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Translational ​Stroke Research

2023

本篇文献由机器智能翻译

【Online】2023年12月速览
  • The Role of ICP Monitoring in Minimally Invasive Surgery for the Management of Intracerebral Hemorrhage

    颅内压监测在脑出血微创手术中的作用

    Intracerebral hemorrhage (ICH) is the second major stroke type, with high incidence, high disability rate, and high mortality. At present, there is no effective and reliable treatment for ICH. As a result, most patients have a poor prognosis. Minimally invasive surgery (MIS) is the fastest treatment method to remove hematoma, which is characterized by less trauma and easy operation. Some studies have confirmed the safety of MIS, but there are still no reports showing that it can significantly improve the functional outcome of ICH patients. Intracranial pressure (ICP) monitoring is considered to be an important part of successful treatment in traumatic brain diseases. By monitoring ICP in real time, keeping stable ICP could help patients with craniocerebral injury get a good prognosis. In the course of MIS treatment of ICH patients, keeping ICP stable may also promote patient recovery. In this review, we will take ICP monitoring as the starting point for an in-depth discussion.

    脑出血(ICH)是第二大卒中类型,发病率高、致残率高、死亡率高。目前,对脑出血尚无有效可靠的治疗方法。因此,大多数患者的预后都很差。微创手术是清除血肿最快的治疗方法,具有创伤小、操作简单等特点。已有研究证实了脑出血微创手术的安全性,但尚无研究表明其能显著改善脑出血患者的功能预后。颅内压监测被认为是创伤性脑部疾病成功治疗的重要组成部分。通过实时监测颅内压,保持稳定的颅内压可帮助颅脑损伤患者获得良好的预后。在脑出血患者的管理信息系统治疗过程中,保持颅内压的稳定也可能促进患者的康复。在本次综述中,我们将以监测国际比较方案为起点进行深入讨论。

    REF: Zhang G, Li Y, Chen D, et al. The Role of ICP Monitoring in Minimally Invasive Surgery for the Management of Intracerebral Hemorrhage. Transl Stroke Res. Published online December 29, 2023. doi:10.1007/s12975-023-01219-4 PMID: 38157144

  • Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH

    Parkin抑制USP 30促进线粒体自噬调节MFN2泛素化减轻SAH后早期脑损伤

    Subarachnoid hemorrhage (SAH) is a type of stroke with a high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells and inflammatory responses caused by high extracellular ATP lead to poor outcomes. USP30 is a deubiquitinating enzyme that inhibits mitophagy, resulting in a failure to remove damaged mitochondria in a timely manner after SAH; nevertheless, the pathway through which USP30 inhibits mitophagy is unknown. This study evaluated the neuroprotective role and possible molecular basis by which inhibiting USP30 to attenuate SAH-induced EBI by promoting neuronal mitophagy. We used an in vitro model of hemoglobin exposure and an in vivo model of intravascular perforation. Increased expression of USP30 was found after SAH in vivo and in vitro, and USP30 inhibition expression in SAH mice treated with MF094 resulted in significant improvement of neurological injury and inflammatory response and mediated good outcomes, suggesting a neuroprotective effect of USP30 inhibition. In cultured neurons, inhibition of USP30 promoted ubiquitination modification of mitochondrial fusion protein 2 (MFN2) by E3 ubiquitin ligase (Parkin), separating damaged mitochondria from the healthy mitochondrial network and prompting mitophagy, causing early clearance of damaged intracellular mitochondria, and reducing the onset of apoptosis. The high extracellular ATP environment was meliorated, reversing the conversion of microglia to a pro-inflammatory phenotype and reducing inflammatory injury. USP30 inhibition had no autophagy-promoting effect on structurally and functionally sound mitochondria and did not inhibit normal intracellular ATP production. The findings suggest that USP30 inhibition has a neuroprotective effect after SAH by promoting early mitophagy after SAH to clear damaged mitochondria.

    蛛网膜下腔出血(SAH)是一种致残率和死亡率都很高的卒中类型。神经细胞线粒体的大量损伤引起的细胞凋亡和细胞外高水平的三磷酸腺苷引起的炎症反应导致预后不良。USP30是一种去泛素酶,它抑制有丝分裂,导致SAH后不能及时清除受损的线粒体;然而,USP30抑制有丝分裂的途径尚不清楚。本研究评估了抑制USP30通过促进神经元有丝分裂而减轻SAH诱导的EBI的神经保护作用和可能的分子基础。我们使用了血红蛋白暴露的体外模型和血管内穿孔的体内模型。SAH后体内、外USP30表达均增加,MF094抑制USP30表达可明显改善SAH小鼠的神经损伤和炎症反应,并介导良好的预后,提示USP30抑制具有神经保护作用。在培养的神经元中,抑制USP30促进了E3泛素连接酶(Parkin)对线粒体融合蛋白2(Mfn2)的泛素化修饰,使受损的线粒体从健康的线粒体网络中分离出来,促进有丝分裂,使受损的细胞内线粒体提前清除,减少了细胞凋亡的发生。细胞外高ATP环境得到改善,逆转了小胶质细胞向促炎表型的转变,减轻了炎性损伤。抑制USP30对结构和功能健全的线粒体没有促进自噬的作用,也不抑制正常的细胞内ATP的产生。结果提示,抑制USP30通过促进SAH后早期吞噬有丝分裂,清除受损线粒体而起到保护SAH后神经的作用。

    REF: Liu Y, Yao C, Sheng B, et al. Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH. Transl Stroke Res. Published online December 26, 2023. doi:10.1007/s12975-023-01228-3 PMID: 38147294

  • Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria

    按阶梯标准模拟卒中后静脉注射miR-21的治疗潜力

    The microRNA-21 (miR-21) levels in the brain are crucial in determining post-stroke brain damage and recovery. The miR-21 exerts neuroprotection by targeting mRNAs that translate proteins that mediate brain damage. We currently determined the efficacy and efficiency of intravenously administered miR-21 mimic after focal cerebral ischemia in mice. Adult male mice were intravenously administered with either control mimic or miR-21 mimic at 5 min/2 h after reperfusion following 1 h transient middle cerebral artery occlusion to determine the therapeutic window of miR-21 mimic. Adult female, type-2 diabetic male, aged male, and aged female mice were administered with control/miR-21 mimic at 5 min after reperfusion following 35 min/1 h transient middle cerebral artery occlusion. Early administration of miR-21 mimic significantly reduced brain damage and promoted long-term recovery after stroke. Further, miR-21 mimic is more effective in males than in females subjected to stroke. However, delayed treatment with miR-21 mimic is not efficacious, and type-2 diabetic subjects show no improvement with miR-21 mimic treatment.

    大脑中的microRNA-21(miR-21)水平在决定中风后脑损伤和恢复方面至关重要。miR-21通过靶向翻译介导脑损伤的蛋白质的mRNA来发挥神经保护作用。我们目前确定了小鼠局灶性脑缺血后静脉内施用miR-21模拟物的功效和效率。在短暂性大脑中动脉闭塞1小时后再灌注后5分钟/2小时,向成年雄性小鼠静脉内施用对照模拟物或miR-21模拟物,以确定miR-21模拟物的治疗窗。成年雌性、2型糖尿病雄性、老年雄性和老年雌性小鼠在35分钟/1小时短暂大脑中动脉闭塞后再灌注后5分钟时施用对照/miR-21模拟物。早期给予miR-21模拟物可显著降低脑损伤,促进卒中后的长期恢复。此外,miR-21模拟物在遭受中风的男性中比在女性中更有效。然而,用miR-21模拟物延迟治疗是无效的,并且2型糖尿病受试者用miR-21模拟物治疗没有显示出改善。

    REF: Chelluboina B, Jeong S, Davis CK, Mehta SL, Vemuganti R. Therapeutic Potential of Intravenous miR-21 Mimic after Stroke Following STAIR Criteria. Transl Stroke Res. Published online December 22, 2023. doi:10.1007/s12975-023-01223-8 PMID: 38129636

  • The Drainage Dysfunction of Meningeal Lymphatic Vessels Is Correlated with the Recurrence of Chronic Subdural Hematoma: a Prospective Study

    脑膜淋巴管引流功能障碍与慢性硬膜下血肿复发的相关性:一项前瞻性研究

    Meningeal lymphatic vessels (mLVs) were recently discovered to be involved in the waste drainage process in the brain, which has also been associated with a variety of neurological diseases. This research paper hypothesizes that the drainage function of mLVs may be affected after chronic subdural hematoma (CSDH) and the alterations of mLVs' drainage may predict CSDH recurrence. In this prospective observational study, unenhanced 3D T2-fluid-attenuated inversion recovery (3D T2-FLAIR) MRI data were collected from CSDH patients and healthy participants for analysis. Patients with CSDH who underwent surgery received MRI scans before and after surgery, whereas healthy controls and patients with CSDH who received pharmaceutical treatment received only one MRI scan at enrollment. The signal unit ratio (SUR) of mLVs were then measured according to the MRI data and calculated to define mLVs' drainage function. Finally, the relationship between mLVs' drainage function and CSDH recurrence was analyzed accordingly. Thirty-four participants were enrolled in this study, including 27 CSDH patients and 7 controls. The SUR of mLVs in all CSDH patients changed significantly before and after surgery. Moreover, the drainage function of the mLVs ipsilateral to hematoma (mLVs-IH) in CSDH patients was significantly lower than that in the controls (p < 0.05). Last, a higher improvement rate of the drainage function of the mLVs-IH is correlated to a lower risk of recurrence (p < 0.05). This study revealed the mLVs' drainage dysfunction after CSDH through non-invasive MRI. Furthermore, the drainage function of mLVs is an independent predictive factor of CSDH recurrence.

    脑膜淋巴管(MLV)最近被发现参与脑内废物的引流过程,这也与多种神经系统疾病有关。本研究假设慢性硬膜下血肿(CSDH)后MLVS的引流功能可能受到影响,MLVS引流的改变可能预测CSDH的复发。在这项前瞻性观察研究中,来自CSDH患者和健康参与者的平扫3DT2-液体衰减反转恢复(3DT2-FLAIR)MRI数据被收集用于分析。接受手术的CSDH患者在手术前后接受MRI扫描,而健康对照组和接受药物治疗的CSDH患者在登记时只接受一次MRI扫描。然后根据MRI数据测量MLV的信号单位比(SUR)并计算以确定MLV的引流功能。最后,对MLV的引流功能与CSDH复发的关系进行了分析。34名研究对象,包括27名慢性硬膜下血肿患者和7名对照。所有CSDH患者手术前后MLVSUR值均有明显变化。CSDH患者血肿同侧MLVS的引流功能(MLVS-IH)明显低于对照组(P<0.05)。最后,MLVS-IH引流功能改善率越高,复发风险越低(p<0.05)。本研究通过无创性MRI揭示了CSDH后MLV的引流功能障碍。此外,MLVS的引流功能是CSDH复发的独立预测因素。

    REF: Zhang J, Yu L, Wang X, et al. The Drainage Dysfunction of Meningeal Lymphatic Vessels Is Correlated with the Recurrence of Chronic Subdural Hematoma: a Prospective Study. Transl Stroke Res. Published online December 22, 2023. doi:10.1007/s12975-023-01227-4 PMID: 38133745

  • Crosstalk Between Matrix Metalloproteinases and Their Inducer EMMPRIN/CD147: a Promising Therapeutic Target for Intracerebral Hemorrhage

    基质金属蛋白酶与其诱导因子EMMPRIN/CD 147的相互作用:脑出血治疗的新靶点

    Intracerebral hemorrhage (ICH) is characterized by the disruption of cerebrovascular integrity, resulting in hematoma enlargement, edema formation, and physical damage in the brain parenchyma. Primary ICH also leads to secondary brain injury contributed by oxidative stress, dysregulated immune responses, and proteolysis. In this context, matrix metalloproteinases (MMPs) represent a ubiquitous superfamily of structurally related zinc-dependent endopeptidases capable of degrading all components of the extracellular matrix. They disrupt the blood-brain barrier and promote neuroinflammation. Importantly, several MMP members are upregulated following ICH, and members may have different functions at specific periods in ICH. Hence, the modulation and function of MMPs are more complex than expected. Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that induces the production of MMPs. In this review, we systematically discuss the biology and functions of MMPs and EMMPRIN/CD147 in ICH and the complex crosstalk between them.

    脑出血(ICH)的特征是脑血管完整性的破坏,导致血肿扩大、脑实质水肿形成和物理损害。原发性脑出血还会导致氧化应激、免疫反应失调和蛋白分解所致的继发性脑损伤。在这种背景下,基质金属蛋白酶(MMPs)是一个普遍存在的结构相关的锌依赖内肽酶超家族,能够降解细胞外基质的所有成分。它们破坏血脑屏障,促进神经炎症。重要的是,几个基质金属蛋白酶成员在脑出血后表达上调,并且这些成员在脑出血的特定时期可能具有不同的功能。因此,MMP的调制和功能比预期的要复杂得多。细胞外基质金属蛋白酶诱导物(EMMPRIN,CD147)是一种诱导MMPs产生的跨膜糖蛋白。本文系统地讨论了MMPs和EMMPRIN/CD147在脑出血中的生物学和功能,以及它们之间的复杂串扰。

    REF: Liu Y, Qi L, Li Z, Yong VW, Xue M. Crosstalk Between Matrix Metalloproteinases and Their Inducer EMMPRIN/CD147: a Promising Therapeutic Target for Intracerebral Hemorrhage. Transl Stroke Res. Published online December 15, 2023. doi:10.1007/s12975-023-01225-6 PMID: 38100014

  • Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell

    MFGE8甲基化促进蛛网膜下腔出血后早期脑损伤及抑制神经细胞自噬

    Spontaneous subarachnoid hemorrhage (SAH) is a relatively common clinical hemorrhagic stroke crisis. The important role of early brain injury (EBI) and autophagy in SAH has been increasingly recognized in recent years. This study aims to investigate the function and the undergoing mechanism of MFGE8 in EBI after SAH. High expression of DNMT1 and P2X7R and low expression of MFGE8 were observed in SAH mice. • Activation of autophagy reduces EBI after SAH in mice. • DNMT1/MFGE8 reduces autophagy in EBI after SAH in both mouse and cell models. • DNMT1 targets the MFGE8 promoter to upregulate its methylation level. • MFGE8 inhibits P2X7R to activate PI3k/AKT/mTOR pathway and autophagy, thus inhibiting EBI after SAH.

    自发性蛛网膜下腔出血(SAH)是临床上较为常见的出血性卒中危象。近年来,早期脑损伤(EBI)和自噬在蛛网膜下腔出血(SAH)中的重要作用日益受到重视。本研究旨在探讨MFGE8在SAH后EBI中的作用及其作用机制。SAH小鼠DNMT1、P2X7R高表达,MFGE8低表达。·自噬的激活减少了小鼠SAH后的EBI。·在小鼠和细胞模型中,DNMT1/MFGE8减少SAH后EBI中的自噬。·DNMT1靶向MFGE8启动子,上调其甲基化水平。·MFGE8抑制P2X7R激活PI3K/AKT/mTOR通路和自噬,从而抑制SAH后的EBI。

    REF: Zou L, Xu S, Wang C, Wu P, Xu C, Shi H. Methylated MFGE8 Promotes Early Brain Injury After Subarachnoid Hemorrhage and Inhibiting Autophagy of Nerve Cell. Transl Stroke Res. Published online December 14, 2023. doi:10.1007/s12975-023-01217-6 PMID: 38095841

  • Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts

    近期单发皮质下梗塞MRI远期随访中出血灶的患病率及预测因素

    Hemorrhagic foci surrounding the lacune in the long-term evolution of recent single subcortical infarcts (RSSIs) remains largely unexplored. We aimed to determine the prevalence, characteristics, and predictors of hemorrhagic foci in patients with RSSI. From a prospective, longitudinal study of RSSIs, we recruited patients who underwent multimodal MRI assessments both at baseline and approximately one year after the stroke onset. Hemorrhagic foci were identified using susceptibility-weighted imaging (SWI). Among 101 patients with RSSI, nearly half (n = 45, 44.6%) had hemorrhagic foci within the index RSSI lesions on follow-up SWI. RSSIs with hemorrhagic foci formation were associated with a longer time to follow-up imaging (median 449 versus 401 days, P = 0.005) and higher likelihood of being located in the anterior circulation compared to those without hemorrhagic foci (88.9% versus 64.3%, P = 0.003). Hemorrhagic foci were also associated with larger lesion size (P < 0.001), a higher proportion of cavitation formation (P = 0.003), higher baseline NIHSS scores (P = 0.004), and poorer functional outcomes (P = 0.001). In the subset of RSSIs in the lenticulostriate artery (LSA) territory, after adjustment for covariates, larger initial lesion volume (OR 1.80, 95% CI 1.13-2.87; P = 0.014) and greater decreases in LSA total length (OR 0.59, 95% CI 0.36-0.96; P = 0.035) were independently associated with hemorrhagic foci formation. The extent of ischemia in the initial infarct is predictive of the presence of hemorrhagic residues. Our findings contribute to the current understanding of the mechanisms underlying the evolution of RSSIs.

    在近期单个皮质下梗塞(RSSI)的长期演变中,腔隙周围的出血灶在很大程度上仍未被探索。我们的目标是确定RSSI患者出血灶的患病率、特征和预测因素。从一项前瞻性、纵向的RSSI研究中,我们招募了在基线和卒中发病后大约一年接受多模式MRI评估的患者。用磁化率加权成像(SWI)确定出血灶。在101例RSSI患者中,近一半(n=45,44.6%)的患者在随访的SWI上发现了RSSI指数范围内的出血灶。有出血灶形成的RSSI与无出血灶的RSSI相比,随访时间长(中位数449d比401d,P=0.005),位于前循环的可能性高(88.9%比64.3%,P=0.003)。出血灶还与较大的病灶(P<0.001)、较高的空洞形成比例(P=0.003)、较高的基线NIHSS评分(P=0.004)和较差的功能预后(P=0.001)相关。在豆纹动脉区域的RSSI子集中,调整协变量后,较大的初始病变体积(OR1.8,95%CI1.13~2.87;P=0.014)和较大的豆纹动脉全长减少(OR0.59,95%CI0.36~0.96;P=0.035)与出血灶的形成独立相关。脑梗塞初期的缺血程度预示着出血残留物的存在。我们的发现有助于目前对RSSI进化机制的理解。

    REF: Jiang S, Shang WZ, Cui JY, et al. Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts. Transl Stroke Res. Published online December 14, 2023. doi:10.1007/s12975-023-01224-7 PMID: 38095840

  • Platelet Analysis in the Thrombus Plus Serum BNP for Detecting Clot-Related Atrial Fibrillation. Results From the ITACAT Multicentric Registry

    血栓中血小板分析加血清BNP检测血栓相关性心房颤动ITACAT多中心注册的结果

    Occult atrial fibrillation (AF) is a common cause of cryptogenic stroke. This study aimed to investigate the utility of surrogate markers within the clot (clot markers), in combination with serum biomarkers, to identify AF-associated clots in patients who underwent mechanical thrombectomy. Each retrieved thrombus was analyzed to identify fibrin, red blood cells, platelets - CD61 staining (PLT) and T-CD4 lymphocyte/macrophage/monocyte (CD4) profile. Serum biomarkers such as D-dimer, lipoprotein (A), and brain natriuretic peptide (BNP) were also assessed in the acute phase of the stroke. Patients with stroke-related AF and large artery atherosclerosis (LAA) stroke were compared by matched case-control design to identify markers associated with AF clot profile. The predictive abilities of clot markers and serum biomarkers to detect AF clot were tested in patients with cryptogenic stroke. In patients with AF clot, the PLT percentage was higher (66.64% vs. 55.43%, OR = 1.03); CD4 percentage was lower (3.84% vs. 7.95%, OR = 0.95); and BNP marker was higher (2114 pg/ml vs. 276 pg/ml, OR = 1.04) compared to LAA clot. PLT was independently associated to AF-clot (OR, 1.04) but demonstrated moderate ability to identify AF-clot cases (C-test 0.668, p = 0.018). The combination of PLT with BNP significantly improved AF-clot prediction (C-test 0.847, p < 0.001). The clot composition of patients with cryptogenic stroke and AF detection showed four-fold higher PLT and BNP pattern of risk than patients with cryptogenic stroke without AF detection (38.5% vs. 8.7%) (OR = 1.40). Integrating intra-thrombus platelet with serum BNP offers a promising approach for detecting AF-associated clots in patients with cryptogenic stroke.

    隐匿性心房颤动(AF)是隐源性卒中的常见原因。本研究旨在探讨血栓内替代标记物(血栓标记物)与血清生物标记物相结合,在接受机械血栓切除术的患者中识别房颤相关血栓的实用性。对每一个回收的血栓进行分析,以确定纤维蛋白、红细胞、血小板CD61染色(PLT)和T-CD4淋巴细胞/巨噬细胞/单核细胞(CD4)图谱。中风急性期的血清生物标志物,如D-二聚体、脂蛋白(A)和脑利钠肽(BNP)也被评估。采用配对病例对照设计对卒中相关房颤和大动脉粥样硬化(LAA)卒中患者进行比较,以确定与房颤凝块特征相关的标志物。在隐源性卒中患者中测试血栓标志物和血清生物标志物检测房颤血栓的预测能力。房颤血栓患者的PLT百分比高于LAA血栓患者(66.64%vs.55.43%,OR=1.03),CD4百分比低于LAA血栓患者(3.84%vs.7.95%,OR=0.95),BNP标志物高于LAA血栓患者(2114 pg/ml vs.276 pg/ml,OR=1.04)。PLT与房颤血栓独立相关(OR1.04),但对房颤血栓的识别能力中等(C检验0.668,p=0.018)。血小板和脑钠素的结合显著改善了房颤-血栓的预测(C-检验0.847,p<0.001)。伴房颤的隐源性卒中患者的血栓成分显示PLT和BNP模式的风险是未检出房颤的隐源性卒中患者的四倍(38.5%vs.8.7%)(OR=1.40)。血栓内血小板与血清BNP的结合为检测不明原因卒中患者的房颤相关血栓提供了一种有前景的方法。

    REF: Pagola J, Juega J, Dorado L, et al. Platelet Analysis in the Thrombus Plus Serum BNP for Detecting Clot-Related Atrial Fibrillation. Results From the ITACAT Multicentric Registry. Transl Stroke Res. Published online December 13, 2023. doi:10.1007/s12975-023-01220-x PMID: 38091189

  • Time Dimension Influences Severity of Stroke and Heightened Immune Response in Mice

    时间维度对小鼠卒中严重程度和免疫应答增强的影响

    Ischemic stroke is caused by obstructed cerebral blood flow, which results in neurological injury and poor outcomes. Pro-inflammatory signaling from both residential and infiltrating immune cells potentiates cerebral injury and worsens patient outcomes after stroke. While the occurrence of a stroke exhibits a time-of-day-dependent pattern, it remains unclear whether disrupted circadian rhythms modulate post-stroke immunity. In this study, we hypothesized that stroke timing differentially affects immune activation in mice. Following middle cerebral artery occlusion (MCAO), circadian genes BMAL1, CLOCK, Cry1, and Cry2 elevated at ZT06, with a significant difference between ZT06 and ZT18. Conversely, expression of the negative limb circadian clock gene, Per1, decreased at ZT06 and ZT18 in stroke mice compared to sham. Paralleling these circadian gene expression changes, we observed a significant increase in TNF-α and a decrease in IL-10 expression at 48 h post-MCAO, when the procedure was performed at ZT06 (MCAO-ZT6), which corresponds to a deep sleep period, as compared to when the stroke was induced at ZT12 (MCAO-ZT12), ZT18 (MCAO-ZT18), or ZT0 (MCAO-ZT12). Similarly, increased pro-inflammatory, decreased anti-inflammatory monocytes, and increased NLRP3 were observed in blood, while changes in the expression of CD11b and Iba1 were noted within brain tissue at 48 h of MCAO-ZT06, as compared to MCAO-ZT18. Consistent with the increased immune response, infarct volume and sensorimotor deficits were greater in MCAO-ZT06 mice compared to MCAO-ZT18 mice at 48 h. Finally, we found reduced weight and length of the spleen while splenocytes showed significant time-dependent changes in Tregs, Bregs, and monocytes in MCAO-ZT06 mice. Taken together, this study demonstrates that circulating and splenic immune responses following ischemic stroke exhibit a circadian expression pattern which may contribute to time-of-day-dependent stroke outcomes.

    缺血性中风是由脑血流受阻引起的,导致神经损伤和预后不良。来自居留和渗入的免疫细胞的促炎信号加重了脑损伤,并恶化了中风后的患者预后。虽然中风的发生表现出一天中的时间依赖模式,但目前尚不清楚昼夜节律紊乱是否调节了中风后的免疫力。在这项研究中,我们假设中风时机对小鼠的免疫激活有不同的影响。大脑中动脉闭塞(MCAO)后,昼夜节律基因BMAL1、Clock、Cry1和Cry2在ZT06升高,ZT06与ZT18差异有统计学意义。相反,与假手术相比,中风小鼠负肢生物钟基因PER1在ZT06和ZT18的表达减少。与这些昼夜节律基因的表达变化相平行,我们观察到在大脑中动脉阻塞后48h,与在大脑中动脉12号(MCAO-ZT12)、ZT18(MCAO-ZT18)或ZT0(MCAO-ZT12)诱发卒中时相比,在对应于深睡眠时期的ZT06(MCAO-ZT6)进行该程序时,肿瘤坏死因子-α显著增加,而IL-10表达显著降低。类似地,与MCAO-ZT18相比,MCAO-ZT06组大鼠血液中促炎症细胞增加,抗炎单核细胞减少,NLRP3增加,而CD11b和Iba1在脑组织中的表达发生了变化。与免疫反应增强一致的是,48h时MCAO-ZT06小鼠的脑梗塞体积和感觉运动障碍比MCAO-ZT18小鼠更大。最后,我们发现MCAO-ZT06小鼠的脾重量和长度减少,而脾细胞在Tregs、Bregs和单核细胞中显示出显著的时间依赖性变化。综上所述,这项研究表明,缺血性中风后的循环和脾免疫反应表现出昼夜节律的表达模式,这可能有助于一天中的时间依赖的中风结果。

    REF: Kamat PK, Khan MB, Siddiqui S, et al. Time Dimension Influences Severity of Stroke and Heightened Immune Response in Mice. Transl Stroke Res. Published online December 13, 2023. doi:10.1007/s12975-023-01226-5 PMID: 38091188

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