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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.)

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.)

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.)

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.)

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.)

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.)

Oxidative stress (OS) is a major mediator of secondary brain injury following intracerebral hemorrhage (ICH). Thus, antioxidant therapy is emerging as an attractive strategy to combat ICH. To achieve both reactive oxygen species (ROS) scavenging ability and on-demand drug release ability, we constructed a novel polydopamine (PDA)-coated diselenide-bridged mesoporous silica nanoparticle (DSeMSN) drug delivery system (PDA-DSeMSN). Edaravone (Eda) was blocked in the pores of DSeMSN by covering the pores with PDA as a gatekeeper. The drug maintained nearly "zero release" before reaching the lesion site, while in the ROS-enriched circumstances, the PDA shell went through degradation and the doped diselenide bonds broke up, triggering the disintegration of nanoparticles and leading to Eda release. Interestingly, the ROS-degradable property of the PDA shell and diselenide bond endowed the system with enhanced ROS-eliminating capacity. The synergistic effect of ROS-responsive drug delivery and ROS-scavenging PDA-DSeMSN showed efficient antioxidative and mitochondria protective performance without apparent toxicity in vitro . Importantly, PDA-DSeMSN@Eda through intravenous administration specifically accumulated in perihematomal sites and demonstrated robust neuroprotection in an ICH mouse model through antioxidative and antiapoptotic effects with high biological safety. Thus, the PDA-DSeMSN platform holds tremendous potential as an excellent carrier for on-demand delivery of drugs and provides a new and effective strategy for the clinical treatment of ICH.

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.)

Although the current surgical hematoma removal treatment saves patients' lives in critical moments of intracerebral hemorrhage (ICH), the lethality and disability rates of ICH are still very high. Due to the individual differences of patients, postoperative functional improvement is still to be confirmed, and the existing drug treatment has limited benefits for ICH. Recent advances in biomaterials may provide new ideas for the therapy of ICH. This review first briefly describes the pathogenic mechanisms of ICH, including primary and secondary injuries such as inflammation and intracerebral edema, and briefly describes the existing therapeutic approaches and their limitations. Secondly, existing nanomaterials and hydrogels for ICH, including exosomes, liposomes, and polymer nanomaterials, are also described. In addition, the potential challenges and application prospects of these biomaterials for clinical translation in ICH treatment are discussed.

Background: Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and antisympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage., Methods: In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) 150 mmHg or greater were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (less than 140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function, and clinical outcomes., Results: A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101 of 161, 62.7% vs. 66 of 166, 39.8%; difference, 23.2%; 95% CI, 12.4 to 34.1%; P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group., Conclusions: Among intracerebral hemorrhage patients with a SBP 150 mmHg or greater, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.)

Menaquinone-4 (MK-4) is an isoform of vitamin K 2 that has been shown to exert various biological actions besides its functions in blood coagulation and bone metabolism. Here we examined the effect of MK-4 on a mouse model of intracerebral hemorrhage (ICH). Daily oral administration of 200 mg/kg MK-4 starting from 3 h after induction of ICH by intrastriatal collagenase injection significantly ameliorated neurological deficits. Unexpectedly, MK-4 produced no significant effects on various histopathological parameters, including the decrease of remaining neurons and the increase of infiltrating neutrophils within the hematoma, the increased accumulation of activated microglia/macrophages and astrocytes around the hematoma, as well as the injury volume and brain swelling by hematoma formation. In addition, ICH-induced increases in nitrosative/oxidative stress reflected by changes in the immunoreactivities against nitrotyrosine and heme oxygenase-1 as well as the contents of malondialdehyde and glutathione were not significantly affected by MK-4. In contrast, MK-4 alleviated axon tract injury in the internal capsule as revealed by neurofilament-H immunofluorescence. Enhanced preservation of the corticospinal tract by MK-4 was also confirmed by retrograde labeling of neurons in the primary motor cortex innervating the spinal cord. These results suggest that MK-4 produces therapeutic effect on ICH by protecting structural integrity of the corticospinal tract., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Edaravone dexborneol is neuroprotective against ischemic stroke, with free radical-scavenging and anti-inflammatory effects, but its effects in hemorrhagic stroke remain unclear. We evaluated whether edaravone dexborneol has a neuroprotective effect in intracerebral hemorrhage, and its underlying mechanisms., Materials and Methods: Bioinformatics were used to predict the pathway of action of edaravone dexborneol. An intracerebral hemorrhage model was established using type IV collagenase in edaravone dexborneol, intracerebral hemorrhage, Sham, adeno-associated virus + edaravone dexborneol, and adeno-associated virus + intracerebral hemorrhage groups. The modified Neurological Severity Score was used to evaluate neurological function in rats. Brain water content was measured using the dry-wet weight method. Tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and γ-aminobutyric acid levels were determined by enzyme-linked immunosorbent assay. The expression levels of neurofilament light chain and γ-aminobutyric acid transaminase were determined by western blot. Nissl staining was used to examine neuronal morphology. Cognitive behavior was evaluated using a small-animal treadmill., Results: Edaravone dexborneol alleviated neurological defects, improved cognitive function, and reduced cerebral edema, neuronal degeneration, and necrosis in rats with cerebral hemorrhage. The expression levels of neurofilament light chain, tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and γ-aminobutyric acid were decreased, while γ-aminobutyric acid transaminase expression was up-regulated., Conclusions: Edaravone dexborneol regulates γ-aminobutyric acid content by acting on the γ-aminobutyric acid transaminase signaling pathway, thus alleviating oxidative stress, neuroinflammation, neuronal degeneration, and death caused by excitatory toxic injury of neurons after intracerebral hemorrhage., Competing Interests: Declaration of competing interest The authors have no potential conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Neurogenesis as a potential strategy to improve the consequences of intracerebral hemorrhage (ICH). The current study investigates the effects of withaferin A (WFA) in combination with leptin (LEP) on ICH and neurogenesis mechanisms. LEP levels were dramatically reduced on days 7 and 14 following ICH insults in mice, but continuous WFA therapy significantly improved the potency of intrinsic LEP on day 14 after ICH. Furthermore, WFA combined with LEP enhances intrinsic neurogenesis and lessen motor deficits and long-term cognitive outcomes after ICH. In parallel, leptin deficiency in ob/ob mice limits enhancement of neurogenesis following ICH in response to WFA combined with LEP treatment. Importantly, the functional recovery conferred by WFA combined with LEP after ICH was inhibited by neurogenesis suppression. Mechanistically, this study unveiled that the signal transducer and activator of transcription-3 (STAT3) / suppressor of cytokine signaling-3 (SOCS3) pathway is a critical signaling pathway through which WFA combined with LEP treatment promotes intrinsic neurogenesis after ICH. Collectively, the results of this study elucidate the neuroprotective effects of WFA and LEP in ICH, and highlight a potential approach for ICH cell therapy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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).)

Ethnopharmacological Relevance: The repairment of myelin sheaths is crucial for mitigating neurological impairments of intracerebral hemorrhage (ICH). However, the current research on remyelination processes in ICH remains limited. A representative traditional Chinese medicine, Buyang Huanwu decoction (BYHWD), shows a promising therapeutic strategy for ICH treatment., Aim of the Study: To investigate the pro-remyelination effects of BYHWD on ICH and explore the underlying mechanisms., Materials and Methods: The collagenase-induced mice ICH model was created for investigation. BYHWD's protective effects were assessed by behavioral tests and histological staining. Transmission electron microscopy was used for displaying the structure of myelin sheaths. The remyelination and oligodendrocyte differentiation were evaluated by the expressions of myelin proteolipid protein (PLP), myelin basic protein (MBP), MBP/TAU, Olig2/CC1, and PDGFRα/proliferating cell nuclear antigen (PCNA) through RT-qPCR and immunofluorescence. Transcriptomics integrated with disease database analysis and experiments in vivo and in vitro revealed the microRNA-related underlying mechanisms., Results: Here, we reported that BYHWD promoted the neurological function of ICH mice and improved remyelination by increasing PLP, MBP, and TAU, as well as restoring myelin structure. Besides, we showed that BYHWD promoted remyelination by boosting the differentiation of PDGFRα + oligodendrocyte precursor cells into olig2 + /CC1 + oligodendrocytes. Additionally, we demonstrated that the remyelination effects of BYHWD worked by inhibiting G protein-coupled receptor 17 (GPR17). miRNA sequencing integrated with miRNA database prediction screened potential miRNAs targeting GPR17. By applying immunofluorescence, RNA in situ hybridization and dual luciferase reporter gene assay, we confirmed that BYHWD suppressed GPR17 and improved remyelination by increasing miR-760-3p., Conclusions: BYHWD improves remyelination and neurological function in ICH mice by targeting miR-760-3p to inhibit GPR17. This study may shed light on the orchestration of remyelination mechanisms after ICH, thus providing novel insights for developing innovative prescriptions with brain-protective properties., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Intracerebral haemorrhage (ICH) is a neurological emergency with high morbidity and mortality, and current treatment is limited. Emerging evidence has reported that statins can exert neuroprotective effects in cerebrovascular diseases. However, most of the published clinical studies are retrospective. Therefore, it is important to conduct a prospective randomised controlled trial to further validate the efficacy and safety of statins in patients with ICH., Methods and Analysis: The present study is performed at Xuan Wu Hospital Capital Medical University, Beijing Fengtai You'anmen Hospital and Shunping County Hospital, Hebei Province. The target number of patients is 98. Eligible patients are randomly assigned in a 1:1 ratio to the statins group or the control group. The primary outcome is the perihaemorrhagic oedema to haematoma ratio at 7 days. Secondary outcomes include mortality at 30 days, haematoma resolution rate at 7 days, National Institute of Health stroke scale (NIHSS) score at 7 days or discharge, ordinal distribution of modified Rankin scale (mRS) score at 90 days, the proportion of patients with an mRS score of 0-2 on day 90, the proportion of patients with an mRS score of 0-3 on day 90, absolute haematoma volume changes between initial and 7-day follow-up CT scan, absolute perihaematomal oedema changes between initial and 7-day follow-up CT scan., Ethics and Dissemination: The trial has been approved by the ethics committees of Xuan Wu Hospital Capital Medical University, Beijing Fengtai You'anmen Hospital and Shunping County Hospital, Hebei Province. The results will be disseminated in a peer-reviewed journal and in conference reports., Trial Registration Number: NCT04857632., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stroke is the world's second-leading cause of death. Current treatments for cerebral edema following intracerebral hemorrhage (ICH) mainly involve hyperosmolar fluids, but this approach is often inadequate. Propolis, known for its various beneficial properties, especially antioxidant and anti-inflammatory properties, could potentially act as an adjunctive therapy and help alleviate stroke-associated injuries. The chemical composition of Geniotrigona thoracica propolis extract was analyzed by GC-MS after derivatization for its total phenolic and total flavonoid content. The total phenolic content and total flavonoid content of the propolis extract were 1037.31 ± 24.10 μg GAE/mL and 374.02 ± 3.36 μg QE/mL, respectively. By GC-MS analysis, its major constituents were found to be triterpenoids (22.4% of TIC). Minor compounds, such as phenolic lipids (6.7% of TIC, GC-MS) and diterpenic acids (2.3% of TIC, GC-MS), were also found. Ninety-six Sprague Dawley rats were divided into six groups; namely, the control group, the ICH group, and four ICH groups that received the following therapies: mannitol, propolis extract (daily oral propolis administration after the ICH induction), propolis-M (propolis and mannitol), and propolis-B+A (daily oral propolis administration 7 days prior to and 72 h after the ICH induction). Neurocognitive functions of the rats were analyzed using the rotarod challenge and Morris water maze. In addition, the expression of NF-κB, SUR1-TRPM4, MMP-9, and Aquaporin-4 was analyzed using immunohistochemical methods. A TUNEL assay was used to assess the percentage of apoptotic cells. Mannitol significantly improved cognitive-motor functions in the ICH group, evidenced by improved rotarod and Morris water maze completion times, and lowered SUR-1 and Aquaporin-4 levels. It also significantly decreased cerebral edema by day 3. Similarly, propolis treatments (propolis-A and propolis-B+A) showed comparable improvements in these tests and reduced edema. Moreover, combining propolis with mannitol (propolis-M) further enhanced these effects, particularly in reducing edema and the Virchow-Robin space. These findings highlight the potential of propolis from the Indonesian stingless bee, Geniotrigona thoracica , from the Central Tapanuli region as a neuroprotective, adjunctive therapy.

Aim: Systolic blood pressure (SBP) >180mmHg following stroke thrombolysis has been associated with increased bleeding and poorer outcome. Aiming for the guideline SBP of <180mmHg often leads to SBP overshoot, as treatment is only triggered if this threshold is passed. We tested whether a lower target would result in fewer high SBP protocol violations., Method: This is a single-centre, sequential comparison of two blood pressure protocols. Between 2013 and 2017, the guideline-based post-thrombolysis SBP target of <180mmHg was compared with a new protocol aiming for 140-160mmHg. The primary outcome was rate of patients with SBPs >180mmHg. Secondary outcomes included rates of SBP <120 mmHg, antihypertensive infusion use, symptomatic intracerebral haemorrhage (sICH) and 3-month functional independence (modified Rankin Score [mRS] 0-2). Results were adjusted for age, baseline function and stroke severity using regression analysis., Results: During the 23 months preceding and 18 months following the transition to the new protocol, 68 and 100 patients were thrombolysed respectively. Baseline characteristics were similar between groups. The odds of one or more SBPs >180mmHg trended lower in the intensive group (adjusted odds ratio [aOR] 0.61; 95% confidence interval [CI] 0.32-1.17; p=0.14). There was a higher rate of SBPs <120mmHg (aOR 3.09; 95% CI 1.49-6.40; p=0.002) in the intensive BP protocol group. sICH rate and 3-month mRS 0-2 were similar between groups., Conclusions: The more intensive post-thrombolysis BP protocol was associated with a significant increase in sub-optimally low BP events, with a non-significant trend toward fewer high BP protocol violations and unaffected patient outcomes., Competing Interests: BH, HM and AR disclose employment at Wellington Regional Hospital during the period this study was conducted. AR also discloses employment at the University of Otago Wellington and contract work for the Health New Zealand – Te Whatu Ora, and HM discloses employment at the Medical Research Institute of New Zealand. AR is an executive committee member of the Australian and New Zealand Stroke Organisation, a board member of the New Zealand World Stroke and Asia Pacific Stroke organisations and the medical director of the New Zealand Stroke Foundation. SM has no disclosures., (© PMA.)

Objective: To verify the incidence of bleeding events in patients on ongoing anticoagulant treatment in the real world and compare the results of different reversal or repletion strategies currently available for pharmacological treatment., Methods: Patients managed in the emergency department (ED) with major bleeding events, on ongoing anticoagulation were stratified according to bleeding site and reversal or repletion therapy with andexanet alfa (ADX), idarucizumab (IDA), prothrombin complex concentrate (PCC), and vitamin K (Vit-K)., Endpoint: Death at 30 days was compared in the subgroups with cerebral hemorrhage (CH) and gastrointestinal (GI) bleeding., Results: Of the 809,397 visits in the years 2022-2023 at 6 EDs in the northwestern health district of Tuscany, 5372 patients with bleeding events were considered; 3740 were excluded due to minor bleeding or propensity score matching. Of the remaining 1632 patients with major bleeding, 548 on ongoing anticoagulation were enrolled; 334 received reversal or repletion agents. Patients with CH (n = 176) and GI bleeding (n = 108) represented the primary analysis cohorts in the study's strategic treatment assessment. Overall, 30-day survival of patients on ongoing aFXa treatment receiving on-label ADX versus off-label PCC showed a relative increase of 71%, while 30-day survival of patients on ongoing aFII receiving on-label IDA versus off-label PCC showed a relative increase of 30%; no substantial difference was found when comparing on-label PCC combined with Vit-K versus off-label Vit-K alone. Indeed, patients undergoing on-label ADX or IDA showed a statistically significant difference over off-label PCC (ADX vs. PCC: n = 15, events = 4, mean ± SD 82.50 ± 18.9, vs. 49, 13, 98.82 ± 27, respectively; analysis of variance [ANOVA] variance 8627; P < 0.001; posthoc test diff 32, 95% confidence interval: 28-35; P < 001; IDA vs. PCC: 20, 5, 32.29 ± 15.0 vs. 2, 1, 28.00 ± 0.0, respectively; ANOVA 1484; P < 0.001; posthoc test -29, -29 -29, respectively; P = n.d.). On-label PCC combined with Vit-K showed overall a slight statistically significant difference versus off-label Vit-K alone (52, 16, 100.58 ± 22.6 vs. 53, 11, 154.62 ± 29.8, respectively; ANOVA 310; P < 0.02; posthoc test 4, 0.7-7.2, respectively; P < 0.02). Data were confirmed in the group of patients with CH (ADX vs. PCC: n = 13, events = 3, mean ± SD 91.55 ± 18.6 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA variance 10,091, F = 261; P < 0.001; posthoc difference test 36, 95% confidence interval: 30-41; P < 0.001; IDA vs. PCC: 10, 2, 4.50 ± 2.5 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA 16,876,303, respectively; P < 0.001; posthoc test 41, 34-47, respectively; P < 0.001). On-label PCC combined with Vit-K showed an overall slight statistically significant difference compared with off-label Vit-K alone (P < 0.01 and P < 0.001 in the subgroups of CH and GI bleeding)., Conclusions: Patients undergoing specific reversal therapy with on-label ADX or IDA, when treated with aFXa or aFII anticoagulants, respectively, showed statistically elevated differences in 30-day death compared with off-label repletion therapy with PCC. Overall, 30-day survival of patients on ongoing aFXa or aFII receiving on-label reversal therapy with ADX or IDA compared with off-label PCC repletion agents showed an increase of 71% and 30%, respectively., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: In patients with acute intracerebral haemorrhage (ICH) and elevated systolic blood pressure (BP), guidelines suggest that systolic BP reduction to <140 mmHg should be rapidly initiated. Compared with conventional care, Mobile Stroke Units (MSUs) allow for earlier ICH diagnosis through prehospital imaging and earlier BP lowering., Patients and Methods: ICH patients were prospectively evaluated as a cohort of the controlled B&#95;PROUD-study in which MSU availability alone determined MSU dispatch in addition to conventional ambulance. We used inverse probability of treatment weighting to adjust for confounding to estimate the effect of additional MSU dispatch in ICH patients. Outcomes of interest were 7-day mortality (primary), systolic BP (sBP) at hospital arrival, dispatch-to-imaging time, largest haematoma volume, anticoagulation reversal, length of in-hospital stay, 3-month functional outcome., Results: Between February 2017 and May 2019, MSUs were dispatched to 95 (mean age: 72 ± 13 years, 45% female) and only conventional ambulances to 78 ICH patients (mean age: 71 ± 12 years, 44% female). After adjusting for confounding, we found shorter dispatch-to-imaging time (mean difference: -17.75 min, 95% CI: -27.16 to -8.21 min) and lower sBP at hospital arrival (mean difference = -16.31 mmHg, 95% CI: -30.64 to -6.19 mmHg) in the MSU group. We found no statistically significant difference for the other outcomes, including 7-day mortality (adjusted odds ratio: 1.43, 95% CI: 0.68 to 3.31) or favourable outcome (adjusted odds ratio = 0.67, 95% CI: 0.27 to 1.67)., Conclusions: Although MSU dispatch led to sBP reduction and lower dispatch-to-imaging time compared to conventional ambulance care, we found no evidence of better outcomes in the MSU dispatch group., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MP reports funding from Novartis Pharma and being awarded a research grant from the Center for Stroke Research Berlin (private donations). ME reports grants from Bayer and fees paid to the Charité from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Sanofi, Novartis, Pfizer, all outside the submitted work. HJA reports personal fees from AstraZeneca, Boehringer-Ingelheim, Novo -Nordisk, and Roche. All other authors do not report conflicts of interest related to the submitted work.

Background: Yi-Qi-Huo-Xue Decoction (YQHXD), a traditional Chinese medicine formula, has demonstrated efficacy in the clinical treatment of intracerebral hemorrhage (ICH) for over a decade. Nevertheless, the precise pharmacotherapeutic compounds of YQHXD capable of penetrating into cerebral tissue and the pharmacological underpinnings of YQHXD remain ambiguous., Methods: The active components of YQHXD in rat brains was analyzed by ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The potential targets, pathways and biological progresses of YQHXD ameliorating ICH induced injury was predicted by network pharmacology. Moreover, collagenase-induced ICH rat model, primary cortex neurons exposed to hemin and molecular docking were applied to validate the molecular mechanisms of YQHXD., Results: Eleven active components of YQHXD were identified within the brains. Employing the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, our investigation concentrated on the roles of autophagy and the BDNF/TrkB signaling pathway in the pharmacological context. The pharmacological results revealed that YQHXD alleviated neurological dysfunction, brain water content, brain swelling, and pathological injury caused by ICH. Meanwhile, YQHXD inhibited autophagy influx and autophagosome in vivo, and regulated cortex neuronal autophagy and TrkB/BDNF pathway both in vivo and in vitro. Subsequently, N-acetyl serotonin (NAS), a selective TrkB agonist, was employed to corroborate the significance of the BDNF/TrkB pathway in this process. The combination of NAS and YQHXD did not further enhance the protective efficacy of YQHXD in ICH rats. Additionally, outcomes of molecular docking analysis revealed that nine compounds of YQHXD exhibited potential regulatory effects on TrkB., Conclusions: Ipsilateral neuronal autophagy and BDNF/TrkB pathway were activated 72 h after ICH. YQHXD effectively resisted injury induced by ICH, which was related with suppression of ipsilateral neuronal autophagy via BDNF/TrkB pathway. This study provides novel insights into the therapeutic mechanisms of traditional Chinese medicine in the context of ICH treatment., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Background: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo., Methods: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete., Findings: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98])., Interpretation: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings., Funding: Australian Government Medical Research Future Fund., Competing Interests: Declaration of interests HZ is a board member of the Pre-hospital Stroke Treatment Organization. GCC has received honoraria from AstraZeneca for lectures and advisory board participation. HM has received honoraria for lectures from the Indonesia Stroke Society Meeting and is the co-chair of the scientific committee for the Asia Pacific Stroke Conference (2024). AM has received consulting fees and participated on an advisory board for Boehringer Ingelheim, and is a member of the board of the World Stroke Organisation. AR has received grants from the Health Research Council of New Zealand, New Zealand Ministry of Health, and Australian and New Zealand Association of Neurologists; participated in a Data Safety Monitoring Board for Argenica Therapeutics; is secretary of the Australia and New Zealand Stroke Organisation; and board member of the World Stroke Organisation and New Zealand Stroke Foundation. VT has received honoraria from Boehringer Ingelheim, Bayer, and Medtronic, and participated in a Data Safety Monitoring Board for EMVision and Itreas. BY has received institutional research grants and honoraria for lectures and conference attendance from Stryker and Medtronic. LMS has received honoraria for lectures and educational materials from Biogen, Pfizer, and AbbVie, and support for conference attendance from Abbott. 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.)

Background and Aims: Cerebral microbleeds are magnetic imaging resonance (MRI) markers of hemorrhage-prone cerebral small vessel disease that predict future risk of ischemic stroke and intracranial hemorrhage (ICrH). There exist concerns about the net benefit of antithrombotic therapy in patients with microbleeds. We aimed to investigate the effects of an oral factor-XIa inhibitor (asundexian), that is hypothesized to inhibit thrombosis without compromising hemostasis, on the development of new microbleeds over time and interactions between microbleeds and asundexian treatment on clinical outcomes. We additionally assessed associations between baseline microbleeds and the risks of clinical and neuroimaging outcomes in patients with non-cardioembolic ischemic stroke., Methods: This is a secondary analysis of the PACIFIC-STROKE, international, multi-center Phase 2b double-blind, randomized clinical trial. PACIFIC-STROKE enrolled patients aged ⩾ 45 years with mild-to-moderate non-cardioembolic ischemic stroke who presented within 48 h of symptom onset for whom antiplatelet therapy was intended. Microbleeds were centrally adjudicated, and participants with an interpretable T2*-weighted sequence at their baseline MRI were included in this analysis. Patients were randomized to asundexian (10/20/50 mg daily) versus placebo plus standard antiplatelet treatment. Regression models were used to estimate the effects of (1) all pooled asundexian doses and (2) asundexian 50 mg daily on new microbleed formation on 26-week MRIs. Cox proportional hazards or regression models were additionally used to estimate interactions between treatment assignment and microbleeds for ischemic stroke/transient ischemic attack (TIA) (primary outcome), and ICrH, all-cause mortality, hemorrhagic transformation (HT), and new microbleeds (secondary outcomes)., Results: Of 1746 participants (mean age, 67.0 ± 10.0; 34% female) with baseline MRIs, 604 (35%) had microbleeds. During a median follow-up of 10.6 months, 7.0% (n = 122) had ischemic stroke/TIA, 0.5% (n = 8) ICrH, and 2.1% (n = 37) died. New microbleeds developed in 10.3% (n = 155) of participants with adequate follow-up MRIs and HT in 31.4% (n = 345). In the total sample of patients with adequate baseline and 26-week follow-up MRIs (n = 1507), new microbleeds occurred in 10.2% of patients assigned to any asundexian dose and 10.5% of patients assigned to placebo (OR, 0.96; 95% CI, 0.66-1.41). There were no interactions between microbleeds and treatment assignment for any of the outcomes (p for interaction > 0.05). The rates of new microbleeds, HT, and ICrH were numerically less in patients with microbleeds assigned to asundexian relative to placebo. The presence of microbleeds was associated with a higher risk of HT (aOR, 1.6; 95% CI, 1.2-2.1) and new microbleeds (aOR, 4.4; 95% CI, 3.0-6.3)., Conclusion: Factor XIa inhibition with asundexian appears safe in patients with non-cardioembolic ischemic stroke and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI. These preliminary findings will be confirmed in the ongoing OCEANIC-STROKE randomized trial., Trial Registration: ClinicalTrials.gov Identifier: NCT04304508., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All co-authors or their institutions received financial support from Bayer for participation in the PACIFIC-STROKE trial except H.M. and P.C., who are employees of Bayer.

Aims: The extent of perihematomal edema following intracerebral hemorrhage (ICH) significantly impacts patient prognosis, and disruption of the blood-brain barrier (BBB) exacerbates perihematomal edema. However, the role of peripheral IL-10 in mitigating BBB disruption through pathways that link peripheral and central nervous system signals remains poorly understood., Methods: Recombinant IL-10 was administered to ICH model mice via caudal vein injection, an IL-10-inhibiting adeno-associated virus and an IL-10 receptor knockout plasmid were delivered intraventricularly, and neurobehavioral deficits, perihematomal edema, BBB disruption, and the expression of JAK1 and STAT3 were evaluated., Results: Our study demonstrated that the peripheral cytokine IL-10 mitigated BBB breakdown, perihematomal edema, and neurobehavioral deficits after ICH and that IL-10 deficiency reversed these effects, likely through the IL-10R/JAK1/STAT3 signaling pathway., Conclusions: Peripheral IL-10 has the potential to reduce BBB damage and perihematomal edema following ICH and improve patient prognosis., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Background: The effect of antithrombotic therapy on patients with atrial fibrillation who sustained previous intracerebral hemorrhage (ICH) remains uncertain. Data regarding antithrombotic therapy use in these patients are limited. This study aims to compare the clinical and overall outcomes of antithrombotic therapy and usual care in patients with atrial fibrillation who sustained ICH., Methods: We assembled consecutive patients with atrial fibrillation sustaining an ICH from our institution. Multivariable regression analysis and propensity-matched analysis were applied to assess associations of different antithrombotic therapies and outcomes. The primary outcome was mortality within the longest follow-up. Kaplan-Meier curves and log-rank tests of the time-to-event data were used to assess differences in survival., Results: In total, 296 consecutive patients with atrial fibrillation who survived an ICH were included in this study. Our analysis demonstrated that antithrombotic therapy was associated with reduced mortality up to a 4-year duration of follow-up (OR, 0.49, 95 % CI 0.30-0.81). Similar results were obtained from the propensity-matched analysis (OR, 0.58, 95 % CI 0.34-0.98). Subgroup analysis showed that compared with usual care, direct oral anticoagulant (DOAC) with or without antiplatelet was associated with a lower risk of long-term mortality (OR, 0.34, 95 % CI 0.17-0.69). In addition, our analysis observed a significant interaction between cardiac insufficiency and treatment effect (P = 0.04)., Conclusions: In patients with atrial fibrillation who have a history of ICH, administration of antithrombotic therapy, especially DOAC, was associated with lower mortality. Future randomized trials are warranted to test the positive net clinical benefit of DOAC therapy., 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.)

Objective: Hematoma expansion (HE) predicts disability and death after acute intracerebral hemorrhage (ICH). Aspirin and anticoagulants have been associated with HE. We tested the hypothesis that P2Y12 inhibitors predict subsequent HE in patients. We explored laboratory measures of P2Y12 inhibition and dual antiplatelet therapy with aspirin (DAPT)., Methods: We prospectively identified patients with ICH. Platelet activity was measured with the VerifyNow-P2Y12 assay. Hematoma volumes for initial and follow-up CTs were calculated using a validated semi-automated technique. HE was defined as the difference between hematoma volumes on the initial and follow-up CT scans. Nonparametric statistics were performed with Kruskal-Wallis H, and correction for multiple comparisons performed with Dunn's test., Results: In 194 patients, 15 (7.7%) were known to take a P2Y12 inhibitor (clopidogrel in all but one). Patients taking a P2Y12 inhibitor had more HE compared to patients not taking a P2Y12 inhibitor (3.5 [1.2-11.9] vs. 0.1 [-0.8-1.4] mL, p = 0.004). Patients taking DAPT experienced the most HE (7.2 [2.6-13.8] vs. 0.0 [-1.0-1.1] mL, p = 0.04). The use of P2Y12 inhibitors was associated with less P2Y12 activity (178 [149-203] vs. 288 [246-319] P2Y12 reaction units, p = 0.005)., Interpretation: Patients taking a P2Y12 inhibitor had more HE and less P2Y12 activity. The effect was most pronounced in patients on DAPT, suggesting a synergistic effect of P2Y12 inhibitors and aspirin with respect to HE. Acute reversal of P2Y12 inhibitors in acute ICH requires further study., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Intracerebral hemorrhage (ICH) is a debilitating condition characterized by the rupture of cerebral blood vessels, resulting in profound neurological deficits. A significant challenge in the treatment of ICH lies in the brain's limited capacity to regenerate damaged blood vessels. This study explores the potential synergistic effects of Ginsenoside Rh2 and Chrysophanol in promoting angiogenesis following ICH in a rat model., Methods: Network pharmacology was employed to predict the potential targets and pathways of Ginsenoside Rh2 and Chrysophanol for ICH treatment. Molecular docking was utilized to assess the binding affinity between these compounds and their respective targets. Experimental ICH was induced in male Sprague-Dawley rats through stereotactic injection of type VII collagenase into the right caudate putamen (CPu). The study encompassed various methodologies, including administration protocols, assessments of neurological function, magnetic resonance imaging, histological examination, observation of brain tissue ultrastructure, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), immunofluorescence staining, Western blot analysis, and statistical analyses., Results: Network pharmacology analysis indicated that Ginsenoside Rh2 and Chrysophanol may exert their therapeutic effects in ICH by promoting angiogenesis. Results from animal experiments revealed that rats treated with Ginsenoside Rh2 and Chrysophanol exhibited significantly improved neurological function, reduced hematoma volume, and diminished pathological injury compared to the Model group. Immunofluorescence analysis demonstrated enhanced expression of vascular endothelial growth factor receptor 2 (VEGFR2) and CD31, signifying augmented angiogenesis in the peri-hematomal region following combination therapy. Importantly, the addition of a VEGFR2 inhibitor reversed the increased expression of VEGFR2 and CD31. Furthermore, Western blot analysis revealed upregulated expression of angiogenesis-related factors, including VEGFR2, SRC, AKT1, MAPK1, and MAPK14, in the combination therapy group, but this effect was abrogated upon VEGFR2 inhibitor administration., Conclusion: The synergistic effect of Ginsenoside Rh2 and Chrysophanol demonstrated a notable protective impact on ICH injury in rats, specifically attributed to their facilitation of angiogenesis. Consequently, this research offers a foundation for the utilization of Ginsenosides Rh2 and Chrysophanol in medical settings and offers direction for the advancement of novel pharmaceuticals for the clinical management of 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 Inc. All rights reserved.)

Intracerebral haemorrhage (ICH) presents significant challenges in clinical management because of the high morbidity and mortality, necessitating novel therapeutic approaches. This study aimed to assess the neuroprotective effects of loganin in a rat ICH model. Sprague-Dawley rats were used, subjected to a collagenase-induced ICH model, followed by loganin treatment at doses of 2.5, 5 and 10 mg/kg. Neurological functions were evaluated using the modified neurological severity score (mNSS) and a rotarod test. Results indicated a significant improvement in neurological functions in loganin-treated groups, evident from the mNSS and rotarod tests, suggesting dose-dependent neuroprotection. Loganin also effectively reduced the blood-brain barrier (BBB) permeability and cerebral oedema. Additionally, it mitigated cellular pyroptosis, as shown by terminal deoxynucleotidyl transferase dUTP nick-end labelling staining and western blot analysis, which indicated reduced levels of pyroptosis markers in treated rats. Furthermore, loganin's regulatory effects on the adenosine A2A receptor and myosin light chain kinase pathways were observed, potentially underpinning its protective mechanism against ICH. The study concludes that loganin exhibits significant neuroprotective properties in a rat ICH model, highlighting its potential as a novel therapeutic strategy. Despite promising results, the study needs further research to determine loganin's therapeutic potential in human ICH patients. This research paves the way for further exploration into loganin's clinical applications, potentially revolutionizing treatment strategies for patients suffering from intracerebral haemorrhage., (© 2024 John Wiley & Sons Australia, Ltd.)

Intracerebral hemorrhage (ICH) is a common cerebral vascular disease with high incidence, disability, and mortality. Ferroptosis is a regulated type of iron-dependent, non-apoptotic programmed cell death. There is increasing evidence that ferroptosis may lead to neuronal damage mediated by hemorrhagic stroke mediated neuronal damage. Salvianolic acid A (SAA) is a natural bioactive polyphenol compound extracted from salvia miltiorrhiza, which has anti-inflammatory, antioxidant, and antifibrosis activities. SAA is reported to be an iron chelator that inhibits lipid peroxidation and provides neuroprotective effects. However, whether SAA improves neuronal ferroptosis mediated by hemorrhagic stroke remains unclear. The study aims to evaluate the therapeutic effect of SAA on Ferroptosis mediated by Intracerebral hemorrhage and explore its potential mechanisms. We constructed in vivo and in vitro models of intracerebral hemorrhage in rats. Multiple methods were used to analyze the inhibitory effect of SAA on ferroptosis in both in vivo and in vitro models of intracerebral hemorrhage in rats. Then, network pharmacology is used to identify potential targets and mechanisms for SAA treatment of ICH. The SAA target ICH network combines SAA and ICH targets with protein-protein interactions (PPIs). Find the specific mechanism of SAA acting on ferroptosis through molecular docking and functional enrichment analysis. In rats, SAA (10 mg/kg in vivo and 50 μM in vitro, p < 0.05) alleviated dyskinesia and brain injury in the ICH model by inhibiting ferroptosis (p < 0.05). The molecular docking results and functional enrichment analyses suggested that AKT (V-akt murine thymoma viral oncogene homolog) could mediate the effect of SAA. NRF2 (Nuclear factor erythroid 2-related factor 2) was a potential target of SAA. Our further experiments showed that salvianolic acid A enhanced the Akt /GSK-3β/Nrf2 signaling pathway activation in vivo and in vitro. At the same time, SAA significantly expanded the expression of GPX4, XCT proteins, and the nuclear expression of Nrf2, while the AKT inhibitor SH-6 and the Nrf2 inhibitor ML385 could reduce them to some extent. Therefore, SAA effectively ameliorated ICH-mediated neuronal ferroptosis. Meanwhile, one of the critical mechanisms of SAA inhibiting ferroptosis was activating the Akt/GSK-3β/Nrf2 signaling pathway., (© 2024. The Author(s).)

Microglia play a pivotal role in the neuroinflammatory response after brain injury, and their proliferation is dependent on colony-stimulating factors. In the present study, we investigated the effect of inhibiting microglia proliferation on neurological damage post intracerebral hemorrhage (ICH) in a mouse model, an aspect that has never been studied before. Using a colony-stimulating factor-1 receptor antagonist (GW2580), we observed that inhibition of microglia proliferation significantly ameliorated neurobehavioral deficits, attenuated cerebral edema, and reduced hematoma volume after ICH. This intervention was associated with a decrease in pro-inflammatory factors in microglia and an increased infiltration of peripheral regulatory CD8 + CD122+ T cells into the injured brain tissue. The CXCR3/CXCL10 axis is the mechanism of brain homing of regulatory CD8 + CD122+ T cells, and the high expression of IL-10 is the hallmark of their synergistic anti-inflammatory effect with microglia. And activated astrocytes around the insult site are a prominent source of CXCL10. Thus, inhibition of microglial proliferation offers a new perspective for clinical translation. The cross-talk between multiple cells involved in the regulation of the inflammatory response highlights the comprehensive nature of neuroimmunomodulation., 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) can induce intensive oxidative stress, neuroinflammation, and brain cell apoptosis. However, conventional methods for ICH treatment have many disadvantages. There is an urgent need for alternative, effective therapies with minimal side effects. Pharmacodynamics experiment, molecular docking, network pharmacology, and metabolomics were adopted to investigate the treatment and its mechanism of Jingfang Granules (JFG) in ICH. In this study, we investigated the therapeutic effects of JFG on ICH using behavioral, brain water content and Magnetic resonance imaging experiments. However, the key active component and targets of JFG remain unknown. Here we verified that JFG was beneficial to improve brain injury after ICH. A network pharmacology analysis revealed that the anti-inflammatory effect of JFG is predominantly mediated by its activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway through Luteolin, (+)-Anomalin and Phaseol and their targeting of AKT1, tumor necrosis factorα (TNF-α), and interleukin-1β (IL-1β). Molecular docking analyses revealed an average affinity of -8.633 kcal/mol, indicating a binding strength of less than -5 kcal/mol. Metabolomic analysis showed that JFG exerted its therapeutic effect on ICH by regulating metabolic pathways, such as the metabolism of taurine and hypotaurine, biosynthesis of valine, leucine, and isoleucine. In conclusion, we demonstrated that JFG attenuated neuroinflammation and BBB injury subsequent to ICH by activating the PI3K/Akt signaling pathway.

Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes, but the effects of direct oral anticoagulants (DOACs) remain unclear. This study aimed to clarify trends in prior antithrombotic use and to assess the associations between prior use of antithrombotics and in-hospital mortality using a multicenter prospective registry in Japan. In total, 1085 patients were analyzed. Prior antithrombotic medication included antiplatelets in 14.2%, oral anticoagulants in 8.1%, and both in 1.8%. Prior warfarin use was significantly associated with in-hospital mortality (odds ratio [OR] 5.50, 95% confidence interval [CI] 1.30-23.26, P < 0.05) compared to no prior antithrombotic use. No such association was evident between prior DOAC use and no prior antithrombotic use (OR 1.34, 95% CI 0.44-4.05, P = 0.606). Concomitant use of antiplatelets and warfarin further increased the in-hospital mortality rate (37.5%) compared to warfarin alone (17.2%), but no such association was found for antiplatelets plus DOACs (8.3%) compared to DOACs alone (11.9%). Prior use of warfarin remains an independent risk factor for in-hospital mortality after SICH in the era of DOACs. Further strategies are warranted to reduce SICH among patients receiving oral anticoagulants and to prevent serious outcomes., (© 2024. The Author(s).)

Background: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied., Methods: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death., Results: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days., Conclusions: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Objectives: The time taken to achieve blood pressure (BP) control could be pivotal in the benefits of reducing BP in acute intracerebral hemorrhage (ICH). We aimed to assess the relationship between the rapid achievement and sustained maintenance of an intensive systolic BP (SBP) target with radiologic, clinical, and functional outcomes., Methods: Rapid, Intensive, and Sustained BP lowering in Acute ICH (RAINS) was a multicenter, prospective, observational cohort study of adult patients with ICH <6 hours and SBP ≥150 mm Hg at 4 Comprehensive Stroke Centers during a 4.5-year period. Patients underwent baseline and 24-hour CT scans and 24-hour noninvasive BP monitoring. BP was managed under a rapid (target achievement ≤60 minutes), intensive (target SBP <140 mm Hg), and sustained (target stability for 24 hours) BP protocol. SBP target achievement ≤60 minutes and 24-hour SBP variability were recorded. Outcomes included hematoma expansion (>6 mL or >33%) at 24 hours (primary outcome), early neurologic deterioration (END, 24-hour increase in NIH Stroke Scale score ≥4), and 90-day ordinal modified Rankin scale (mRS) score. Analyses were adjusted by age, sex, anticoagulation, onset-to-imaging time, ICH volume, and intraventricular extension., Results: We included 312 patients (mean age 70.2 ± 13.3 years, 202 [64.7%] male). Hematoma expansion occurred in 70/274 (25.6%) patients, END in 58/291 (19.9%), and the median 90-day mRS score was 4 (interquartile range, 2-5). SBP target achievement ≤60 minutes (178/312 [57.1%]) associated with a lower risk of hematoma expansion (adjusted odds ratio [aOR] 0.43, 95% confidence interval [CI] 0.23-0.77), lower END rate (aOR 0.43, 95% CI 0.23-0.80), and lower 90-day mRS scores (aOR 0.48, 95% CI 0.32-0.74). The mean 24-hour SBP variability was 21.0 ± 7.6 mm Hg. Higher 24-hour SBP variability was not related to expansion (aOR 0.99, 95% CI 0.95-1.04) but associated with higher END rate (aOR 1.15, 95% CI 1.09-1.21) and 90-day mRS scores (aOR 1.06, 95% CI 1.04-1.10)., Discussion: Among patients with acute ICH, achieving an intensive SBP target within 60 minutes was associated with lower hematoma expansion risk. Rapid SBP reduction and stable sustention within 24 hours were related to improved clinical and functional outcomes. These findings warrant the design of randomized clinical trials examining the impact of effectively achieving rapid, intensive, and sustained BP control on hematoma expansion., Classification of Evidence: This study provides Class III evidence that in adults with spontaneous ICH and initial SBP ≥150 mm Hg, lowering SBP to <140 mm Hg within the first hour and maintaining this for 24 hours is associated with decreased hematoma expansion.

Secondary brain injury exacerbates neurological dysfunction and neural cell death following intracerebral hemorrhage (ICH), targeting the pathophysiological mechanism of the secondary brain injury holds promise for improving ICH outcomes. Adjudin, a potential male contraceptive, exhibits neuroprotective effects in brain injury disease models, yet its impact in the ICH model remains unknown. In this study, we investigated the effects of adjudin on brain injury in a mouse ICH model and explored its underlying mechanisms. ICH was induced in male C57BL/6 mice by injecting collagenase into the right striatum. Mice received adjudin treatment (50 mg/kg/day) for 3 days before euthanization and the perihematomal tissues were collected for further analysis. Adjudin significantly reduced hematoma volume and improved neurological function compared with the vehicle group. Western blot showed that Adjudin markedly decreased the expression of MMP-9 and increased the expression of tight junctions (TJs) proteins, Occludin and ZO-1, and adherens junctions (AJs) protein VE-cadherin. Adjudin also decreased the blood-brain barrier (BBB) permeability, as indicated by the reduced albumin and Evans Blue leakage, along with a decrease in brain water content. Immunofluorescence staining revealed that adjudin noticeably reduced the infiltration of neutrophil, activation of microglia/macrophages, and reactive astrogliosis, accompanied by an increase in CD206 positive microglia/macrophages which exhibit phagocytic characteristics. Adjudin concurrently decreased the generation of proinflammatory cytokines, such as TNF-α and IL-1β. Additionally, adjudin increased the expression of aquaporin 4 (AQP4). Furthermore, adjudin reduced brain cell apoptosis, as evidenced by increased expression of anti-apoptotic protein Bcl-2, and decreased expression of apoptosis related proteins Bax, cleaved caspase-3 and fewer TUNEL positive cells. Our data suggest that adjudin protects against ICH-induced secondary brain injury and may serve as a potential neuroprotective agent 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 Elsevier B.V. All rights reserved.)

Background: Intracerebral hemorrhage (ICH) is a critical neurological condition with few treatment options, where secondary immune responses and specific cell death forms, like pyroptosis, worsen brain damage. Pyroptosis involves gasdermin-mediated membrane pores, increasing inflammation and neural harm, with the NLRP3/Caspase-1/GSDMD pathway being central to this process. Peroxiredoxin II (Prx II), recognized for its mitochondrial protection and reactive oxygen species (ROS) scavenging abilities, appears as a promising neuronal pyroptosis modulator. However, its exact role and action mechanisms need clearer definition. This research aims to explore Prx II impact on neuronal pyroptosis and elucidate its mechanisms, especially regarding endoplasmic reticulum (ER) stress and oxidative stress-induced neuronal damage modulation., Methods and Results: Utilizing MTT assays, Microscopy, Hoechst/PI staining, Western blotting, and immunofluorescence, we found Prx II effectively reduces LPS/ATP-induced pyroptosis and neuroinflammation in HT22 hippocampal neuronal cells. Our results indicate Prx II's neuroprotective actions are mediated through PI3K/AKT activation and ER stress pathway inhibition, diminishing mitochondrial dysfunction and decreasing neuronal pyroptosis through the ROS/MAPK/NF-κB pathway. These findings highlight Prx II potential therapeutic value in improving intracerebral hemorrhage outcomes by lessening secondary brain injury via critical signaling pathway modulation involved in neuronal pyroptosis., Conclusions: Our study not only underlines Prx II importance in neuroprotection but also opens new therapeutic intervention avenues in intracerebral hemorrhage, stressing the complex interplay between redox regulation, ER stress, and mitochondrial dynamics in neuroinflammation and cell death management., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis., Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays., Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis., Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH., Competing Interests: The authors declare the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Chen, Ge, Jiang, Hu and Yin.)

Intracerebral hemorrhage (ICH) is a prevalent cerebrovascular disorder. The inflammation induced by cerebral hemorrhage plays a crucial role in the secondary injury of ICH and often accompanied by a poor prognosis, leading to disease exacerbation. However, blood-brain barrier (BBB) limiting the penetration of therapeutic drugs to the brain. In this paper, our primary objective is to develop an innovative, non-invasive, safe, and targeted formulation. This novel approach aims to synergistically harness the combined therapeutic effects of drugs to intervene in inflammation via a non-injectable route, thereby significantly mitigating the secondary damage precipitated by inflammation following ICH. Thus, a novel "anti-inflammatory" cationic solid lipid nanoparticles (SLN) with targeting ability were constructed, which can enhance the stability of curcumin(CUR) and siRNA. We successfully developed SLN loaded with TGF-β1 siRNA and CUR (siRNA/CUR@SLN) that adhere to the requirements of drug delivery system by transnasal brain targeting. Through the characterization of nanoparticle properties, cytotoxicity assessment, in vitro pharmacological evaluation, and brain-targeting evaluation after nasal administration, siRNA/CUR@SLN exhibited a nearly spherical structure with a particle size of 125.0±1.93 nm, low cytotoxicity, high drug loading capacity, good sustained release function and good stability. In vitro anti-inflammatory results showcasing its remarkable anti-inflammatory activity. Moreover, in vivo pharmacological studies revealed that siRNA/CUR@SLN can be successfully delivered to brain tissue. Furthermore, it also elicited an effective anti-inflammatory response, alleviating brain inflammation. These results indicated that favorable brain-targeting ability and anti-inflammatory effects of siRNA/CUR@SLN in ICH model mice. In conclusion, our designed siRNA/CUR@SLN showed good brain targeting and anti-inflammatory effect ability after nasal administration, which lays the foundation for the treatment of inflammation caused by ICH and offers a novel approach for brain-targeted drug delivery and brings new hope., 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 B.V. All rights reserved.)

Background: Naoxueshu oral liquid is the only approved drug for acute treatment of cerebral hemorrhage in China. It has been used widely for the treatment of acute ischemic stroke and acute hemorrhagic stroke. However, safety and efficacy data on the early use of Naoxueshu oral liquid are lacking. The main purpose of this study is to observe the benefit and safety of early use of Naoxueshu oral liquid (< 72 h of cerebral hemorrhage) and offer evidence into the potential superiority of Naoxueshu oral liquid in patients with hemorrhagic stroke, and its healthcare costs., Methods: This registration study for the prevention and treatment of cerebral hemorrhage using Naoxueshu oral liquid will be a quantitative, prospective, multicenter, observational clinical registry study. We aim to register 2000 patients with cerebral hemorrhage within 7 days of disease onset. This study will be an observational study and not interfere with the medication regimen of participants. Hence, we will not allocate patients. The main observation indicators will be the hematoma volume and the proportion of reduction 14 days post-cerebral hemorrhage (or at hospital discharge), onset of new stroke (ischemic stroke, hemorrhagic stroke) within 12 months of disease onset, independence in everyday life activities (modified Rankin Scale score ≤ 2), total cost during hospitalization, and treatment costs., Conclusion: This registration study will offer strong evidence for the efficacy and safety of Naoxueshu oral liquid for the prevention and treatment of cerebral hemorrhage, particularly with regard to early use (72 h after onset). It will offer evidence into the potential advantages of Naoxueshu oral liquid in patients with hemorrhagic stroke, including healthcare costs., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH-induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood-induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single-cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP-activated exchange protein-1 (EPAC-1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC-1) to inhibit its interaction with voltage-dependent anion-selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron-specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC-1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC-1 with celastrol can be a promising therapeutic approach for treating ICH-induced SBI., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

The use of anticoagulants has become more frequent due to the progressive aging population and increased thromboembolic events. Consequently, the proportion of anticoagulant-associated intracerebral hemorrhage (AAICH) in stroke patients is gradually increasing. Compared with intracerebral hemorrhage (ICH) patients without coagulopathy, patients with AAICH may have larger hematomas, worse prognoses, and higher mortality. Given the need for anticoagulant reversal and resumption, the management of AAICH differs from that of conventional medical or surgical treatments for ICH, and it is more specific. Understanding the pharmacology of anticoagulants and identifying agents that can reverse their effects in the early stages are crucial for treating life-threatening AAICH. When patients transition beyond the acute phase and their vital signs stabilize, it is important to consider resuming anticoagulants at the right time to prevent the occurrence of further thromboembolism. However, the timing and strategy for reversing and resuming anticoagulants are still in a dilemma. Herein, we summarize the important clinical studies, reviews, and related guidelines published in the past few years that focus on the reversal and resumption of anticoagulants in AAICH patients to help implement decisive diagnosis and treatment strategies in the clinical setting., (© 2024. The Author(s).)

Background and Purpose: It has been reported activation of NLRP3 inflammasome after intracerebral hemorrhage (ICH) ictus exacerbates neuroinflammation and brain injury. We hypothesized that inhibition of NLRP3 by OLT1177 (dapansutrile), a novel NLRP3 inflammasome inhibitor, could reduce brain edema and attenuate brain injury in experimental ICH., Methods: ICH was induced by injection of autologous blood into basal ganglia in mice models. Sixty-three C57Bl/6 male mice were randomly grouped into the sham, vehicle, OLT1177 (Dapansutrile, 200 mg/kg intraperitoneally) and treated for consecutive three days, starting from 1 h after ICH surgery. Behavioral test, brain edema, brain water content, blood-brain barrier integrity and vascular permeability, cell apoptosis, and NLRP3 and its downstream protein levels were measured., Results: OLT1177 significantly reduced cerebral edema after ICH and contributed to the attenuation of neurological deficits. OLT1177 could preserve blood-brain barrier integrity and lessen vascular leakage. In addition, OLT1177 preserved microglia morphological shift and significantly inhibited the activation of caspase-1 and release of IL-1β. We also found that OLT1177 can protect against neuronal loss in the affected hemisphere., Conclusions: OLT1177 (dapansutrile) could significantly attenuate the brain edema after ICH and effectively alleviate the neurological deficit. This result suggests that the novel NLRP3 inhibitor, OLT1177, might serve as a promising candidate for the treatment of 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 The Author(s). Published by Elsevier B.V. All rights reserved.)