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Background and Objectives: The antifibrinolytic agent tranexamic acid has been tested in intracerebral hemorrhage trials with overall neutral results. Ongoing contrast extravasation on CT angiography (spot sign) can identify individuals with ongoing bleeding who may benefit from anti-fibrinolytic therapy. We aimed to investigate the effect of tranexamic acid on hematoma growth in patients with spot signs treated within 4.5 hours of onset., Methods: We conducted a systematic review and individual patient meta-analysis, which we report according to the Preferred Reporting Items for Systematic Review and Meta-analyses of Individual Participant Data guidelines. PubMed and Embase were searched from inception to May 29, 2023, using the terms ((stroke) AND (randomised OR randomized) AND (tranexamic acid) AND (haemorrhage OR hemorrhage)). We included randomized trials comparing tranexamic acid with placebo in participants with primary intracerebral hemorrhage who had a spot sign and who had follow-up imaging within the required timeframe. Individual patient data were provided by each study and were integrated by the coordinating center. Data were pooled using a random-effects model. The primary endpoint was hematoma growth within 24 hours, defined as ≥33% relative or ≥6 mL absolute hematoma expansion compared with baseline, analyzed using mixed-effects-modified Poisson regression with robust standard errors, adjusted for baseline hematoma volume. Safety outcomes were mortality and major thromboembolic events within 90 days., Results: Of 197 studies identified, 3 were eligible, contributing 162 participants for the primary analysis (60 female and 102 male). Hematoma growth occurred in 36 of 74 (49%) participants treated with tranexamic acid, compared with 48 of 88 (55%) participants treated with placebo (adjusted risk ratio 0.86, 95% CI 0.84-0.89, p < 0.001). Adjusted median absolute hematoma growth was 1.60 mL (95% CI 0.77-2.43) lower with tranexamic acid vs placebo. No differences in functional outcome or safety were observed., Discussion: Tranexamic acid modestly reduced hematoma growth in patients with CT angiography spot signs treated within 4.5 hours of onset. Given the trials in the meta-analysis were individually neutral, these results require further validation before clinical application.

Background: Hematoma clearance is crucial for treating intracerebral hemorrhage (ICH). Currently, there is a lack of pharmacological therapy aimed at promoting hematoma absorption. Meningeal lymphatic system, as a drain of brain, is a potential therapeutic approach in ICH. Panax Notoginseng Saponins (PNS), proven to promote lymphangiogenesis in periphery, effectively reduces hematoma in ICH patients. However, the potential pharmacological effect of PNS on meningeal lymphatic vessels (MLVs) remains unknown., Purpose: In this study, we aimed to investigate the impact of PNS on the meningeal lymphatic system and ICH., Methods: The collagenase-ICH model was conducted to investigate the effect of PNS. Behavioral tests, including modified neurological severity score (mNSS) and foot-fault test, and hematoma volume were used to estimate the neurological function and curative effect. The structure and drainage function of MLVs was detected by immunohistochemical staining. Visudyne intracisternal magna injection combined with red laser photoconversion was performed to ablate MLVs. RNA-sequencing was used to obtain mRNA profiles for mechanistic investigation., Results: The meningeal lymphatic drainage function was enhanced after ICH on day 14 without obvious lymphangiogenesis. Additionally, PNS further facilitated the process of drain with simultaneously inducing lymphangiogenesis. Moreover, ablation of MLVs by photoconverting of visudyne significantly blocked the benefits of neurological deficits improvement and hematoma absorption conducted by PNS. Furthermore, RNA-sequencing revealed that PNS regulated axonogenesis and inflammation, relying on the intact MLVs. In which, solute carrier family 17 member 7 (Slc17a7) and tumor necrosis factor (Tnf) were identified as bottleneck and hub nodes of the protein-protein interaction network of target genes, respectively., Conclusion: PNS might be effective for ICH treatment by enhancing lymphangiogenesis and the meningeal lymphatic drainage function, thereby attenuating inflammation and promoting neurological recovery. The role of PNS in regulation of MLVs was investigated for the first time. This study provides a novel insight for PNS in the medical therapy of ICH., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in our manuscript., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Background: Oral anticoagulation (OAC) is a risk factor for intracerebral hemorrhage (ICH) which is an important source of disability and mortality. OAC-associated ICH (OAC-ICH) patients have worse outcomes as compared to ICH patients not on OAC, likely because of the associated larger stroke volumes, higher propensity to intraventricular hemorrhage, and a higher risk of rebleeding. Although current guidelines recommend that OAC should be reversed quickly, many health care systems have not developed a process for optimizing that aspect of care., Methods: Through the IMPROVE Stroke Care Consortium, a group of nine Hub hospitals and their 57 regional community hospitals, a systems of care improvement project was implemented. Performance reviews identified best practices which were disseminated throughout all centers. We compared the median door-to-reversal (DTR) time before and after an institutional campaign to speed the process with a target time of 60 min., Results: Over two years of the study, there were 6,699 ischemic strokes, 152 subarachnoid hemorrhages, and 889 intracerebral hemorrhages. During that time, 73 ICH patients received reversal agents emergently. The overall baseline median DTR time was 123 min (IQR 99, 361 minutes). By the end of the program, the median DTR time had trended down to 84 min (IQR 58.5, 151 min) which is a 31.7 % reduction of DTR from baseline, though times remained somewhat variable (p=0.08)., Conclusions: An integrated stroke systems of care approach was associated with a reduction in DTR times for patients presenting with acute ICH and concurrent use of anticoagulants despite lack of definitive guidelines around targets for OAC reversal times or operational guidance on protocols and agents., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brad Kolls, MD, PhD reports financial support was provided by Medtronic Inc. Brad Kolls, MD, PhD reports financial support was provided by Daiichi Sankyo Inc. Brad Kolls, MD, PhD reports financial support was provided by Chiesi Pharmaceuticals Inc. Brad Kolls, MD, PhD reports financial support was provided by Pulsara. Brad Kolls, MD, PhD reports financial support was provided by Corazon. Brad Kolls, MD, PhD reports financial support was provided by Amwell. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Intracerebral hemorrhage, is a cerebrovascular disease with high morbidity, mortality, and disability. Due to the lack of effective clinical treatments, the development of new drugs to treat intracerebral hemorrhage is necessary. In recent years, ferroptosis has been found to play an important role in the pathophysiological process of intracerebral hemorrhage, which can be treated by inhibiting ferroptosis and thus intracerebral hemorrhage. This article aims to explain the mechanism of ferroptosis and its relationship to intracerebral hemorrhage. In the meantime, it briefly discusses the molecules identified to alleviate intracerebral hemorrhage by inhibiting ferroptosis, along with other clinical agents that are expected to treat intracerebral hemorrhage through this mechanism. In addition, a brief overview of the morphological alterations of different forms of cell death and their role in ICH is provided. Finally, the challenges that may arise in translating ferroptosis inhibitors from basic research to clinical use are presented. This article serves as a reference and provides insights to aid in the treatment of intracerebral hemorrhage in the clinic., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Hemorrhagic strokes constitute 10-15% of all strokes and have the worst mortality and morbidity of all subtypes. Mortality and morbidity of spontaneous intracerebral hemorrhage (sICH) are often secondary to the effects of inflammation, brain edema, and swelling. Studies have shown that celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, reduces perihematomal edema formation and inflammation. This study aimed to examine the impact of celecoxib on sICH outcomes., Methods: TriNetX, a multi-institutional research database, was retrospectively queried to identify patients with sICH. Outcomes in patients who received celecoxib within 5 days (cohort 1) were analyzed and compared to those in patients who did not receive celecoxib (cohort 2). The primary end point was mortality within 1 year of sICH. Secondary end points included ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures. Further analysis was performed to assess these outcomes for patients treated with ibuprofen, a nonselective COX inhibitor., Results: After propensity score matching, 833 patients were identified in each cohort based on celecoxib use. Mortality at 1 year was significantly reduced in patients with sICH receiving celecoxib compared to those who did not (13.33% vs. 17.77%; p = 0.0124). Risks of ventilator dependence, tracheostomy, percutaneous endoscopic gastrostomy tube placement, craniotomy, deep venous thrombosis, pulmonary embolism, ischemic stroke, transient ischemia attack, myocardial infarction, and seizures were not significantly increased in patients who received celecoxib within 5 days of sICH compared to those who did not receive celecoxib. There was no significant difference in mortality between patients based on ibuprofen administration., Conclusions: There exists a growing interest in using COX-2 as a potential target strategy for neuroprotection in patients with sICH, with some evidence of a mortality benefit in small cohort studies. This study shows that early celecoxib use is associated with decreased mortality in patients with sICH., Competing Interests: Conflict of interest: The authors declare that they have no conflicts of interest. Ethical approval: This study used a deidentified database that does not require prior institutional review board approval., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: There are few proven treatments for acute spontaneous intracerebral haemorrhage, and they all target reducing expansion of the haematoma. The traditional Chinese medicine FYTF-919 (Zhongfeng Xingnao) in an oral solution is comprised of several Chinese herbs that are widely used to treat patients with intracerebral haemorrhage in China on the understanding that they enhance resorption of the haematoma and reduce neuroinflammation. We aimed to provide a reliable assessment of the safety and efficacy of FYTF-919 in patients with moderate to severe acute intracerebral haemorrhage., Methods: We did a pragmatic, multicentre, randomised, double-blind, placebo-controlled trial at 26 hospitals in China. We enrolled adults (age ≥18 years) with a diagnosis of symptomatic spontaneous intracerebral haemorrhage (confirmed by brain imaging) within 48 h after the onset of symptoms (or last seen well), which resulted in moderate to severe neurological impairment defined by scores of at least 8 on the National Institute of Health Stroke Scale or between 7 and 14 inclusive on the Glasgow Coma Scale. Randomisation (1:1) was via a central internet-based system with a block grouping method stratified by provincial location of the hospital, severity of neurological impairment, and site of the haematoma in the brain. FYTF-919 and the placebo were masked through consistency in appearance, smell, taste, and other aspects. Participants were allocated to receive 33 mL (or 25 mL via a nasogastric tube if a participant's swallowing was impaired) of either oral liquid FYTF-919 or matching placebo administered at least 30 min after a meal every 8 h (or 6 h via nasogastric tube) over 24 h for 28 days. The primary efficacy outcome was the utility weighted modified Rankin Scale (a seven-level ordinal scale that ranges from 0 [no symptoms] to 6 [death], in which the utility weights of 0·97, 0·88, 0·74, 0·55, 0·20, -0·19, and 0·00 were assigned to the seven levels respectively, with higher scores indicating a better outcome according to the participants' perspective) at 90 days analysed in a general linear model with adjustment for baseline factors. We did several adjusted and sensitivity analyses. Primary analyses were assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT05066620 and is complete., Findings: Between Nov 24, 2021, and Dec 28, 2023, of 9000 patients screened, 1648 were randomly assigned to treatment, 817 to the FYTF-919 group and 831 to the placebo group. Before receiving any treatment two patients in the FYTF-919 group and five patients in the placebo group immediately withdrew their consent leaving 1641 participants with available primary outcome data in the intention-to-treat population, 815 in the FYTF-919 group and 826 in the placebo group. 1242 (75·7%) participants consumed 80% or more of the study medication and 994 (60·6%) consumed all of it within 28 days. Mean utility weighted modified Rankin Scale scores at 90 days were 0·44 in the FYTF-919 group and 0·44 in the placebo group (difference 0·01, 95% CI -0·02 to 0·04; p=0·63). The neutral result was consistent in adjusted and sensitivity analyses. There was no significant difference in serious adverse events., Interpretation: This large, randomised, placebo-controlled, double-blind, clinical trial showed no effect of the traditional Chinese medicine herbal compound FYTF-919 on functional recovery, survival, and health-related quality of life in patients with moderate to severe intracerebral haemorrhage. The results reaffirm the need for methodologically rigorous, randomised controlled trials to evaluate the effectiveness of existing therapies, including traditional Chinese medicines that are already in widespread use throughout the world., Funding: Key-Area Research and Development Program of Guangdong Province., Competing Interests: Declaration of interests JG received grants from The Department of Science and Technology of Guangdong Province, and Guangzhou Municipal Science and Technology Bureau. GJH is a member of of the data safety monitoring board (DSMB) of the Triple Therapy Prevention of Recurrent Intracerebral Disease Events Trial (TRIDENT) of which CSA is the principal investigator, and is an Associate Editor of Circulation. CSA has received grants from the National Health and Medical Research Council (NHMRC) of Australia, the Medical Research Council and Medical Research Foundation of the UK, and Penumbra and Takeda China. He also reports receiving advisory committee fees from AstraZeneca, is President-elect of the World Stroke Organization, editor-in-chief of Cerebrovascular Diseases, and associate editor of the International Journal of Stroke. He is a member of the DSMB for the PROTECT-MT, MAGIC-MT, and DIST trials. LS has received grants from Takeda China and Unionstrong Technology, and is a member of the DSMB for the PROTECT-MT and STROKE-ICAS trials. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Oxidative stress (OS) and neuroinflammation are critical pathological processes in secondary brain injury (SBI) after intracerebral hemorrhage(ICH), and their intimate interactions initiate and aggravate brain damage. Thus, targeting oxidative stress and neuroinflammation could be a promising therapeutic strategy for ICH treatment. Here, we report a high-performance platform using polydopamine (PDA)-coated diselenide bridged mesoporous silica nanoparticle (PDA-DSeMSN) as a smart ROS scavenger and ROS-responsive drug delivery system. Caffeic acid phenethyl ester (CAPE) was blocked in the pore of DSeMSN by covering the pore with PDA as a gatekeeper. PDA-DSeMSN @CAPE maintained high stability and underwent reactive oxygen species (ROS)-responsive degradation and drug release. The intelligent nanomaterial effectively eliminated ROS, promoted M1 to M2 microglial conversion and suppressed neuroinflammation in vitro and in vivo. Importantly, intravenous administration of PDA-DSeMSN@CAPE specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model with high biological safety. Taking together, the synergistic effect of ROS-responsive drug delivery ability and ROS scavenging ability of PDA-DSeMSN makes it a powerful drug delivery platform and provided new considerations into the therapeutic action to improve ICH-induce brain injury., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were approved by the Laboratory Animal Center in The Second Xiangya Hospital of Central South University with an approval number: 20230132. Consent for publication: Written informed consent for publication was obtained from all participants. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Neuronal apoptosis, oxidative stress, and ferroptosis play a crucial role in the progression of secondary brain injury following intracerebral hemorrhage (ICH). Although studies have highlighted the important functions of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in various experimental models, its precise role and mechanism in ICH remain unclear. In this study, we investigated the effects of DNA-PKcs on N2A cells under a hemin-induced hemorrhagic state in vitro and a rat model of collagenase-induced ICH in vivo . The results revealed a notable increase in DNA-PKcs levels during the acute phase of ICH. As anticipated, DNA-PKcs and γ-H2AX had consistent upregulations after ICH. Administration of NU7441, a selective inhibitor of DNA-PKcs, alleviated neurological impairment, histological damage, and ipsilateral brain edema in vivo . Mechanistically, NU7441 attenuated neuronal apoptosis both in vivo and in vitro , alleviated oxidative stress by decreasing ROS levels, and suppressed ferroptosis by enhancing GPX4 activity. These results suggest that inhibition of DNA-PKcs is a promising therapeutic target for ICH., Competing Interests: The authors declare that they have no competing interests., (© 2024 Gong et al.)

Background: Preclinical studies indicate that the systemic application of C1-inhibitor, clinically used to treat hereditary angioedema, reduces secondary brain injury after ischemic stroke. This study assessed the effect of C1-inhibitor on secondary brain injury after hemorrhagic stroke., Methods: We used an established striatal whole-blood injection mouse model to mimic intracerebral hemorrhage-related secondary brain injury. Based on the spatiotemporal dynamics in our model, we calculated the necessary sample size (n = 24) and determined the most sensitive time point to detect potential group differences (48 h) prior to the experiments. The experimental setup, tissue processing and image analysis adhered to our published protocol. We randomized mice into three groups: C1-inhibitor treatment, placebo, and sham. Histology was standardized by taking eight anatomically predefined slices across the entire lesion. Lesion size, vascular leakage, and inflammatory responses were assessed using automated thresholding and dextran/ICAM1/CD45 intensity mapping. Investigators were blinded to group allocation during the experiment, tissue processing, and image analysis., Results: Whole blood injection resulted in significantly larger lesion size and more pronounced vascular leakage and cellular inflammation compared to the sham group. However, there was no difference in lesion size or inflammatory markers between the C1-inhibitor and placebo groups. In addition, there was no difference in the inflammatory response of the choroid plexus, which has been identified as a central organ orchestrating inflammation after intracerebral hemorrhage., Conclusion: The protective effect of C1-inhibitor might be isolated to pathophysiological processes with a predominant thromboinflammatory component, as in ischemia-reperfusion, but less so in permanent ischemia or intracerebral hemorrhage., Competing Interests: Declarations Ethics approval and consent to participate All experiments were approved by the Swiss Federal Veterinary Office (ZH89/2019). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Germinal matrix-intraventricular hemorrhage (GM-IVH) is one of the most common complications of the preterm newborn. The pathology of the GM-IVH is not completely understood and even regions distant from the lesion area are severely affected. It has been suggested that cerebellar diaschisis may underlie the neurodevelopmental problems that many of these kids show, including cerebral palsy, attention deficit disorders or hyperactivity. Additionally, GM-IVH has no successful treatment. VP3.15 is a dual action phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3β (GSK-3β) inhibitor that limits neuroinflammation and neuronal loss. Therefore, it might also provide a relevant tool to reduce complications associated with GM-IVH. We have used a murine model of GM-IVH to analyze the short and long-term effects of VP3.15 in brain pathology and behavioral complications. In our hands, the induction of unilateral GM-IVH to P7 CD1 mice results in a short-term (P14) compromise of the cerebellar neuronal population and Purkinje cells arborization, an increase of microglia burden in the nuclei and an overall increase of punctuate cerebellar hemorrhages. Whereas brain alterations are no longer observed in the long term (P110), these animals present overt hyperactivity when analyzed in the adulthood, supporting the long-term behavioral impairment. Also, hyperactivity significantly correlates with ipsi and contralateral cerebellar sizes, neuronal densities and myelin basic protein levels. Importantly, treatment with VP3.15 significantly reduces neuronal loss, Purkinje cells simplification, the presence of cerebellar hemorrhages, as well as hyperactivity. Altogether, our data support the neuroprotective effects of VP3.15 in GM-IVH of the PT., Competing Interests: Declaration of Competing Interest Authors have nothing to declare., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Approximately 20% to 30% of intracerebral hemorrhage (ICH) patients were reported to be on antiplatelet therapy (APT), and association between prior APT and prognosis was unclear. We aimed to clarify the impact of APT on the prognosis of ICH through an updated systematic review and meta-analysis, and to further compare the risk of single APT (SAPT) or dual APT (DAPT) prior to ICH as well as the risk associated with various antiplatelet drugs., Methods: EMBASE, MEDLINE via Ovid SP and Web of Science were searched from inception of each database to November 4, 2023. Included studies reported prognosis in both patients with prior APT and those without., Findings: A total of 433,103 patients from 43 studies were included in the meta-analysis. Both univariate and multivariate analyses demonstrated a significant association between prior-APT and an increased mortality risk (odd ratio [OR] 1.43, 95% confidence interval [CI] 1.28-1.59; OR 1.20, 95%CI 1.10-1.30, respectively). The risk was higher in short term follow-up (Univariate OR 1.73, 95%CI 1.22-2.46; Multivariate OR 1.94, 95%CI 1.48-2.55). A notably increased risk of hematoma expansion was also observed in patients previously treated with APT (Univariate OR 1.47, 95%CI 1.12-1.94; Multivariate OR 1.88, 95%CI 1.30-2.71), which were mainly attributed to events within 24 hours. The impact of prior-APT on poor functional outcome was inconsistent between univariate and multivariate analyses. Both direct and indirect comparisons showed that SAPT significantly reduced the risk of mortality (OR 0.67, 95%CI 0.64-0.70; OR 0.84, 95%CI 0.71-0.99) and poor functional outcome (OR 0.84, 95%CI 0.72-0.98; OR 0.81, 95%CI 0.72-0.91) compared to DAPT., Implications: Prior-APT increased the risk of mortality and hematoma expansion in patients with ICH. The increased risk of mortality and hematoma expansion was more obvious in the short term follow-up and within 24 hours, respectively. The effect of APT on poor functional outcome exhibited inconsistency between univariate and multivariate analyses, suggesting that further investigation is warranted to clarify this relationship. In comparison with DAPT, SAPT could decrease the risk of mortality and poor functional outcome. Further studies focusing on antiplatelet drug response, racial differences, and specific APT regimens may help verify the influence., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Post thrombolytic intracerebral hemorrhage (ICH) is associated with higher rate of death or disability in acute ischemic stroke patients. We investigated the relationship between post thrombolytic ICH volume and change in volume and death or disability at 90 days in acute ischemic stroke patients., Methods: We analyzed 110 patents recruited in the Safety Evaluation of 3K3A-APC in Ischemic Stroke (RHAPSODY) trial who received intravenous tissue plasminogen activator (tPA) followed by mechanical thrombectomy (if indicated) and 3K3A-APC or placebo. ICH volume was measured at Day 2 and Day 7 using susceptibility weighted sequence (SWI) on magnetic resonance imaging (MRI). We also calculated the post thrombolytic ICH volume change between Day 2 and Day 7. Outcomes were determined by using utility weighted modified Rankin scale (UW-mRs) at 90-days, Outcomes were determined by using utility weighted modified Rankin scale (UW-mRS) at 90 days. To minimize interpretation bias, outcome assessors were blinded to the treatment allocation and clinical data.We adjusted for age, gender, National Institutes of Health Stroke Scale (NIHSS) score (<10,10-19 and ≥20), location of hemorrhage (single basal ganglia hemorrhage, single lobar, single cerebellum, and multiple sites) in multivariate regression analysis., Results: A total of 88 (80%) of 110 patients had post thrombolytic ICH (mean volume 28.3 ml ± SD 62 ml). The strata of ICH volume were not associated with UW-mRs at 90 days: <20 cc (regression coefficient (RC)-0.05, p= 0.58), 20-39 cc (RC-0.22, p=0.17), or ≥40 cc (RC-0.34, p= 0.083) compared with no ICH after adjusting for potential confounders. Change in ICH mean volume 26.78 ml ±59.68, 52 had increase in volume) between Day 2 and day 7 was not associated with UW-mRS at 90 days (RC -67.71, p= 0.06)., Conclusions: We did not observe any independent effect of post thrombolytic ICH volume on death or disability in acute ischemic stroke patients. Although further studies must be done, our data suggest that strategies to prevent ICH expansion such as antifibrinolytic medications and reduction in ICH volume such as surgical evacuation may not reduce death or disability in acute ischemic stroke patients with post thrombolytic ICH., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Oxidative stress and neuroapoptosis are significant pathological processes that occur in response to intracerebral hemorrhage (ICH), however, the optimal therapeutic strategy to treat these responses remains unknown. Pterostilbene (PTE) influences neural cell survival in in the pathology of a number of neurological diseases, but the mechanisms underlying this influence at present are not clear. The objective of the present study was to examine the potential impact of PTE on mitigating oxidative stress and neuronal apoptosis following ICH, while also elucidating the potential underlying pathways., Material & Method: For in vivo experimentation, male C57BL/6 mice were used to establish ICH models. Wet-to-dry weight ratios were utilized to assess the degree of cerebral edema in the context of PTE intervention. Behavioral experiments were conducted to evaluate neurological dysfunction and cognitive impairment, and hematoxylin and eosin staining was employed to observe histopathological changes in the brain. Furthermore, oxidative stress levels in hippocampal tissues were measured, and cell apoptosis was examined using TUNEL staining and western blotting techniques. In vitro experiments were conducted to evaluate the extent of oxidative stress and neural apoptosis after sirtuin 1 (SIRT1) siRNA treatment. Immunofluorescence cytochemistry was used to analyze the immunofluorescence colocalization of SIRT1 and NeuN., Result: Mice that experienced ICH exhibited worsening neurological deterioration, increased oxidative stress and neuronal cell apoptosis. However, the addition of PTE was found to lessen these effects. Furthermore, PTE was found to activate the SIRT1-mediated Nrf2 pathway in mice with ICH. When SIRT1 was inhibited, levels of oxidative stress and neuronal apoptosis increased, even in the presence of PTE., Conclusion: The present study provided evidence to indicate that PTE can suppress oxidative damage and neuronal apoptosis following ICH by activating the SIRT1/Nrf2 pathway., Competing Interests: Declaration of competing interest Authors report no conflict of interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Secondary brain injury (SBI) is a noticeable contributor to the high mortality and morbidity rates associated with intracerebral hemorrhage (ICH), and effective treatment options remain limited. Cystatin C (CysC) emerges as a novel candidate for SBI intervention. The therapeutic effects and underlying mechanisms of CysC in mitigating SBI following ICH were explored in the current research. An in vivo ICH rat model was established by injecting autologous blood into the right caudate nucleus. Western blotting (WB) was utilized to assess the levels of CysC, cathepsin B (CTSB), and the NLRP3 inflammasome. Subsequently, the ICH rat model was treated with exogenous CysC supplementation or CysC knockdown plasmids. Various parameters, including Evans blue (EB) extravasation, brain water content, and neurological function in rats, were examined. RT-qPCR and WB were employed to determine the expression levels of CTSB and the NLRP3 inflammasome. The co-expression of CTSB, CysC, and NLRP3 inflammasome with GFAP, NeuN, and Iba1 was assessed through double-labeled immunofluorescence. The interaction between CysC and CTSB was investigated using double-labeled immunofluorescence and co-immunoprecipitation. The findings revealed an elevation of CysC expression level, particularly at 24 h after ICH. Exogenous CysC supplementation alleviated severe brain edema, neurological deficit scores, and EB extravasation induced by ICH. Conversely, CysC knockdown produced opposite effects. The expression levels of CTSB and the NLRP3 inflammasome were significantly risen following ICH, and exogenous CysC supplement attenuated their expression levels. Double-labeled immunofluorescence illustrated that CysC, CTSB, and the NLRP3 inflammasome were predominantly expressed in microglial cells, and the interaction between CysC and CTSB was evidenced. CysC exhibited potential in ameliorating SBI following ICH via effectively suppressing the activation of the NLRP3 inflammasome mediated by CTSB specifically in microglial cells. These findings underscore the prospective therapeutic efficacy of CysC in the treatment of ICH-induced complications., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intracerebral hemorrhage (ICH) is a stroke subtype with a high mortality rate (~ 40%). After ICH, the mass effect of the hematoma and edema contribute to raised intracranial pressure (ICP) and poor outcome. Endogenous compensatory mechanisms that blunt ICP elevations include redirection of venous blood and cerebrospinal fluid, along with brain tissue compliance (e.g., decreased cell volume, increased cell density); however, these limited reserves can be exhausted after severe stroke, resulting in decompensated ICP that requires careful clinical management. Management strategies can include administration of hypertonic saline (HTS), an osmotic agent that putatively attenuates edema, and thereby ICP elevations. Evidence regarding the efficacy of HTS treatment following ICH remains limited. In this study, adult male rats were given a collagenase-induced striatal ICH and a bolus of either 3% HTS or 0.9% saline vehicle at 2- and 14-hours post-stroke onset. Neurological deficits, edema, ipsilateral cell volume and density (in areas S1 and CA1), and contralateral CA1 ultrastructural morphology were assessed 24 h post-ICH. Animals had large bleeds (median 108.2 µL), extensive edema (median 83.9% brain water content in ipsilateral striatum), and evident behavioural deficits (median 5.4 neurological deficit scale score). However, HTS did not affect edema (p ≥ 0.4797), behaviour (p = 0.6479), cell volume (p ≥ 0.1079), or cell density (p ≥ 0.0983). Qualitative ultrastructural assessment of contralateral area CA1 suggested that HTS administration was associated with paradoxical cellular swelling in ICH animals. Overall, there was no benefit with administering 3% HTS after ICH., (© 2024. The Author(s).)

Background: Intracerebral hemorrhage (ICH) is a severe form of stroke characterized by high incidence and mortality rates. Currently, there is a significant lack of effective treatments aimed at improving clinical outcomes. Our research team has developed a three-dimensional (3D) biological scaffold that incorporates Bergenin, allowing for the sustained release of the compound., Methods: This 3D biological scaffold was fabricated using a combination of photoinitiator, GEMA, silk fibroin, and decellularized brain matrix (dECM) to encapsulate Bergenin through advanced 3D bioprinting techniques. The kinetics of drug release were evaluated through both in vivo and in vitro studies. A cerebral hemorrhage model was established, and a 3D biological scaffold containing Bergenin was transplanted in situ. Levels of inflammatory response, oxidative stress, and apoptosis were quantified. The neurological function of rats with cerebral hemorrhage was assessed on days 1, 3, and 5 using the turning test, forelimb placement test, Longa score, and Bederson score., Results: The 3D biological scaffold incorporating Bergenin significantly enhances the maintenance of drug concentration in the bloodstream, leading to a marked reduction in inflammatory markers such as IL-6, iNOS, and COX-2 levels in a cerebral hemorrhage model, primarily through the inhibition of the NF-κB pathway. Additionally, the scaffold effectively reduces the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in primary cultured astrocytes, which in turn decreases the production of reactive oxygen species (ROS) and inhibits IL-6 production induced by hemin. Subsequent experiments reveal that the 3D biological scaffold containing Bergenin promotes the activation of the Nrf-2/HO-1 signaling pathway, both in vivo and in vitro, thereby preventing cell death. Moreover, the application of this 3D biological scaffold has been demonstrated to improve drug retention in the bloodstream., Conclusion: This strategy effectively mitigates inflammation, oxidative stress, and cell death in rats with cerebral hemorrhage by inhibiting the NF-κB pathway while concurrently activating the Nrf-2/HO-1 pathway., (© 2024. The Author(s).)

Objective: It remains unclear whether low-molecular-weight heparin (LMWH) is effective and safe for intracerebral hemorrhage (ICH) patients. This study presents a meta-analysis for elucidating effect of LMWH on preventing venous thromboembolism (VTE) among ICH patients., Methods: Articles were located by systematically searching PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG DATA, VIP, and SinoMed databases. The literature was independently screened by two authors, who also extracted data and conducted a qualitative evaluation. With regard to outcomes, their risk ratios (RRs) and 95% confidence intervals (CIs) were computed, and the findings were combined using the random effects model by using Mantel-Haenszel approach., Results: 30 studies involving 2904 patients were analyzed and compared to control group. According to our findings, early low-dose LMWH, prophylaxis for VTE, was related to the markedly reduced deep vein thrombosis (DVT) (3.6% vs. 17.5%; RR, 0.25; 95% CI, 0.18-0.35; p-value<0.00001) and pulmonary embolism (PE) (0.4% vs. 3.2%; RR, 0.29; 95% CI, 0.14-0.57; p-value = 0.003), while the non-significantly increased hematoma progression (3.8% vs. 3.4%; RR, 1.06; 95% CI, 0.68-1.68; p-value = 0.79) and gastrointestinal bleeding (3.6% vs. 6.1%; RR, 0.63; 95% CI, 0.31-1.28; p-value = 0.20). Also, mortality (14.1% vs. 15.8%; RR, 0.90; 95% CI, 0.63-1.28; p-value = 0.55) did not show any significant difference in LMWH compared with control groups., Conclusions: Our meta-analysis suggested that early low-dose of LMWH are safe and effective in ICH patients. More extensive, multicenter, high-quality randomized clinical trials (RCTs) should be conducted to validate the findings and inform clinical practice., Competing Interests: The authors have declared that nocompeting interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: As antioxidant and anti-inflammatory agents, carbonic anhydrase inhibitors can exert potentially useful therapeutic effects following central nervous system trauma, including intracerebral hemorrhage (ICH). However, the therapeutic efficacy of ethoxyzolamide (ETZ) as a novel carbonic anhydrase inhibitor for ICH has not yet been determined., Methods: An autologous blood injection method was used to establish ICH models, which were then used to establish the effects of intraperitoneal injection of ETZ on ICH. Neuronal damage, apoptotic protein expression, oxidative and inflammatory factor content, microglia marker Iba-1 positivity, hepatic and renal pathological changes, and serum concentrations of hepatic and renal function indices were assessed by Nissl staining, western blotting, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, hematoxylin and eosin (HE) staining, and automatic biochemical analysis in brain tissues., Results: The ICH group showed massive hemorrhagic foci; significant increases in brain water content, modified mouse neurological deficit scoring (mNSS) score, pro-apoptotic protein expression, oxidative factors, pro-inflammatory factors, and Iba-1 positivity; and significant reductions in Nissl body size, anti-apoptotic protein expression, and antioxidant factors, all of which were reversed by ETZ in a dose-dependent manner. ETZ has a good biosafety profile with no significant burden on the human liver or kidneys. The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was mildly activated in ICH mice, and was further increased after ETZ injection. Molecular docking experiments revealed that ETZ could dock onto the Nrf2-binding domain of keap1., Conclusions: ETZ, as a novel carbonic anhydrase inhibitor, further activated the Keap1/Nrf2 pathway by docking with the Nrf2-binding domain of keap1, thereby exerting antioxidant, anti-inflammatory, anti-apoptotic, and cerebral neuroprotective effects in ICH mice., (© 2024 The Author(s). Published by IMR Press.)

Background: Tenecteplase is increasingly used off-label as an alternative to alteplase for ischemic stroke thrombolysis. Our aim was to evaluate the safety of tenecteplase versus alteplase in comprehensive real-world data., Methods: We compared the outcomes for adult patients with acute ischemic stroke treated with alteplase or tenecteplase, registered in the Swedish Stroke Register between January 1, 2018 and December 31, 2020. The primary outcome was symptomatic intracerebral hemorrhage or death during hospital stay. Secondary outcomes were death within 90 days, modified Rankin Scale at 90 days, and mean door-to-needle time (DNT)., Results: There were no significant differences in age or risk factors between 6,560 patients (45% women, mean age 74) treated with alteplase and 888 patients (43% women, mean age 74) treated with tenecteplase, although tenecteplase was more commonly used in non-university hospitals, hospitals with high use of thrombolysis, and in wake-up strokes. Tenecteplase was not non-inferior compared to alteplase in terms of symptomatic intracerebral hemorrhage or death during hospital stay (13.2% vs. 10.7%, absolute risk difference [95% confidence interval, CI] 2.5% [0.1 to 4.9%], adjusted odds ratio 1.44 [1.07-1.94]). There were no significant differences in functional outcome or death at 90 days, but tenecteplase was associated with decreased DNT (mean difference 9 min)., Conclusion: Tenecteplase was not non-inferior in safety outcome, although associated with decreased DNT. As accumulating randomized controlled studies support the non-inferiority of tenecteplase regarding functional outcome, it is important to keep scrutinizing the safety outcomes., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 The Author(s). Published by Upsala Medical Society.)

Background: The aim of this study was to explore the molecular mechanism of quercetin in the treatment of intracerebral hemorrhage., Methods: Quercetin target genes and intracerebral hemorrhage target genes were collected from 5 databases. After standardized conversion of the obtained target genes through uniprot database, cross genes of the 2 were obtained using Venny 2.1 online tool. Further, protein interaction relationships were obtained in the String database, and then core target genes were screened and visualized by Cytoscape software, and cross genes were enriched by GO and KEGG pathways. Finally, the active drug ingredients and target proteins were verified and visualized by computer., Results: In this study, 197 quercetin targets were identified as potential targets for the treatment of intracerebral hemorrhage, and 7 core target genes (TP53, STAT3, AKT1, SRC, JUN, TNF, and IL6) were screened. The GO and KEGG analyses further shed light on the molecular mechanisms underlying quercetin's treatment of intracerebral hemorrhage, involving multiple biological processes and signaling pathways (such as cancer pathways, lipids, and atherosclerosis). The stable binding of quercetin to these 7 key targets was confirmed by molecular docking simulation., Conclusion: Quercetin may treat intracerebral hemorrhage through multi-target-multi-pathway mechanisms, including regulating apoptosis, inhibiting inflammatory response, inhibiting iron death, and regulating angiogenesis, which can help alleviate nerve damage caused by intracerebral hemorrhage., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To determine the molecular mechanisms underlying the neuroprotective effects of Naochuxue prescription (,NCXP) in rats with intracerebral hemorrhage (ICH)., Methods: Sprague-Dawley rats were injected with collagenase to generate ICH models, which were then randomly divided into six groups, including control, sham, model, and three intervention groups. The intervention groups received different doses of NCXP (0.13, 0.26, and 0.52 g/kg) daily for 10 d. High-performance liquid chromatography (HPLC) was used to analyze the chemical characteristics of NCXP. The neurobehavioral outcomes of the rats were evaluated using neurological deficit scores (Zea Longa 5) and the corner turn test. Pathomorphological changes in perihematomal tissues after ICH were observed using hematoxylin and eosin staining. Immunohistochemistry (IHC) was used to detect the inflammation expression of interleukin 6 (IL-6) and toll-like receptor 4 (TLR4). High mobility group box-1 (HMGB1), Beclin1, microtubule-associated protein 1 light chain 3 beta (LC3), and sequestosome 1 (p62) were detected using real-time quantitative polymerase chain reaction and Western blotting in perihematomal tissues., Results: HPLC showed that the NCXP had good stability. Rats with ICH had severe neurological function deficits compared to the control group. IHC results showed that NCXP significantly downregulated the expression of the inflammatory proteins IL-6 and TLR4. ICH rats treated with NCXP showed less neurological injury than the model group, accompanied by a significantly decreased expression of HMGB1, Beclin1, and LC3 and an increased expression of p62., Conclusions: The neuroprotective effect of NCXP alleviated inflammation and autophagy possibly by downregulating HMGB1 expression. However, further research on the signaling pathways is required to verify this hypothesis.

Stroke has emerged as the primary cause of disability and death globally in recent years. Intracerebral hemorrhage (ICH), a particularly severe kind of stroke, is occurring in an increasing number of people. The two main clinical treatments for ICH now in use are conservative pharmaceutical therapy and surgical intervention, both of which have risks and drawbacks. Consequently, it is crucial to look into the pathophysiology of ICH and consider cutting-edge therapeutic approaches. Recent research has revealed that pyroptosis is a newly identified type of cell death distinguished by the break of the cell membrane and the discharge of pro-inflammatory substances through different routes. Following ICH, glial cells experience pyroptosis, which worsens neuroinflammation. Hence, the onset and progression of ICH are strongly linked to pyroptosis, which is facilitated by different inflammasomes. It is essential to conduct a comprehensive investigation of ICH damage processes and uncover new targets for treatment. The impact and function of pyroptosis in ICH, as well as the activation and regulation of inflammasomes and their mediated pyroptosis pathways will be fully discussed in this review., Competing Interests: Declaration of Competing Interest The authors whose names are listed immediately below certify that they have NO afiliations with or involvement in any organization or entity with any inancial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership,employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-inancial interest (such as personal or professional relationships, afiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Intracerebral hemorrhage (ICH) is a hemorrhagic disease with high mortality and disability rates. Curcumin is a promising drug for ICH treatment due to its multiple biological activities, but its application is limited by its poor watersolubility and instability. Herein, platelet membrane-coated curcumin polylactic-co-glycolic acid (PLGA) nanoparticles (PCNPs) are prepared to achieve significantly improved solubility, stability, and sustained release of curcumin. Fourier transform infrared spectra and X-ray diffraction assays indicate good encapsulation of curcumin within nanoparticles. Moreover, it is revealed for the first time that curcumin-loaded nanoparticles can not only suppress hemin-induced astrocyte proliferation but also induce astrocytes into neuron-like cells in vitro. PCNPs are used to treat rat ICH by tail vein injection, using in situ administration as control. The results show that PCNPs are more effective than curcumin-PLGA nanoparticles in concentrating on hemorrhagic lesions, inhibiting inflammation, suppressing astrogliosis, promoting neurogenesis, and improving motor functions. The treatment efficacy of intravenously administered PCNPs is comparable to that of in situ administration, indicating a good targeting effect of PCNPs on the hemorrhage site. This study provides a potent treatment for hemorrhagic injuries and a promising solution for efficient delivery of water-insoluble drugs using composite materials of macromolecules and cell membranes., (© 2024 Wiley‐VCH GmbH.)

Oxidative stress (OS) is the main cause of secondary damage following intracerebral hemorrhage (ICH). The polarity expression of aquaporin-4 (AQP4) has been shown to be important in maintaining the homeostasis of water transport and preventing post-injury brain edema in various neurological disorders. This study primarily aimed to investigate the effect of the oxygen free radical scavenger, edaravone, on AQP4 polarity expression in an ICH mouse model and determine whether it involves in AQP4 polarity expression via the OS/MMP9/β-dystroglycan (β-DG) pathway. The ICH mouse model was established by autologous blood injection into the basal nucleus. Edaravone or the specific inhibitor of matrix metalloproteinase 9 (MMP9), MMP9-IN-1, called MMP9-inh was administered 10 min after ICH via intraperitoneal injection. ELISA detection, neurobehavioral tests, dihydroethidium staining (DHE staining), intracisternal tracer infusion, hematoxylin and eosin (HE) staining, immunofluorescence staining, western blotting, Evans blue (EB) permeability assay, and brain water content test were performed. The results showed that OS was exacerbated, AQP4 polarity was lost, drainage function of brain fluids was damaged, brain injury was aggravated, expression of AQP4, MMP9, and GFAP increased, while the expression of β-DG decreased after ICH. Edaravone reduced OS, restored brain drainage function, reduced brain injury, and downregulated the expression of AQP4, MMP9. Both edaravone and MMP9-inh alleviated brain edema, maintained blood-brain barrier (BBB) integrity, mitigated the loss of AQP4 polarity, downregulated GFAP expression, and upregulated β-DG expression. The current study suggests that edaravone can maintain AQP4 polarity expression by inhibiting the OS /MMP9/β-DG pathway after ICH., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023. The Author(s).)

Background: We performed an analysis of a large intensive care unit electronic database to provide preliminary estimates of various blood pressure parameters in patients with acute stroke receiving intravenous (IV) antihypertensive medication and determine the relationship with in-hospital outcomes., Methods: We identified the relationship between pre-treatment and post-treatment systolic blood pressure (SBP) and heart rate (HR)-related variables and in-hospital mortality and acute kidney injury in patients with acute stroke receiving IV clevidipine, nicardipine, or nitroprusside using data provided in the Medical Information Mart for Intensive Care (MIMIC) IV database., Results: A total of 1830 patients were treated with IV clevidipine (n = 64), nicardipine (n = 1623), or nitroprusside (n = 143). The standard deviations [SDs] of pre-treatment SBP (16.3 vs. 13.7, p ≤ 0.001) and post-treatment SBP (15.4 vs. 14.4, p = 0.004) were higher in patients who died compared with those who survived, particularly in patients with intracerebral hemorrhage (ICH). The mean SBP was significantly lower post treatment compared with pre-treatment values for clevidipine (130.7 mm Hg vs. 142.5 mm Hg, p = 0.006), nicardipine (132.8 mm Hg vs. 141.6 mm Hg, p ≤ 0.001), and nitroprusside (126.2 mm Hg vs. 139.6 mm Hg, p ≤ 0.001). There were no differences in mean SDs post treatment compared with pre-treatment values for clevidipine (14.5 vs. 13.5, p = 0.407), nicardipine (14.2 vs. 14.6, p = 0.142), and nitroprusside (14.8 vs. 14.8, p = 0.997). The SDs of pre-treatment and post-treatment SBP were not significantly different in patients with ischemic stroke treated with IV clevidipine, nicardipine, or nitroprusside or for patients with ICH treated with IV clevidipine or nitroprusside. However, patients with ICH treated with IV nicardipine had a significantly higher SD of post-treatment SBP (13.1 vs. 14.2, p = 0.0032)., Conclusions: We found that SBP fluctuations were associated with in-hospital mortality in patients with acute stroke. IV antihypertensive medication reduced SBP but did not reduce SBP fluctuations in this observational study. Our results highlight the need for optimizing therapeutic interventions to reduce SBP fluctuations in patients with acute stroke., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Inflammatory reactions after acute intracerebral hemorrhage (AICH) contribute significantly to a poor prognosis. Liangxue Tongyu Prescription (LTP) has been proven to be clinically effective in treating AICH. Numerous studies have shown that LTP suppresses brain inflammatory damage in AICH, while the internal mechanisms underlying its action remain unclear. The aim of this study was to verify the anti-inflammatory effects of LTP on an AICH rat model and investigate the potential mechanisms. The AICH rat models were created by injecting autologous blood into the right caudate nucleus. LTP markedly decreased cerebral hematoma and brain water content and recovered from neurological deficits. Meanwhile, LTP prevented microglial activation and reduced the inflammatory reaction caused by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). Notably, the expression of cholecystokinin octapeptide (CCK-8) in the brain and intestine was increased by LTP or CCK-8 treatment. LTP further suppressed nuclear factor kappa B (NF-κB) in the brains of rats with AICH. Moreover, LTP increased the protein and mRNA expression of Occludin and Claudin-1 in the intestine and decreased the levels of lipopolysaccharide (LPS) and diamine oxidase (DAO) in serum. Furthermore, the results showed that LTP increased the protein and mRNA expression of Claudin-5 and zonula occludens-1 (ZO-1) in the brain. CCK-8 receptor antagonists increased the expression of NF-κB and the concentration of pro-inflammatory cytokines. These findings suggested that LTP attenuated neuroinflammation by increasing CCK-8 in the brain and intestine, and its mechanism might be related to alterations in the gut-brain axis (GBA)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: A randomized trial suggested that treatment with metoclopramide reduces the risk of pneumonia in patients with acute stroke and a nasogastric tube. We assessed whether this finding could be replicated in a post hoc analysis of the randomized PRECIOUS trial (Prevention of Complications to Improve Outcome in Elderly Patients With Acute Stroke)., Methods: PRECIOUS was an international, 3×2 partial-factorial, randomized controlled, open-label clinical trial with blinded outcome assessment assessing preventive treatment with metoclopramide, paracetamol, and ceftriaxone in patients aged ≥66 years with acute ischemic stroke or intracerebral hemorrhage and a National Institutes of Health Stroke Scale score ≥6. In the present study, we analyzed patients who had a nasogastric tube within 24 hours after randomization. Patients who were allocated to metoclopramide (10 mg TID) were compared with patients who were not. Treatment was started within 24 hours after symptom onset and continued for 4 days or until discharge if earlier. The primary outcome was pneumonia in the first week after stroke. The score on the modified Rankin Scale after 90 days was a secondary outcome and analyzed with ordinal logistic regression., Results: From April 2016 through June 2022, a total of 1493 patients were enrolled with 1376 included in this analysis, of whom 1185 (86%) had ischemic stroke and 191 (14%) had intracerebral hemorrhage. The first day after randomization, 329 (23.9%) patients had a nasogastric tube, of whom 156 were allocated to metoclopramide and 173 to standard care. Metoclopramide was not associated with a reduction of pneumonia (41.0% versus 35.8%; adjusted odds ratio, 1.35 [95% CI, 0.79-2.30]) or with poor functional outcome (adjusted odds ratio, 1.07 [95% CI, 0.71-1.61])., Conclusions: In patients with stroke who had a nasogastric tube shortly after stroke onset, metoclopramide for 4 days did not reduce pneumonia or have an effect on the functional outcome., Competing Interests: Drs Sluis, de Jonge, and Reinink all report grants from the European Union, all paid to their institution. Dr Bath reports having received grants from the UK National Institutes of Health Research and fees as a consultant from CoMind, DiaMedica, Phagenesis, and Roche. In addition, he reports compensation from World Stroke Organisation and the Stroke Association for other services and has stock options in CoMind. Dr van de Beek reports having received research grants from the European Union, The Netherlands Organisation for Health Research and Development, ItsMe Foundation, AMC Foundation, and Roche, none related. Dr van der Worp reports having received grants from the European Union, the Dutch Heart Foundation, and Stryker for research and funding for consultancy from Bayer and TargED, all paid to his institution. The other authors report no conflicts.

Current clinical practice primarily relies on surgical intervention to remove hematomas in patients with intracerebral hemorrhage (ICH), given the lack of effective drug therapies. Previous research indicates that simvastatin (SIM) may enhance hematoma absorption and resolution in the acute phase of ICH, though the precise mechanisms remain unclear. Recent findings have highlighted the glymphatic system (GS) as a crucial component in intracranial cerebrospinal fluid circulation, playing a significant role in hematoma clearance post-ICH. This study investigates the link between SIM efficacy in hematoma resolution and the GS. Our experimental results show that SIM alleviates GS damage in ICH-induced rats, resulting in improved outcomes such as reduced brain edema, neuronal apoptosis, and degeneration. Further analysis reveals that SIM's effects are mediated through the VEGF-C/VEGFR3/PI3K-Akt pathway. This study advances our understanding of SIM's mechanism in promoting intracranial hematoma clearance and underscores the potential of targeting the GS for ICH treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Ischaemic stroke characterises impulsive cerebral-region hypoxia due to deep intracerebral arteriole blockage, often accompanied by permanent cerebral infarction and cognitive impairment. Thrombolysis with recombinant tissue plasminogen activator (rtPA) and thrombectomy remain the only guidance-approved therapies. However, emerging data draws clear links between such therapies and haemorrhage transformation, which occur when cerebral vasculature is damaged during ischaemia/reperfusion. Studies have shown that matrix metalloproteinases (MMPs) play a significant role in haemorrhage transformation, by depleting the extracellular matrix (ECM) and disrupting the blood brain barrier (BBB). Inhibitors of MMPs may be used to prevent ischaemic stroke patients from BBB disruption and haemorrhage transformation, particularly for those receiving rtPA treatment. Preclinical studies found that inhibition of MMPs with agents or in knock out mice, effectively reduced BBB disruption and infarct volume, leading to improved ischaemic stroke outcomes. At present, MMP inhibition is not an approved therapy for stroke patients. There remain concerns about timing, dosing, duration of MMP inhibition and selection of either broad spectrum or specific MMP inhibitors for stroke patients. This review aims to summarize current knowledge on MMP inhibition in ischaemic stroke and explore whether a broad spectrum or a specific MMP inhibitor should be used for ischaemic stroke patient treatment. It is crucial to inhibit MMP activities early and sufficiently to ensure BBB intact during ischaemia and reperfusion, but also to reduce side effects of MMP inhibitors to minimum. Recent advance in stroke therapy by thrombectomy could aid in such treatment with intra-arterially delivery of MMP inhibitors (and/or antioxidants)., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Glycyrrhizin (GL) from licorice alleviates intracerebral hemorrhage (ICH) injuries by interacting with high-mobility group box (HMGB) 1, an inflammatory factor. We found that GL is bioconverted by endophyte coexisting with licorice and succeeded in isolating two derivatives. The aim of this study was to identify the compound with more potent HMGB1 inhibitory activity inspired by these GL derivatives. We took advantage of a ketone introduced by an endophyte at the C-3 position and attempted methyl esterification at the C-30 position because it was suggested that the water or lipid solubility of the molecule plays an important role. Among three derivatives synthesized, the product that is both ketonized and esterified showed more potent HMGB1 inhibitory activity than GL in macrophages and significantly improved adverse events occurred in ICH in vivo. These results suggest that modification of the hydrophilicity of GL, particularly at the C-3 and C-30 positions, enhances the HMGB1 inhibitory activity.

Background: Stereotactic thrombolysis reduces intracerebral haemorrhage (ICH) volume in patients with spontaneous ICH. Whether intrahaematomal alteplase administration is associated with a change in intraventricular haemorrhage volume (deltaIVH) and functional outcomes is unknown., Methods: Post hoc secondary analysis of the Minimally Invasive Surgery plus Alteplase for Intracerebral Hemorrhage Evacuation Phase III (MISTIE-III) trial in patients with IVH on the stability CT scan. Exposure was minimally invasive surgery plus alteplase (MIS+alteplase). Primary outcome was deltaIVH defined as IVH volume on end-of-treatment CT minus IVH volume on stability CT scan. Secondary outcomes were favourable functional outcome (modified Rankin Scale 0-3) and mortality at 365 days. We assessed the relationship between MIS+alteplase and deltaIVH in the primary analysis using multivariable linear regression, and between deltaIVH and functional outcomes in secondary analyses using multiple logistic regression., Results: Of 499 patients in MISTIE-III, 310 (62.1%) had IVH on stability scans; mean age (SD) was 61.2±12.3 years. A total of 146 (47.1%) received the MISTIE procedure and 164 (52.9%) standard medical care (SMC) only. The MIS+alteplase group had a greater mean reduction in IVH volume compared with the SMC group (deltaIVH: -2.35 (5.30) mL vs -1.15 (2.96) mL, p=0.02). While IVH volume decreased significantly in both treatment groups, in the primary analysis, MIS+alteplase was associated with greater deltaIVH in multivariable linear regression analysis adjusted for potential confounders (β -0.80; 95% CI -1.37 to -0.22, p=0.007). Secondary analysis demonstrated no associations between IVH reduction and functional outcomes (adjusted OR (aOR) for poor outcome 1.02; 95% CI 0.96 to 1.08, p=0.61; aOR for mortality 0.99; 95% CI 0.92 to 1.06, p=0.77)., Conclusions: Alteplase delivered into the ICH in MISTIE-III subjects with IVH was associated with a small reduction in IVH volume. This reduction did not translate into a significant benefit in mortality or functional outcomes at 365 days., Trial Registration Number: NCT01827046., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Ferroptosis of neurons is a significant cause of brain injury following intracerebral hemorrhage (ICH). As an iron-containing compound in hemoglobin, heme contributes to nerve injury post-ICH. Melatonin has been shown to mitigate the effects of ICH, yet its specific functions remain largely elusive. In this study, we aimed to explore the roles and mechanisms of melatonin in heme-induced ferroptosis subsequent to ICH., Materials and Methods: C57BL/6 mice were intracranially injected with heme and then treated with melatonin. Behavior tests [modified neurological severity score (mNSS), forelimb placing, and corner turn tests], H&E staining, Nissl staining, and Prussian blue staining were used to evaluate mouse brain tissue injury. In vitro, HT-22 cells were stimulated with heme and cell viability was determined by crystal violet staining. The iron contents were determined in heme-treated brains and cells, and the levels of 4-hydroxynonenal (4-HNE) and malonaldehyde (MDA) were assessed by ELISA. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to investigate the mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Immunoblotting was used to analyze the protein expression of glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), Nrf2, and HO-1. Finally, small interfering RNA (siRNA) was used to knock down Nrf2 in HT-22 cells., Results: Melatonin treatment alleviated heme-induced injuries to neural function, as indicated by improved behavior in the mice. Moreover, melatonin decreased cell death and iron concentrations, increased MDA and 4-HNE levels, and reversed the decreases in GPX4, SLC7A11, Nrf2, and HO-1 induced by heme in vitro and in vivo. These results indicated that melatonin could improve the ferroptosis induced by heme. In addition, we found that Nrf2 knockdown attenuated the therapeutic effect of melatonin on neuronal ferroptosis induced by heme., Conclusions: In general, melatonin alleviates heme-induced ferroptosis by activating the Nrf2/HO-1 pathway, which implies that melatonin is a promising treatment for ferroptosis in ICH.

Zhongfeng Xingnao Decoction(ZFXN) has been utilized for treating intracerebral hemorrhage(ICH) in China, while the pharmacological mechanism of ZFXN remains unclear. Exploring the pharmacological roles of ZFXN is critical for guiding the treatment of cerebrovascular diseases. In this study, a rat model of ICH was constructed by injection of Ⅶ collagenase in the right caudate nucleus. SD rats were randomly assigned into five groups, and the neurological function of rats was evaluated based on the Bederson score. Magnetic resonance imaging(MRI) was used to assess the volume of ICH. Hematoxylin-eosin(HE) staining and transmission electron microscopy(TEM) were employed to observe the pathological and ultrastructural changes in the brain tissue. The levels of reactive oxygen species(ROS) were measured by flow cytometry. The immunofluorescence assay was employed to detect the expression of glutathione peroxidase 4(GPX4) in neurons surrounding the hematoma. Finally, Western blot was employed to determine the expression of ferroptosis-related proteins upstream frameshift 1(UPF1), ferroportin(FPN), acyl-CoA ligase 4(ACSL4), cyclooxyge-nase-2(COX-2), GPX4, NADPH oxidase 1(NOX1), and solute carrier family 7 member 11(SLC7A11) after ICH. Compared with the model(ICH) group, ZFXN treatment for 5 days attenuated neurological dysfunction, reduced the hematoma volume, and alleviated the pathological changes induced by ICH. Meanwhile, ZFXN lowered the levels of Fe~(2+) and oxidative stress and up-regulated the expression of proteins inhibiting ferroptosis. ZFXN improved the prognosis of ICH in rats by inhibiting neuronal ferroptosis, which provided a valuable guide for the clinical application of ZFXN. ZFXN may inhibit ferroptosis by promoting the expression of SLC7A11 and FPN.

Hypertensive intracerebral hemorrhage (HICH) is a destructive disease with high mortality, incidence, and disability. Asiaticoside (AC) is a triterpenoid derivative that has demonstrated to exert a protective effect on neuron and blood vessel. To investigate the function and potential mechanism of AC on HICH. Human brain microvascular endothelial cells (hBMECs) were treated with 20 U/mL thrombin for 24 h to establish the HICH model in vitro, and AC with the concentration of 1, 2 and 4 µM were used to incubate hBMECs. The effect and potential mechanism of AC on HICH were investigated by using cell counting kit-8, flow cytometry, tube forming assays, vascular permeability experiments and western blot assays. In vivo, rats were injected with 20 µL hemoglobin with a concentration of 150 mg/mL, and then intragastrically administrated with 1.25, 2.5 and 5 mg/kg AC. Behavioral tests, brain water content measurement, hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling assays, and western blot were used to assess the effect and potential mechanism of AC on HICH. AC (at 2 and 4 µM) improved the proliferation, apoptosis, angiogenesis and vascular permeability in thrombin-induced hBMECs (p < 0.05). Besides, AC (2.5 and 5 mg/kg) ameliorated behavioral scores, brain water content, pathological lesion, apoptosis and the expression of vascular permeability-related proteins in rats with HICH (p < 0.05). In addition, AC elevated the expression of PI3K/AKT pathway after HICH both in cell and animal models (p < 0.05). Application of LY294002, an inhibitor of PI3K/AKT pathway, reversed the ameliorative effect of AC on the proliferation, apoptosis, angiogenesis and vascular permeability in thrombin-induced hBMECs (p < 0.05). AC reduced brain damage by increasing the expression of the PI3K/AKT pathway after HICH., (© 2024 Wiley Periodicals LLC.)

The aim of this study was to investigate the alleviating effect of wogonin on intracerebral hemorrhage (ICH) and its mechanism. The hemin-treated PC-12 cells were constructed to mimic ICH in vitro. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis was used for cell viability measurement and flow cytometry was for pyroptosis detection. Enzyme-linked immunosorbent assay (ELISA) assay and western blot were used to detect the protein levels of pyroptosis-related proteins. The modification level of N6-methyladenosine (m 6 A) methylation was detected by quantitative real-time polymerase chain reaction (qRT-PCR) combined with m 6 A dot blot assays. Molecular docking experiments analyzed the binding of wogonin and METTL14 protein. The correlation between METTL14 and NLRP3 was confirmed by bioinformatics analysis and dual luciferase reporter gene detection. ICH was induced in mice injected with collagenase into the basal ganglia, and the neurobehavioral damage was evaluated. Triphenyltetrazolium chloride monohydrate (TTC) staining and neurological scores were used to assess brain damage in mice. The results demonstrated that wogonin alleviated neuronal cell pyroptosis, and was molecularly docked with METTL14. Overexpression of METTL14 partly reversed the protecting effects of wogonin on brain in vitro and in vivo. Furthermore, NLRP3 was methylated by METTL14. Taken together, wogonin inhibits neuronal pyroptosis and thus treats IHC by inhibiting METTL14 and its methylated NLRP3., Competing Interests: Declarations. Ethical Approval: No ethics approval was required for this study as it involved no human participants or animals. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Intracerebral hemorrhages are associated with significant morbidity and mortality. While the ENRICH trial supports the efficacy of surgical evacuation for lobar hemorrhages, the impact of antithrombotic therapies on minimally invasive surgery outcomes remains unexplored. This study evaluates the effects of chronic anticoagulants and antiplatelets on the technical and longterm outcomes of minimally invasive intracerebral hemorrhage evacuation., Materials and Methods: A prospectively collected registry of patients undergoing minimally invasive surgery for intracerebral hemorrhage from a single institution was analyzed (December 2015-September 2022). Data included key demographics, comorbidities, antithrombotic/reversal status, presenting clinical/radiographic characteristics, procedural metrics, and clinical outcomes. Patients were divided into control (neither therapy), antiplatelet-only, and anticoagulant-only groups, with antiplatelet/anticoagulant reversals conducted per current American Heart Association/American Stroke Association guidelines. Variables significant in univariate analyses (p<0.05) were advanced to multivariable regression models., Results: Among 226 intracerebral hemorrhage patients treated with minimally invasive surgery, 41% (N=93) had antithrombotic medication history; 28% (N=64) received antiplatelets, and 9% (N=21) received anticoagulants. Patients on both therapies (N=6) were excluded. The antiplatelet group presented more frequently with lobar hemorrhages (56% vs. 37%; p=0.022), while patients on anticoagulants showed increased rates of intraventricular hemorrhage co-presentation (62% vs. 46%; p=0.011) compared to controls. Despite univariate analyses showing a higher postoperative hematoma volume (3.9 vs. 2.9 milliliters; p=0.020) and lower evacuation percentage (88% vs. 92%; p=0.019) for the antiplatelet group, and longer procedures for patients on anticoagulants (2.3 vs. 1.7 hours; p=0.042) compared to control, multivariable analyses indicated that antiplatelets and anticoagulants had no significant impact on these technical outcomes. Longitudinally, antithrombotics were not associated with increased rebleeding, less frequent discharge to home, lower 30-day mortality, or worse, 6-month Modified Rankin Scale scores., Conclusions: Patients on chronic antiplatelets and anticoagulants exhibited characteristic intracerebral hemorrhage phenotypes without worse technical or long-term outcomes after minimally invasive intracerebral hemorrhage evacuation, suggesting the procedure's safety for these patients., Competing Interests: Declaration of competing interest JM receives research support from Penumbra to evaluate the feasibility of ICH evacuation; this funding was not involved in this study. CPK receives research grant support from Integra, Penumbra, Viz.AI, Siemens, Medtronic, Minnetronix, Longeviti, Irras, ICE Neurosystems, CVAID, Endostream, and Microtransponder; and has equity in Precision Recovery, Borealis, E8, Borvo, and Metis Innovative. Metis Innovative is an investment group that has coordinated investments in Synchron, Proprio, Fluid Biomed, Von Vascular, and Precision Recovery. The other authors report no conflict of interest relevant to the work presented in this article., (Copyright © 2024. Published by Elsevier Inc.)

Intracerebral hemorrhage (ICH) is a major health problem. It is one of the most common types of stroke and results in mortality in approximately half of patients. More than half of the fatalities occur in the first 2 days. In addition to the mass effect after ICH hemorrhage, complex pathophysiological mechanisms such as intracranial vessel vasospasm, microthrombosis, and inflammatory immune reaction also increase brain damage. Both resident (including microglia and astrocytes) and circulating immune cells (including neutrophils, macrophages, and lymphocytes) involved in the inflammatory process. The inflammatory response is especially harmful in the acute phase due to harmful substances secreted by infiltrating immune cells. The inflammatory response also has beneficial effects, especially in the later stages. Their role in pathophysiology makes immune cells important therapeutic targets. General immunosuppressive approaches and depleting cell groups such as neutrophils or keeping them away from the lesion site may not be sufficient to prevent poor outcomes after ICH. This is most likely because they suppress anti-inflammatory activities and pro-inflammatory effects. Instead, directing immune cells to the beneficial subpopulation seems like a more rational solution. The pro-inflammatory N1 subpopulation of neutrophils damages the tissue surrounding ICH. In contrast, the N2 subpopulation is associated with anti-inflammatory reactions and tissue repair. Studies show that when neutrophils are polarized toward the N2 subpopulation, clinical outcomes improve and the volume of the infarct decreases. However, more research is still needed. This study aims to evaluate the role of neutrophils as immunotherapeutic targets in ICH in light of current knowledge., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Intracerebral hemorrhage (ICH) is a prevalent hemorrhagic cerebrovascular emergency. Alleviating neurological damage in the early stages of ICH is critical for enhancing patient prognosis and survival rate. A novel form of cell death called ferroptosis is intimately linked to hemorrhage-induced brain tissue injury. Although studies have demonstrated the significant preventive impact of bovine serum albumin-stabilized selenium nanoparticles (BSA-SeNPs) against disorders connected to the neurological system, the neuroprotective effect on the hemorrhage stroke and the mechanism remain unknown. Therefore, based on the favorable biocompatibility of BSA-SeNPs, h-ICH (hippocampus-intracerebral hemorrhage) model was constructed to perform BSA-SeNPs therapy. As expected, these BSA-SeNPs could effectively improve the cognitive deficits and ameliorate the damage of hippocampal neuron. Furthermore, BSA-SeNPs reverse the morphology of mitochondria and enhanced the mitochondrial function, evidenced by mitochondrial respiration function (OCR) and mitochondrial membrane potential (MMP). Mechanistically, BSA-SeNPs could efficiently activate the Nrf2 to enhance the expression of antioxidant GPX4 at mRNA and protein levels, and further inhibit lipid peroxidation production in erastin-induced ferroptotic damages. Taken together, this study not only sheds light on the clinical application of BSA-SeNPs, but also provides its newly theoretical support for the strategy of the intervention and treatment of neurological impairment following ICH., Competing Interests: Declaration of competing interest All authors declare that there are no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: An important proportion of patients with spontaneous intracerebral hemorrhage (ICH) undergo neurosurgical intervention to reduce mass effect from large hematomas and control the complications of bleeding, including hematoma expansion and hydrocephalus. The Tranexamic acid (TXA) for hyperacute primary IntraCerebral Hemorrhage (TICH-2) trial demonstrated that tranexamic acid (TXA) reduces the risk of hematoma expansion. We hypothesized that TXA would reduce the frequency of surgery (primary outcome) and improve functional outcome at 90 days in surgically treated patients in the TICH-2 data set., Methods: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not., Results: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P -value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P -value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P -value = .45)., Conclusion: TXA was not associated with less neurosurgical intervention, reduced HV, or improved outcomes after surgery., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Congress of Neurological Surgeons.)

In intracerebral hemorrhage (ICH), the mechanical brain injury is a considerable and indispensable factor determining the neurological functions and poor outcomes. Previous studies indicate the mechanically gated ion channel-Piezo1 can transduce mechanical effects following ICH. Isoquercitrin (ISQ) is a well-studied ion channel inhibitor. Furthermore, whether the following Piezo1-mediated neurological impairment can be ameliorated by ISQ remains unclear. Herein, we constructed the hydrostatic pressure model and ICH rat model. Firstly, we found that Piezo1 agonists Yoda1 and Jedi1 facilitated extracellular calcium influx dramatically, but ISQ could depress intracellular Ca 2+ overload under hydrostatic pressure in primary neurons. Then we detected the expression profile of Piezo1, NLRP3 and NF-κB p-p65 after ICH, and found that the expression of Piezo1 was much earlier than NLRP3 and NF-κB p-p65. Furthermore, by western blot and immunofluorescence, ISQ decreased the expression of Piezo1 and NLRP3 dramatically like GsMTx4, but Nigericin as a NLRP3 agonist failed to affect Piezo1. Besides, both ISQ and interfering Piezo1 suppressed the upregulated caspase-1, NF-κB p-p65, p-IκBα, Tunel-positive cells and inflammatory factors (IL-1β, IL-6 and TNF-α) in ICH. At last, the hydrostatic pressure or hematoma induced disturbed neural viability, disordered neural cytomorphology, and increased neurobehavioral and cognitive deficits, but they were improved by ISQ and GsMTx4 strongly. Therefore, ISQ could alleviate neurological injuries induced by Piezo1 via NLRP3 pathway. These observations indicated that Piezos might be the new therapeutic targets, and blocking Piezos/NLRP3 pathway by ISQ could be an auspicious strategy for the treatment of ICH., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Poly (ADP-ribose) polymerase (PARP) inhibitors have potent anti-inflammatory effects, including the suppression of brain microglial activation. Veliparib, a well-known PARP1/2 inhibitor, exhibits particularly high brain penetration, but its effects on stroke outcome is unknown. Here, the effects of veliparib on the short-term outcome of intracerebral hemorrhage (ICH), the most lethal type of stroke, were investigated. Collagenase-induced mice ICH model was applied, and the T2-weighted magnetic resonance imaging was performed to evaluate lesion volume. Motor function and hematoma volume were also measured. We further performed immunofluorescence, enzyme linked immunosorbent assay, flow cytometry, and blood-brain barrier assessment to explore the potential mechanisms. Our results demonstrated veliparib reduced the ICH lesion volume dose-dependently and at a dosage of 5 mg/kg, veliparib significantly improved mouse motor function and promoted hematoma resolution at days 3 and 7 post-ICH. Veliparib inhibited glial activation and downregulated the production of pro-inflammatory cytokines. Veliparib significantly decreased microglia counts and inhibited peripheral immune cell infiltration into the brain on day 3 after ICH. Veliparib improved blood-brain barrier integrity at day 3 after ICH. These findings demonstrate that veliparib improves ICH outcome by inhibiting inflammatory responses and may represent a promising novel therapy for ICH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Vitamin D deficiency (VDD) is emerging as a predictor of poor prognosis in various neurological conditions, where clinical outcomes are often worse in stroke patients with VDD. This study aimed to provide experimental evidence on whether and how pre-existing VDD would affect survival and neurofunctional outcomes in intracerebral haemorrhage (ICH), and to evaluate whether acute vitamin D (VD) supplementation would improve post-stroke outcomes., Methods: Experimental ICH models were induced in mice with and without VDD. Haematoma size was measured using T2*-weighted MRI and haemoglobin concentration. Post-ICH mortality, neurofunctional outcomes and the extent of blood-brain barrier (BBB) leakage were assessed to identify their correlations with VD status. Therapeutic benefits of acute VD administration were also evaluated., Results: Mice with VDD exhibited significantly higher acute mortality rates and more severe motor deficits than mice without VDD post-ICH. Marked haematoma expansion and increased Evans blue extravasation were observed in VDD mice, suggesting that VDD was associated outcomes with increased BBB disruption. Acute treatment with a loading dose of VD (calcitriol) significantly improved outcomes in VDD mice., Conclusion: This study provides novel insights into the pathophysiological mechanisms at play in ICH concomitant with VDD and a scientific rationale for acute treatment with VD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

Ethnopharmacological Relevance: Leonurus japonicus Houtt. (Labiatae), commonly known as Chinese motherwort, is a herbaceous flowering plant that is native to Asia. It is widely acknowledged in traditional medicine for its diuretic, hypoglycemic, antiepileptic properties and neuroprotection. Currently, Leonurus japonicus (Leo) is included in the Pharmacopoeia of the People's Republic of China. Traditional Chinese Medicine (TCM) recognizes Leo for its myriad pharmacological attributes, but its efficacy against ICH-induced neuronal apoptosis is unclear., Aims of the Study: This study aimed to identify the potential targets and regulatory mechanisms of Leo in alleviating neuronal apoptosis after ICH., Materials and Methods: The study employed network pharmacology, UPLC-Q-TOF-MS technique, molecular docking, pharmacodynamic studies, western blotting, and immunofluorescence techniques to explore its potential mechanisms., Results: Leo was found to assist hematoma absorption, thus improving the neurological outlook in an ICH mouse model. Importantly, molecular docking highlighted JAK as Leo's potential therapeutic target in ICH scenarios. Further experimental evidence demonstrated that Leo adjusts JAK1 and STAT1 phosphorylation, curbing Bax while augmenting Bcl-2 expression., Conclusion: Leo showcases potential in mitigating neuronal apoptosis post-ICH, predominantly via the JAK/STAT mechanism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Intracerebral hemorrhage (ICH) is a significant public health matter that has no effective treatment. ICH-induced destruction of the blood-brain barrier (BBB) leads to neurological deterioration. Astrocytic sonic hedgehog (SHH) alleviates brain injury by maintaining the integrity of the BBB after ICH. Silent information regulator 1 (SIRT1) is neuroprotective in several central nervous system diseases via BBB regulation. It is also a possible influential factor of the SHH signaling pathway. Nevertheless, the role of SIRT1 on BBB and the underlying pathological process associated with the SHH signaling pathway after ICH remain unclear. We established an intracerebral hemorrhagic mouse model by collagenase injection. SRT1720 (a selective agonist of SIRT1) was used to evaluate the effect of SIRT1 on BBB integrity after ICH. SIRT1 expression was reduced in the mouse brain after ICH. SRT1720 attenuated neurobehavioral impairments and brain edema of ICH mouse. After ICH induction, SRT1720 improved BBB integrity and tight junction expressions in the mouse brain. The SHH signaling pathway-related factors smoothened and glioma-associated oncogene homolog-1 were increased with the intervention of SRT1720, while cyclopamine (a specific inhibitor of the SHH signaling pathway) reversed these effects. These findings suggest that SIRT1 protects from ICH by altering BBB permeability and tight junction expression levels. This process is associated with the SHH signaling pathway, suggesting that SIRT1 may be a potential therapeutic target for ICH., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)