RESUMEN
INTRODUCTION: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH. METHODS: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20-30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events. CONCLUSION: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH.
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Hemorragia Cerebral , Medicamentos Herbarios Chinos , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Método Doble Ciego , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Resultado del Tratamiento , Estudios Prospectivos , China , Factores de Tiempo , Recuperación de la Función , Estudios Multicéntricos como Asunto , Masculino , Femenino , Persona de Mediana Edad , Anciano , Enfermedad Aguda , Evaluación de la Discapacidad , Estado Funcional , AdultoRESUMEN
Hypertensive intracerebral hemorrhage (HICH) is a destructive disease with high mortality, incidence, and disability. Asiaticoside (AC) is a triterpenoid derivative that has demonstrated to exert a protective effect on neuron and blood vessel. To investigate the function and potential mechanism of AC on HICH. Human brain microvascular endothelial cells (hBMECs) were treated with 20 U/mL thrombin for 24 h to establish the HICH model in vitro, and AC with the concentration of 1, 2 and 4 µM were used to incubate hBMECs. The effect and potential mechanism of AC on HICH were investigated by using cell counting kit-8, flow cytometry, tube forming assays, vascular permeability experiments and western blot assays. In vivo, rats were injected with 20 µL hemoglobin with a concentration of 150 mg/mL, and then intragastrically administrated with 1.25, 2.5 and 5 mg/kg AC. Behavioral tests, brain water content measurement, hematoxylin-eosin (HE) staining, terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling assays, and western blot were used to assess the effect and potential mechanism of AC on HICH. AC (at 2 and 4 µM) improved the proliferation, apoptosis, angiogenesis and vascular permeability in thrombin-induced hBMECs (p < 0.05). Besides, AC (2.5 and 5 mg/kg) ameliorated behavioral scores, brain water content, pathological lesion, apoptosis and the expression of vascular permeability-related proteins in rats with HICH (p < 0.05). In addition, AC elevated the expression of PI3K/AKT pathway after HICH both in cell and animal models (p < 0.05). Application of LY294002, an inhibitor of PI3K/AKT pathway, reversed the ameliorative effect of AC on the proliferation, apoptosis, angiogenesis and vascular permeability in thrombin-induced hBMECs (p < 0.05). AC reduced brain damage by increasing the expression of the PI3K/AKT pathway after HICH.
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Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Triterpenos , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Humanos , Triterpenos/farmacología , Hemorragia Intracraneal Hipertensiva/tratamiento farmacológico , Hemorragia Intracraneal Hipertensiva/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Apoptosis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Lesiones Encefálicas/prevención & control , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/patología , Hemorragia Cerebral/complicacionesRESUMEN
Current clinical practice primarily relies on surgical intervention to remove hematomas in patients with intracerebral hemorrhage (ICH), given the lack of effective drug therapies. Previous research indicates that simvastatin (SIM) may enhance hematoma absorption and resolution in the acute phase of ICH, though the precise mechanisms remain unclear. Recent findings have highlighted the glymphatic system (GS) as a crucial component in intracranial cerebrospinal fluid circulation, playing a significant role in hematoma clearance post-ICH. This study investigates the link between SIM efficacy in hematoma resolution and the GS. Our experimental results show that SIM alleviates GS damage in ICH-induced rats, resulting in improved outcomes such as reduced brain edema, neuronal apoptosis, and degeneration. Further analysis reveals that SIM's effects are mediated through the VEGF-C/VEGFR3/PI3K-Akt pathway. This study advances our understanding of SIM's mechanism in promoting intracranial hematoma clearance and underscores the potential of targeting the GS for ICH treatment.
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Hemorragia Cerebral , Sistema Glinfático , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Simvastatina , Animales , Masculino , Ratas , Apoptosis/efectos de los fármacos , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Modelos Animales de Enfermedad , Sistema Glinfático/efectos de los fármacos , Sistema Glinfático/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Simvastatina/farmacologíaRESUMEN
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.
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Barrera Hematoencefálica , Calcitriol , Hemorragia Cerebral , Deficiencia de Vitamina D , Animales , Hemorragia Cerebral/tratamiento farmacológico , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/complicaciones , Calcitriol/farmacología , Calcitriol/uso terapéutico , Calcitriol/administración & dosificación , Masculino , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Ratones , Ratones Endogámicos C57BLAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proyectos de Investigación , Rivaroxabán/efectos adversosAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Rivaroxabán/efectos adversos , Estudios Multicéntricos como Asunto , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Ensayos Clínicos Fase IV como Asunto , Proyectos de Investigación , Ensayos Clínicos Controlados Aleatorios como AsuntoAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proyectos de Investigación , Rivaroxabán/efectos adversosAsunto(s)
Reversión de la Anticoagulación , Hemorragia Cerebral , Inhibidores del Factor Xa , Factor Xa , Proteínas Recombinantes , Humanos , Reversión de la Anticoagulación/efectos adversos , Reversión de la Anticoagulación/métodos , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/tratamiento farmacológico , Ensayos Clínicos Fase IV como Asunto , Factor Xa/administración & dosificación , Factor Xa/efectos adversos , Inhibidores del Factor Xa/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Rivaroxabán/efectos adversos , Estudios Multicéntricos como Asunto , Proyectos de InvestigaciónRESUMEN
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.
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Hemorragia Cerebral , Hemoglobinas , Hidrogeles , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/tratamiento farmacológico , Hidrogeles/química , Hemoglobinas/metabolismo , Animales , Deferoxamina/farmacología , Deferoxamina/uso terapéutico , Deferoxamina/química , ADN/metabolismo , Humanos , Masculino , Ratas , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Hierro/metabolismo , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/diagnóstico , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/químicaRESUMEN
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.
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Hemorragia Cerebral , Ferroptosis , Factor 2 Relacionado con NF-E2 , Nanopartículas , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Selenio , Animales , Humanos , Masculino , Ratones , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Modelos Animales de Enfermedad , Ferroptosis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Nanopartículas/química , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/administración & dosificación , Factor 2 Relacionado con NF-E2/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Selenio/química , Selenio/farmacología , Albúmina Sérica Bovina/químicaRESUMEN
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.
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Hemorragia Cerebral , Edaravona , Indoles , Nanopartículas , Especies Reactivas de Oxígeno , Dióxido de Silicio , Animales , Dióxido de Silicio/química , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/patología , Especies Reactivas de Oxígeno/metabolismo , Ratones , Nanopartículas/química , Edaravona/química , Edaravona/farmacología , Indoles/química , Indoles/farmacología , Porosidad , Polímeros/química , Polímeros/farmacología , Depuradores de Radicales Libres/química , Depuradores de Radicales Libres/farmacología , Masculino , Antioxidantes/química , Antioxidantes/farmacología , Estrés Oxidativo/efectos de los fármacosRESUMEN
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.
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Anticoagulantes , Hemorragia Cerebral , Inhibidores de Agregación Plaquetaria , Sistema de Registros , Humanos , Masculino , Femenino , Anciano , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Anticoagulantes/efectos adversos , Anticoagulantes/administración & dosificación , Anticoagulantes/uso terapéutico , Hemorragia Cerebral/cirugía , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/mortalidad , Factores de Tiempo , Factores de Riesgo , Fibrinolíticos/efectos adversos , Fibrinolíticos/administración & dosificación , Anciano de 80 o más Años , Neuroendoscopía/efectos adversos , Estudios Retrospectivos , Medición de RiesgoRESUMEN
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.
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Materiales Biocompatibles , Hemorragia Cerebral , Humanos , Hemorragia Cerebral/terapia , Hemorragia Cerebral/tratamiento farmacológico , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Animales , Nanoestructuras/química , Hidrogeles/química , Hidrogeles/administración & dosificaciónRESUMEN
Inflammatory reactions after acute intracerebral hemorrhage (AICH) contribute significantly to a poor prognosis. Liangxue Tongyu Prescription (LTP) has been proven to be clinically effective in treating AICH. Numerous studies have shown that LTP suppresses brain inflammatory damage in AICH, while the internal mechanisms underlying its action remain unclear. The aim of this study was to verify the anti-inflammatory effects of LTP on an AICH rat model and investigate the potential mechanisms. The AICH rat models were created by injecting autologous blood into the right caudate nucleus. LTP markedly decreased cerebral hematoma and brain water content and recovered from neurological deficits. Meanwhile, LTP prevented microglial activation and reduced the inflammatory reaction caused by pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6). Notably, the expression of cholecystokinin octapeptide (CCK-8) in the brain and intestine was increased by LTP or CCK-8 treatment. LTP further suppressed nuclear factor kappa B (NF-κB) in the brains of rats with AICH. Moreover, LTP increased the protein and mRNA expression of Occludin and Claudin-1 in the intestine and decreased the levels of lipopolysaccharide (LPS) and diamine oxidase (DAO) in serum. Furthermore, the results showed that LTP increased the protein and mRNA expression of Claudin-5 and zonula occludens-1 (ZO-1) in the brain. CCK-8 receptor antagonists increased the expression of NF-κB and the concentration of pro-inflammatory cytokines. These findings suggested that LTP attenuated neuroinflammation by increasing CCK-8 in the brain and intestine, and its mechanism might be related to alterations in the gut-brain axis (GBA).
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Hemorragia Cerebral , Medicamentos Herbarios Chinos , Enfermedades Neuroinflamatorias , Ratas Sprague-Dawley , Animales , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Masculino , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ratas , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Sincalida/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , FN-kappa B/metabolismoRESUMEN
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.
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Hemorragia Cerebral , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Fármacos Neuroprotectores , Humanos , Hemorragia Cerebral/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Estudios Prospectivos , Fármacos Neuroprotectores/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Femenino , Estudios Multicéntricos como Asunto , Masculino , Persona de Mediana Edad , Adulto , China , AncianoRESUMEN
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.
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Barrera Hematoencefálica , Hemorragia Cerebral , Compuestos Heterocíclicos de 4 o más Anillos , Sirtuina 1 , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Sirtuina 1/metabolismo , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Masculino , Ratones , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Fármacos Neuroprotectores/farmacología , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/agonistas , Edema Encefálico/tratamiento farmacológico , Edema Encefálico/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
AIM: To determine the effectiveness of extraventricular drainage (EVD) combined with fibrinolytics in reducing morbidity and mortality rates associated with intraventricular cerebral hemorrhage (IVH). MATERIAL AND METHODS: A literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO registration number: CRD42022332152). Articles were selected from various sources, including PubMed, Trip Database, LILACS, Cochrane Library, and ScienceDirect. Clinical trials focusing on IVH treatment using EVD and/or fibrinolytics were considered. The Risk of Bias in Non-randomized Studies of Interventions (ROB 2) tool was employed for bias assessment. A fixed-effects regression model was used following heterogeneity analysis. Treatment effectiveness was evaluated based on mortality outcomes. RESULTS: A total of 531 patients from four studies were included. The use of fibrinolytics significantly decreased IVH mortality compared with a placebo. The odds ratio (OR) for recombinant tissue plasminogen activator (rtPA) or alteplase was 0.54 [0.36; 0.82]. For urokinase (UK), the OR was 0.21 [0.03; 1.54], rendering it statistically non-significant. The overall OR was 0.52 [0.35; 0.78], and the heterogeneity I2 was 0% (indicating low heterogeneity). CONCLUSION: While EVD alone is a common approach for managing hydrocephalus, its effectiveness is limited by potential blockages and infections. Combining EVD with UK or rtPA demonstrated improved patient outcomes. rtPA stands out as a reliable and effective option, while limited data are available regarding UK's effectiveness in reducing IVH mortality.
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Fibrinolíticos , Humanos , Fibrinolíticos/uso terapéutico , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/mortalidad , Activador de Tejido Plasminógeno/uso terapéutico , Resultado del Tratamiento , Hemorragia Cerebral Intraventricular/tratamiento farmacológico , Terapia Trombolítica/métodosRESUMEN
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.
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Hemorragia Cerebral , Modelos Animales de Enfermedad , Fármacos Neuroprotectores , Própolis , Ratas Sprague-Dawley , Animales , Própolis/farmacología , Própolis/química , Fármacos Neuroprotectores/farmacología , Hemorragia Cerebral/tratamiento farmacológico , Abejas , Ratas , Masculino , Flavonoides/farmacología , Flavonoides/análisis , Antioxidantes/farmacología , Edema Encefálico/tratamiento farmacológico , Cromatografía de Gases y Espectrometría de Masas , Fenoles/farmacología , Fenoles/análisisRESUMEN
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.
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Edema Encefálico , Hemorragia Cerebral , Interleucina-10 , Janus Quinasa 1 , Receptores de Interleucina-10 , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Factor de Transcripción STAT3/metabolismo , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/metabolismo , Edema Encefálico/etiología , Edema Encefálico/tratamiento farmacológico , Janus Quinasa 1/metabolismo , Janus Quinasa 1/antagonistas & inhibidores , Interleucina-10/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismoRESUMEN
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.