的数量增加。RNAseq和通路分析表明，脑出血改变了与炎症和吞噬途径相关的基因，并且在给予水凝胶后也观察到了这些变化。总体而言，结果表明，这种新型水凝胶在大脑内注射是安全的，并且对功能结果没有负面影响，但促进了细胞增殖。为了获得再生效果，未来的研究可以使用功能化的水凝胶，或者将其与辅助疗法相结合。

REF: Bolan F, Dickie BR, Cook JR, et al. Intracerebral Administration of a Novel Self-Assembling Peptide Hydrogel Is Safe and Supports Cell Proliferation in Experimental Intracerebral Haemorrhage. Transl Stroke Res. Published online October 18, 2023. doi:10.1007/s12975-023-01189-7 PMID: 37853252

Propranolol or Beta-Blockers for Cerebral Cavernous Malformation: a Systematic Review and Meta-analysis of Literature in Both Preclinical and Clinical Studies

普萘洛尔或β-受体阻滞剂治疗脑海绵状血管畸形：临床前和临床研究文献的系统回顾和荟萃分析

Cerebral cavernous malformation (CCM), either sporadic or familial, is a devastating vascular malformation affecting the central nervous system that can present with intracerebral hemorrhage, seizure, and new focal neurologic deficits resulting in substantial morbidity and mortality. To date, there is no effective evidence-based preventive regimen. There have been several preclinical and clinical studies investigating the potential mechanisms and benefits of beta-blockers, especially on propranolol. We aimed to conduct a systematic review on the published literature investigating the use of beta-blockers in the treatment of CCM, including both preclinical and clinical studies between 2008 and 2023 using public databases. A total of 2 preclinical studies and 6 clinical studies met the inclusion/exclusion criteria and were included. Data was extracted and synthesized from 5 clinical studies for meta-analysis. The meta-analysis failed to demonstrate a statistically significant protective effect of beta-blockers in preventing intracerebral hemorrhage or developing focal neurologic deficits in subjects with CCM (overall effect = 0.78 (0.20, 3.11), p = 0.73). Overall, there was a paucity of high quality clinical trials, partially due to limited cases of CCM. Addressing this gap may require collaborative efforts at a national or international level. In this review, we summarized all barriers and opportunities on this topic. Additionally, we proposed establishing an evidence-based approach on the use of beta-blockers in preventing recurrent hemorrhage and focal neurological deficits in patients with CCM.

脑海绵状血管畸形(CCM)是一种影响中枢神经系统的破坏性血管畸形，可表现为脑内出血、癫痫发作和新的局灶性神经功能障碍，导致相当大的发病率和死亡率。到目前为止，还没有有效的循证预防方案。已经有几项临床前和临床研究调查了β-受体阻滞剂的潜在机制和益处，特别是心得安。我们的目的是对已发表的文献进行系统回顾，调查在CCM治疗中使用β-受体阻滞剂的情况，包括2008年至2023年期间使用公共数据库进行的临床前和临床研究。共有2项临床前研究和6项临床研究符合纳入/排除标准并纳入。数据从5个临床研究中提取并合成，用于荟萃分析。Meta分析未显示β-受体阻滞剂对CCM患者预防脑出血或发生局灶性神经功能缺失有统计学意义的保护作用(总体效果=0.78(0.20，3.11)，p=0.73)。总体而言，缺乏高质量的临床试验，部分原因是CCM病例有限。消除这一差距可能需要国家或国际一级的合作努力。在这篇综述中，我们总结了这个主题上的所有障碍和机会。此外，我们建议在CCM患者中使用β-受体阻滞剂预防复发出血和局灶性神经功能障碍方面建立一种循证方法。

REF: Ikramuddin S, Liu S, Ryan D, Hassani S, Hasan D, Feng W. Propranolol or Beta-Blockers for Cerebral Cavernous Malformation: a Systematic Review and Meta-analysis of Literature in Both Preclinical and Clinical Studies. Transl Stroke Res. Published online October 19, 2023. doi:10.1007/s12975-023-01199-5 PMID: 37857790

Cerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms

脑小血管病的病理生理机制研究进展

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.

脑小血管病(CSVD)是指累及脑部小血管并导致血管认知障碍、脑内出血和急性腔隙缺血性卒中的年龄相关性病理过程。尽管cSVD给公众带来了巨大的健康负担，但由于对其潜在的病理生理机制的不完全了解，针对疾病的治疗方法仍然不可用。神经影像获取和处理能力的最新进展以及cSVD动物模型的发现揭示了几个与年龄相关的过程在cSVD发病中的关键作用，包括动脉僵硬、血管氧化应激、低度全身炎症、肠道生态失调和盐摄入量增加。这些因素相互作用，导致内皮细胞功能障碍，损害脑血流调节，打破血脑屏障。随之而来的神经炎症导致神经元损伤和cSVD的临床表现。通过淋巴系统清除大脑废物的障碍是最近被强调的另一个潜在的过程，导致认知能力下降。这篇综述详细介绍了这些机制，并试图解释它们复杂的相互作用。此外，还发现了cSVD发病机制方面的相关知识空白，并提出了一种系统的方法，用于未来的转化性和早期临床研究，以揭示cSVD的新机制和开发疾病特异性治疗方法。

REF: Hannawi Y. Cerebral Small Vessel Disease: a Review of the Pathophysiological Mechanisms. Transl Stroke Res. Published online October 21, 2023. doi:10.1007/s12975-023-01195-9 PMID: 37864643

Blood Oxygenation Level–Dependent Cerebrovascular Reactivity–Derived Steal Phenomenon May Indicate Tissue Reperfusion Failure After Successful Endovascular Thrombectomy

血氧水平依赖的脑血管反应性窃取现象可能预示成功的血管内血栓消融术后组织再灌注失败

In acute ischemic stroke due to large-vessel occlusion (LVO), the clinical outcome after endovascular thrombectomy (EVT) is influenced by the extent of autoregulatory hemodynamic impairment, which can be derived from blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR). BOLD-CVR imaging identifies brain areas influenced by hemodynamic steal. We sought to investigate the presence of steal phenomenon and its relationship to DWI lesions and clinical deficit in the acute phase of ischemic stroke following successful vessel recanalization.From the prospective longitudinal IMPreST (Interplay of Microcirculation and Plasticity after ischemic Stroke) cohort study, patients with acute ischemic unilateral LVO stroke of the anterior circulation with successful endovascular thrombectomy (EVT; mTICI scale ≥ 2b) and subsequent BOLD-CVR examination were included for this analysis. We analyzed the spatial correlation between brain areas exhibiting BOLD-CVR-associated steal phenomenon and DWI infarct lesion as well as the relationship between steal phenomenon and NIHSS score at hospital discharge.Included patients (n = 21) exhibited steal phenomenon to different extents, whereas there was only a partial spatial overlap with the DWI lesion (median 19%; IQR, 8-59). The volume of steal phenomenon outside the DWI lesion showed a positive correlation with overall DWI lesion volume and was a significant predictor for the NIHSS score at hospital discharge.Patients with acute ischemic unilateral LVO stroke exhibited hemodynamic steal identified by BOLD-CVR after successful EVT. Steal volume was associated with DWI infarct lesion size and with poor clinical outcome at hospital discharge. BOLD-CVR may further aid in better understanding persisting hemodynamic impairment following reperfusion therapy.

在大血管闭塞(LVO)所致的急性缺血性卒中中，血管内血栓摘除术(EVT)后的临床转归受到自身调节性血流动力学损害程度的影响，这种损害可源于血氧水平依赖的脑血管反应性(BOLD-CVR)。BOLD-CVR成像可识别受血流动力学窃取影响的脑区。我们试图调查成功血管再通后急性缺血性卒中患者中存在的盗血现象及其与弥散张量成像损害和临床缺陷的关系。从前瞻性纵向研究(缺血性卒中后微循环和可塑性的相互作用)队列研究中，纳入急性单侧前循环缺血性左心室卒中血管内血栓切除成功的患者(≥2b)和随后的BOLD-CVR检查。我们分析了出院时表现BOLD-CVR相关窃取现象的脑区与DWI梗死灶之间的空间相关性以及窃取现象与NIHSS评分的关系。DWI病变外的盗血现象体积与DWI病变体积呈正相关，是出院时NIHSS评分的重要预测因子。急性缺血性单侧LVO卒中患者在成功的EVT后，BOLD-CVR显示血流动力学盗血。偷血容量与弥散张量成像梗塞灶大小和出院时不良的临床结果相关。BOLD-CVR可能进一步有助于更好地了解再灌注治疗后持续性血流动力学损害。

REF: Bellomo J, Sebök M, Stumpo V, et al. Blood Oxygenation Level-Dependent Cerebrovascular Reactivity-Derived Steal Phenomenon May Indicate Tissue Reperfusion Failure After Successful Endovascular Thrombectomy. Transl Stroke Res. Published online October 25, 2023. doi:10.1007/s12975-023-01203-y PMID: 37880561