Mitophagy in intracerebral hemorrhage:a new target for therapeutic intervention

Intracerebral hemorrhage is a life-threatening condition with a high fatality rate and severe sequelae.However,there is currently no treatment available for intracerebral hemorrhage,unlike for other stroke subtypes.Recent studies have indicated that mitochondrial dysfunction and mitophagy likely relate to the pathophysiology of intracerebral hemorrhage.Mitophagy,or selective autophagy of mitochondria,is an essential pathway to preserve mitochondrial homeostasis by clearing up damaged mitochondria.Mitophagy markedly contributes to the reduction of secondary brain injury caused by mitochondrial dysfunction after intracerebral hemorrhage.This review provides an overview of the mitochondrial dysfunction that occurs after intracerebral hemorrhage and the underlying mechanisms regarding how mitophagy regulates it,and discusses the new direction of therapeutic strategies targeting mitophagy for intracerebral hemorrhage,aiming to determine the close connection between mitophagy and intracerebral hemorrhage and identify new therapies to modulate mitophagy after intracerebral hemorrhage.In conclusion,although only a small number of drugs modulating mitophagy in intracerebral hemorrhage have been found thus far,most of which are in the preclinical stage and require further investigation,mitophagy is still a very valid and promising therapeutic target for intracerebral hemorrhage in the long run.

Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage

Cholesterol is an important component of plasma membranes and participates in many basic life functions,such as the maintenance of cell membrane stability,the synthesis of steroid hormones,and myelination.Cholesterol plays a key role in the establishment and maintenance of the central nervous system.The brain contains 20%of the whole body’s cholesterol,80%of which is located within myelin.A huge number of processes(e.g.,the sterol regulatory element-binding protein pathway and liver X receptor pathway)participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis,intracellular transport,and efflux.Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences.Therefore,we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases.Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype,with high mortality and morbidity.Historical cholesterol levels are associated with the risk of intracerebral hemorrhage.Moreover,secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation,such as neuroinflammation,demyelination,and multiple types of programmed cell death.Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage.In this paper,we review normal cholesterol metabolism in the central nervous system,the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage,and the links between cholesterol metabolism and cell death.We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

Spi1 regulates the microglial/macrophage inflammatory response via the PI3K/AKT/mTOR signaling pathway after intracerebral hemorrhage

Preclinical and clinical studies have shown that microglia and macrophages participate in a multiphasic brain damage repair process following intracerebral hemorrhage.The E26 transformation-specific sequence-related transcription factor Spi1 regulates microglial/macrophage commitment and maturation.However,the effect of Spi1 on intracerebral hemorrhage remains unclear.In this study,we found that Spi1 may regulate recovery from the neuroinflammation and neurofunctional damage caused by intracerebral hemorrhage by modulating the microglial/macrophage transcriptome.We showed that high Spi1expression in microglia/macrophages after intracerebral hemorrhage is associated with the activation of many pathways that promote phagocytosis,glycolysis,and autophagy,as well as debris clearance and sustained remyelination.Notably,microglia with higher levels of Soil expression were chara cterized by activation of pathways associated with a variety of hemorrhage-related cellular processes,such as complement activation,angiogenesis,and coagulation.In conclusion,our results suggest that Spi1 plays a vital role in the microglial/macrophage inflammatory response following intracerebral hemorrhage.This new insight into the regulation of Spi1 and its target genes may advance our understanding of neuroinflammation in intracerebral hemorrhage and provide therapeutic targets for patients with intracerebral hemorrhage.

ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage

MIcroglia/macrophage-mediated erythrophagocytosis plays a crucial role in hematoma clearance after intracerebral hemorrhage.Dynamic cytoskeletal changes accompany phagocytosis.However,whether and how these changes are associated with microglia/macrophage-mediated erythrophagocytosis remain unclear.In this study,we investigated the function of acetylatedα-tubulin,a stabilized microtubule form,in microglia/macrophage erythrophagocytosis after intracerebral hemorrhage both in vitro and in vivo.We first assessed the function of acetylatedα-tubulin in erythrophagocytosis using primary DiO GFP-labeled red blood cells co-cultured with the BV2 microglia or RAW264.7 macrophage cell lines.Acetylatedα-tubulin expression was significantly decreased in BV2 and RAW264.7 cells during erythrophagocytosis.Moreover,silencingα-tubulin acetyltransferase 1(ATAT1),a newly discoveredα-tubulin acetyltransferase,decreased Ac-α-tub levels and enhanced the erythrophagocytosis by BV2 and RAW264.7 cells.Consistent with these findings,in ATAT1-/-mice,we observed increased ionized calcium binding adapter molecule 1(Iba1)and Perls-positive microglia/macrophage phagocytes of red blood cells in peri-hematoma and reduced hematoma volume in mice with intracerebral hemorrhage.Additionally,knocking out ATAT1 alleviated neuronal apoptosis and pro-inflammatory cytokines and increased anti-inflammatory cytokines around the hematoma,ultimately improving neurological recovery of mice after intracerebral hemorrhage.These findings suggest that ATAT1 deficiency accelerates erythrophagocytosis by microglia/macrophages and hematoma absorption after intracerebral hemorrhage.These results provide novel insights into the mechanisms of hematoma clearance and suggest ATAT1 as a potential target for the treatment of intracerebral hemorrhage.

Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis

Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes.

Exosomal miR-23b from bone marrow mesenchymal stem cells alleviates oxidative stress and pyroptosis after intracerebral hemorrhage

Our previous studies showed that miR-23b was downregulated in patients with intracerebral hemorrhage(ICH). This indicates that miR-23b may be closely related to the patho-physiological mechanism of ICH, but this hypothesis lacks direct evidence. In this study, we established rat models of ICH by injecting collagenase Ⅶ into the right basal ganglia and treating them with an injection of bone marrow mesenchymal stem cell(BMSC)-derived exosomal miR-23b via the tail vein. We found that edema in the rat brain was markedly reduced and rat behaviors were improved after BMSC exosomal miR-23b injection compared with those in the ICH groups. Additionally, exosomal miR-23b was transported to the microglia/macrophages, thereby reducing oxidative stress and pyroptosis after ICH. We also used hemin to mimic ICH conditions in vitro. We found that phosphatase and tensin homolog deleted on chromosome 10(PTEN) was the downstream target gene of miR-23b, and exosomal miR-23b exhibited antioxidant effects by regulating the PTEN/Nrf2 pathway. Moreover, miR-23b reduced PTEN binding to NOD-like receptor family pyrin domain containing 3(NLRP3) and NLRP3 inflammasome activation, thereby decreasing the NLRP3-dependent pyroptosis level. These findings suggest that BMSC-derived exosomal miR-23b exhibits antioxidant effects through inhibiting PTEN and alleviating NLRP3 inflammasome-mediated pyroptosis, thereby promoting neurologic function recovery in rats with ICH.

Piezo1 suppression reduces demyelination after intracerebral hemorrhage

Piezo1 is a mechanically-gated calcium channel.Recent studies have shown that Piezo1,a mechanically-gated calcium channel,can attenuate both psychosineand lipopolysaccharide-induced demyelination.Because oligodendrocyte damage and demyelination occur in intracerebral hemorrhage,in this study,we investigated the role of Piezo1 in intracerebral hemorrhage.We established a mouse model of cerebral hemorrhage by injecting autologous blood into the right basal ganglia and found that Piezo1 was largely expressed soon(within 48 hours)after intracerebral hemorrhage,primarily in oligodendrocytes.Intraperitoneal injection of Dooku1 to inhibit Piezo1 resulted in marked alleviation of brain edema,myelin sheath loss,and degeneration in injured tissue,a substantial reduction in oligodendrocyte apoptosis,and a significant improvement in neurological function.In addition,we found that Dooku1-mediated Piezo1 suppression reduced intracellular endoplasmic reticulum stress and cell apoptosis through the PERK-ATF4-CHOP and inositol-requiring enzyme 1 signaling pathway.These findings suggest that Piezo1 is a potential therapeutic target for intracerebral hemorrhage,as its suppression reduces intracellular endoplasmic reticulum stress and cell apoptosis and protects the myelin sheath,thereby improving neuronal function after intracerebral hemorrhage.

Knockdown of NADPH oxidase 4 reduces mitochondrial oxidative stress and neuronal pyroptosis following intracerebral hemorrhage

Intracerebral hemorrhage is often accompanied by oxidative stress induced by reactive oxygen species,which causes abnormal mitochondrial function and secondary reactive oxygen species generation.This creates a vicious cycle leading to reactive oxygen species accumulation,resulting in progression of the pathological process.Therefore,breaking the cycle to inhibit reactive oxygen species accumulation is critical for reducing neuronal death after intracerebral hemorrhage.Our previous study found that increased expression of nicotinamide adenine dinucleotide phosphate oxidase 4(NADPH oxidase 4,NOX4)led to neuronal apoptosis and damage to the blood-brain barrier after intracerebral hemorrhage.The purpose of this study was to investigate the role of NOX4 in the circle involving the neuronal tolerance to oxidative stress,mitochondrial reactive oxygen species and modes of neuronal death other than apoptosis after intracerebral hemorrhage.We found that NOX4 knockdown by adeno-associated virus(AAV-NOX4)in rats enhanced neuronal tolerance to oxidative stress,enabling them to better resist the oxidative stress caused by intracerebral hemorrhage.Knockdown of NOX4 also reduced the production of reactive oxygen species in the mitochondria,relieved mitochondrial damage,prevented secondary reactive oxygen species accumulation,reduced neuronal pyroptosis and contributed to relieving secondary brain injury after intracerebral hemorrhage in rats.Finally,we used a mitochondria-targeted superoxide dismutase mimetic to explore the relationship between reactive oxygen species and NOX4.The mitochondria-targeted superoxide dismutase mimetic inhibited the expression of NOX4 and neuronal pyroptosis,which is similar to the effect of AAV-NOX4.This indicates that NOX4 is likely to be an important target for inhibiting mitochondrial reactive oxygen species production,and NOX4 inhibitors can be used to alleviate oxidative stress response induced by intracerebral hemorrhage.

Temporal dynamics of microglia-astrocyte interaction in neuroprotective glial scar formation after intracerebral hemorrhage

The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar.We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation.Spatial transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods.During the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue repair.ST analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling activation.Moreover,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar formation.The combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN alone.At the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this.The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH.Inversely,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy.This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.

Cyclophilin D-induced mitochondrial impairment confers axonal injury after intracerebral hemorrhage in mice

The mitochondrial permeability transition pore is a nonspecific transmembrane channel.Inhibition of mitochondrial permeability transition pore opening has been shown to alleviate mitochondrial swelling,calcium overload,and axonal degeneration.Cyclophilin D is an important component of the mitochondrial permeability transition pore.Whether cyclophilin D participates in mitochondrial impairment and axonal injury after intracerebral hemorrhage is not clear.In this study,we established mouse models of intracerebral hemorrhage in vivo by injection of autologous blood and oxyhemoglobin into the striatum in Thy1-YFP mice,in which pyramidal neurons and axons express yellow fluorescent protein.We also simulated intracerebral hemorrhage in vitro in PC12 cells using oxyhemoglobin.We found that axonal degeneration in the early stage of intracerebral hemorrhage depended on mitochondrial swelling induced by cyclophilin D activation and mitochondrial permeability transition pore opening.We further investigated the mechanism underlying the role of cyclophilin D in mouse models and PC12 cell models of intracerebral hemorrhage.We found that both cyclosporin A inhibition and short hairpin RNA interference of cyclophilin D reduced mitochondrial permeability transition pore opening and mitochondrial injury.In addition,inhibition of cyclophilin D and mitochondrial permeability transition pore opening protected corticospinal tract integrity and alleviated motor dysfunction caused by intracerebral hemorrhage.Our findings suggest that cyclophilin D is used as a key mediator of axonal degeneration after intracerebral hemorrhage;inhibition of cyclophilin D expression can protect mitochondrial structure and function and further alleviate corticospinal tract injury and motor dysfunction after intracerebral hemorrhage.Our findings provide a therapeutic target for preventing axonal degeneration of white matter injury and subsequent functional impairment in central nervous diseases.

A novel aged mouse model of recurrent intracerebral hemorrhage in the bilateral striatum

The current animal models of stroke primarily model a single intracerebral hemorrhage(ICH)attack,and there is a lack of a reliable model of recurrent ICH.In this study,we established 16-month-old C57 B L/6 male mouse models of ICH by injecting collagenaseⅦ-S into the left striatum.Twenty-one days later,we injected collagenaseⅦ-S into the right striatum to simulate recurrent ICH.Our results showed that mice subjected to bilateral striatal hemorrhage had poorer neurological function at the early stage of hemorrhage,delayed recovery in locomotor function,motor coordination,and movement speed,and more obvious emotional and cognitive dysfunction than mice subjected to unilate ral striatal hemorrhage.These findings indicate that mouse models of bilateral striatal hemorrhage can well simulate clinically common recurrent ICH.These models should be used as a novel tool for investigating the pathogenesis and treatment targets of recurrent ICH.

Injectable collagen scaffold with human umbilical cordderived mesenchymal stem cells promotes functional recovery in patients with spontaneous intracerebral hemorrhage:phase Ⅰ clinical trial

Animal expe riments have shown that injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can promote recovery from spinal cord injury.To investigate whether injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells can be used to treat spontaneous intracerebral hemorrhage,this non-randomized phase I clinical trial recruited patients who met the inclusion criteria and did not meet the exclusion crite ria of spontaneous intracerebral hemorrhage treated in the Characteristic Medical Center of Chinese People’s Armed Police Force from May 2016 to December 2020.Patients were divided into three groups according to the clinical situation and patient benefit:control(n=18),human umbilical cord-derived mesenchymal stem cells(n=4),and combination(n=8).The control group did not receive any transplantation.The human umbilical cord-derived mesenchymal stem cells group received human umbilical cord-derived mesenchymal stem cell transplantation.The combination group received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells.Patients who received injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells had more remarkable improvements in activities of daily living and cognitive function and smaller foci of intra cerebral hemorrhage-related encephalomalacia.Severe adve rse events associated with cell transplantation were not observed.Injectable collagen scaffold with human umbilical cord-derived mesenchymal stem cells appears to have great potential treating spontaneous intracerebral hemorrhage.

Elevated soluble fas blood concentrations in patients dying from spontaneous intracerebral hemorrhage

BACKGROUND Several studies of spontaneous intracerebral hemorrhage(SICH)patients have shown apoptotic changes in brain samples after hematoma evacuation.However,there have been no data on the association between blood concentrations of soluble fas(sFas)(the main surface death receptor of the extrinsic apoptosis pathway)and the prognosis of spontaneous intracranial hypotension(SIH)patients.AIM To determine whether there is an association between blood sFas concentrations and SICH patient mortality.METHODS We included patients with severe and supratentorial SIH.Severe was defined as having Glasgow Coma Scale<9.We determined serum sFas concentrations at the time of severe SICH diagnosis.RESULTS We found that non-surviving patients(n=36)compared to surviving patients(n=39)had higher ICH score(P=0.001),higher midline shift(P=0.004),higher serum sFas concentrations(P<0.001),and lower rate of early hematoma evacuation(P=0.04).Multiple logistic regression analysis showed an association between serum sFas concentrations and 30-d mortality(odds ratio=1.070;95%confidence interval=1.014-1.129;P=0.01)controlling for ICH score,midline shift,and early hematoma evacuation.CONCLUSION The association of blood sFas concentrations and SICH patient mortality is a novel finding in our study.

HICH患者血清VEGF、MIP-1α、CD40水平变化及与预后的关系

目的 探究高血压脑出血(HICH)患者血清血管内皮生长因子(VEGF)、巨噬细胞炎症蛋白-1α(MIP-1α)、CD40水平变化及与预后的关系。方法 选取2020年1月至2023年1月期间于达州市中西医结合医院/成都医学院附属达州市中西医结合医院神经外科就诊的208例HICH患者及同期就诊的208例非HICH的脑血管疾病患者临床资料,分别纳入HICH组和对照组,比较两组患者入院时血清VEGF、MIP-1α、CD40水平差异,经受试者工作特征曲线(ROC)分析入院时血清VEGF、MIP-1α、CD40水平对HICH患者的诊断效能。记录HICH组患者格拉斯哥预后量表(GOS)评分结果,并以其作为预后评估标准将其分为预后不良组(GOS≤3分,n=89)和预后良好组(GOS>3分,n=119)两亚组,比较两亚组患者入院时血清VEGF、MIP-1α、CD40水平和GOS评分的关系;经Pearson相关系数分析HICH患者入院时血清VEGF、MIP-1α、CD40水平与GOS评分的相关性。结果 HICH组入院时的血清VEGF、MIP-1α、CD40水平显著高于对照组,差异有统计学意义(P<0.05)。经受试者工作特征曲线(ROC)分析,血清VEGF、MIP-1α、CD40水平三者单一和联合指标检测的ROC曲线下面积(AUC)值分别是0.828、0.874、0.843、0.930;截断值分别是356.73 pg/mL、350.81 ng/mL、420.60 pg/mL;敏感度分别是66.35%、66.83%、60.01%、86.06%;特异度分别是88.94%、93.27%、91.35%、85.58%(P<0.05)。根据预后评估标准,HICH组中89例患者为预后不良,119例患者预后良好。其中,预后不良组入院时的血清VEGF、MIP-1α、CD40水平显著高于预后良好组,差异有统计学意义(P<0.05)。Pearson相关系数分析显示,HICH患者入院时血清VEGF、MIP-1α、CD40水平与GOS评分呈负相关(P<0.05)。结论 血清VEGF、MIP-1α、CD40等因子在HICH患者中呈现高表达,且影响患者的预后情况,可作为早期临床上的辅助指标,为HICH患者的治疗和康复提供更精准的指导。

机器人辅助下HICH患者颅内血肿穿刺引流术

高血压脑出血(HICH)是一种致死率和致残率均较高的脑卒中类型,外科手术作为HICH的重要治疗方式之一,能有效解除血肿压迫、缓解颅内高压。随着神经外科手术机器人的不断完善与升级,微创外科技术在HICH治疗中已取得重大突破,机器人辅助颅内血肿穿刺引流可有效提高引流管置入精准度并缩短手术时间,在治疗HICH患者中具有明显优势。本文将介绍机器人辅助下颅内血肿穿刺引流术的详细操作步骤,为HICH患者的临床治疗提供参考。

Aggressive Blood Pressure Control in Intracerebral Hemorrhage (the Abc-Ich Study)—A Pilot Study

Spontaneous intracerebral hemorrhage (ICH) accounts for one fifth of all strokes and is associated with an extremely high rate of morbidity and mortality. Affecting greater than 1 million people a year, ICH will leave the majority of its’ patients significantly disabled or dead. An initially high systolic blood pressure upon presentation is associated with hematoma expansion, peri-hema- toma expansion, and increased mortality. The relationship between blood pressure, the degree of blood pressure control and hematoma expansion has yet to be defined, but the literature has ob- served a relationship between tightly controlled blood pressures and decreased hematoma expansion. There have been many proposed mechanisms to explain this effect. Larger initial hematomas may lend greater hydrostatic forces and this could result in greater total hematoma volume, and greater surrounding edema. Recent literature has suggested that blood pressure reductions in acute ICH may be tolerated because of reduced metabolism, and preserved autoreguation in the peri-hematoma region. The volume of the hematoma is a critical determinant of mortality and functional outcome after intracerebral hemorrhage, and early hematoma growth is an important cause of neurologic deterioration. An increase in volume of more than thirty-three percent is detectable on repeated computed tomography (CT) in thirty-eight percent of patients initially scanned within the first three hours of onset of symptoms;in two thirds of these cases this change is noticeable on CT within the first hour. This supports the hypothesis that early aggressive blood pressure optimization would decrease hematoma size and edema. This is further supported by the fact that patients with high blood pressure and acute intracerebral hemorrhage have worse outcomes than their counterparts. We hypothesize that prompt and aggressive, early blood pressure reduction in emergency department patients with acute spontaneous intracerebral hemorrhage will result in a reduction of early hematoma growth. The study institution is a large urban emergency department and tertiary care stoke center, with over 55,000 emergency department visits per year. This prospective cohort study compared the results and outcomes observed within the enrolled prospective study population, to the results and outcomes of a matched historical cohort population (future patients with intracranial hemorrhage that did not receive the ABC-ICH protocol). Methods and Material: A nicardipine infusion was administered to optimize blood pressure in all patients presenting with intracerebral hemorrhage with a target mean arterial pressure (MAP) of 80 - 110. Hematoma volume (primary outcome measure) was measured on cat scans at time of presentation and at twenty-four hours. The hematoma volume in the enrolled prospective study population was compared to those of a matched cohort (patients with intracranial hemorrhage that did not receive the ABC-ICH protocol following the conclusion of the study). Results: One hundred total patients were enrolled into the study. Fifty patients were enrolled prospectively in the study and matched to a similar group of fifty cohort patients. The difference in the mean change of hematoma volume at twenty-four hours was 7.29 ml (control) and 2.84 ml (study). The result was an absolute decrease in hematoma size of 4.45 ml in the group treated aggressively with nicardapine for blood pressure reduction within one hour of their initial presentation. Conclusions: These results support the previous research suggesting that aggressive blood pressure control in intracerebral hemorrhage reduces hematoma growth, however the clinical benefit of such a reduction will have to be evaluated in ongoing research.

2024美国卒中学会Code ICH脑出血早期一体化诊治方案专家共识解读

脑出血(intracerebral hemorrhage,ICH)的急性期治疗一直是备受关注的话题。2024年来自多个国家的ICH专家在Stroke杂志上发布了急性自发性ICH的早期综合管理方案——Code ICH。该专家共识围绕ICH的急性期脑损伤机制、早期一体化诊治方案及未来研究方向提出了详细的推荐意见。本文将对该专家共识进行解读。

Ang-1、HO-1、NGF和MMSE评分在HICH疗效评价中的价值

目的探讨血管生成素-1(Ang-1)、血红素氧化酶1(HO-1)、神经生长因子(NGF)和简易智能精神状态检查量表(MMSE)评分在高血压脑出血(HICH)疗效评估中的价值。方法选取2018年2月—2022年2月张家口市第一医院HICH患者152例(HICH组)和健康体检者68名(正常对照组)。所有患者均接受去骨瓣血肿清除术、支持治疗和脑蛋白水解物治疗,根据疗效分为有效组(105例)和无效组(47例)。分别检测HICH患者治疗前、治疗后和正常对照者的血清Ang-1、HO-1、NGF水平,采用MMSE评分评估HICH患者的认知功能。采用多因素Logistic回归分析评估HICH无效的危险因素。采用受试者工作特征(ROC)曲线评价Ang-1、HO-1、NGF、MMSE评分判断HICH疗效的效能。结果HICH组治疗前血清Ang-1、NGF水平和MMSE评分低于正常对照组(P<0.05),血清HO-1水平高于正常对照组(P<0.05)。有效组治疗后血清Ang-1、NGF水平和MMSE评分显著高于治疗前(P<0.05),血清HO-1水平低于治疗前(P<0.05);无效组治疗前、治疗后各项指标差异均无统计学意义(P>0.05)。无效组治疗前、治疗后血清Ang-1、NGF水平和MMSE评分均显著低于有效组(P<0.05),血清HO-1水平均显著高于有效组(P<0.05)。高血压3级和治疗前HO-1升高、Ang-1降低、NGF降低、MMSE评分降低是HICH患者治疗无效的危险因素[比值比(OR)值分别为2.324、1.442、0.549、0.671、0.716,95%可信区间(CI)分别为1.357~5.468、1.203~4.535、0.211~0.884、0.316~0.854、0.461~0.973,P<0.05]。血清Ang-1、HO-1、NGF水平和MMSE评分单项和联合检测判断HICH疗效的ROC曲线下面积(AUC)分别为0.859、0.848、0.856、0.820、0.958。结论血清Ang-1、NGF、HO-1水平与HICH患者的临床疗效有关,或可作为HICH疗效评估的潜在指标。

成人ICH患者基于MRI-DWI检查远隔病灶发生危险因素研究

目的探讨成人自发性脑出血(ICH)患者基于MRI-DWI检查远隔病灶发生危险因素,旨在为临床早期发现远隔病灶并给予针对性防治干预措施提供更多参考。方法回顾性选取2016年1月—2021年6月山东颐养健康集团莱芜中心医院收治的406例成人ICH患者作为研究对象,均行MRI-DWI检查,并根据是否出现远隔病灶分组,包括出现远隔病灶组(78例)和未出现远隔病灶组(328例),分析一般资料和实验室检查指标,采用多因素Logistic回归模型评价成人ICH患者远隔病灶发生独立危险因素。结果406例患者中78例出现远隔病灶,病灶数共110个,包括皮层-皮层下90个,基底节区16个,脑干和小脑各2个;远隔病灶直径2~20 mm,平均直径(8.33±3.69)mm,其中血肿对侧半球出现84个。出现远隔病灶组收缩压(SBP)水平、舒张压(DBP)水平、白细胞计数(WBC)水平、中性粒细胞计数(NEU)水平、中性粒细胞与淋巴细胞比值(NLR)水平及空腹血糖水平均显著高于未出现远隔病灶组,差异有统计学意义(P<0.05);单因素分析结果显示,SBP、DBP、WBC、NEU、NLR及空腹血糖水平均与成人ICH患者远隔病灶发生有关(P<0.05);多因素Logistic回归模型分析结果显示,高空腹血糖、高NEU及高NLR水平均是成人ICH患者远隔病灶发生独立危险因素(P<0.05)。结论高空腹血糖、高NEU及高NLR水平成人ICH患者更易发生基于MRI-DWI检查远隔病灶,且多见皮层-皮层下区域。

Correlation of free radical level and apoptosis after intracerebral hemorrhage in rats

Objective To investigate the correlation of perihematomal free radical level and neuronal apoptosis following the intracerebral hemorrhage （ICH）. Methods Animals were randomly divided into 4 groups： sham operation group, model group, 1 mg/kg edaravone group, and 3 mg/kg edaravone group. Each group was then divided into seven subgroups, in which the rats were correspondingly killed at 6 h, 12 h, 24 h, 48 h, 72 h, 7 d or 14 d （n = 1 in each subgroup of the sham group, and n = 6 in each subgroup of the other 3 groups）. By Horseley-Clarke technique, autoblood （80 μL） were administered into the left caudate putamen of SD rats in a double administration-withdrawal way. Rats in the sham group were needled in but not administered with autoblood. The ICH model was then evaluated by Bederson＇s scale. Around the hematoma, the levels of malonaldehyde （MDA） and hydroxyl radical were tested by spectrophotometer, and the process of apoptosis was tested by terminal deoxynucleofidyltransferase-mediated dUTP-biotin nick end labeling （TUNEL） method. Results （1） ICH significantly increased the levels of MDA and hydroxyl radicals. Significant differences in MDA and hydroxyl radical contents were observed among the four groups. （2） In the sham group, a small number of TUNEL-positive cells were found. In the other three groups, the TUNEL-positive cells were observed at 6 h, increased significantly at 24 h, and reached peak level at 3 d, then fell profoundly at 7 d, but remained detectable at 14 d. （3） The positive correlation existed between apoptosis and free radical level （r = 0.2003）, and existed between apoptosis and MDA content （r = 0.6563） in the brain. Conclusion Post-hemorrhagic apoptosis was related to the production of free radicals, indicating that the elevated free radicals following the ICH could induce neuron and glial cell apoptosis.