RESUMO
AIMS: We aimed to resolve the uncertainty as to whether betulin exerted neuroprotection on early brain injury (EBI) caused by subarachnoid hemorrhage (SAH), and to investigate the related molecular mechanisms. METHODS: Bioinformatic analysis was performed to pre-study the differently expressed genes (DEGs) and the possible signaling pathways. Rat and cellular model of SAH were introduced in this study, and betulin, an activator of DJ-1 protein, was administered to reveal the effect. Gross assessment regarding mortality, neurofunctions, SAH grade, brain water content (BWC) along with multiple cellular and molecular studies in vivo or/and in vitro such as immunofluorescence (IF) staining, western blot (WB), reactive oxygen species (ROS) assay, and flow cytometry (FCM) were all conducted after SAH induction to verify the protective effect and the relevant mechanisms of DJ-1 in diverse levels. In addition, MK2206 (selective inhibitor of Akt) and iRNADj-1 (interfering RNA to Dj-1) were utilized to confirm the mechanisms of the effect. RESULTS: The data from our study showed that DJ-1 protein was moderately expressed in neurons, microglia, and astrocytes; its level in brain tissue elevated and peaked at 24-72 h after SAH induction. Betulin could efficaciously induce the expression of DJ-1 which in turn activated Akt and Bcl-2, and anti-oxidative enzymes SOD2 and HO-1, functioning to reduce the activation of cleaved caspase-3 (c-Casp-3) and reactive oxygen species (ROS). The induced DJ-1 could upregulate the expression of Nrf2. However, Akt seemed no direct effect on elevating the expression of Nrf2. DJ-1 alone could as well activate Akt-independent antiapoptotic pathway via suppressing the activation of caspase-8 (Casp-8). CONCLUSIONS: Betulin which was a potent agonist of DJ-1 had the ability to induce its expression in brain tissue. DJ-1 had neuroprotective effect on EBI through comprehensive mechanisms, including facilitating intrinsic and extrinsic antiapoptotic pathway, and reducing oxidative injury by upregulating the expression of redox proteins. Betulin as an inexpensive drug showed the potential for SAH treatment.
Assuntos
Apoptose , Fator 2 Relacionado a NF-E2 , Neurônios , Estresse Oxidativo , Proteína Desglicase DJ-1 , Proteínas Proto-Oncogênicas c-akt , Ratos Sprague-Dawley , Transdução de Sinais , Hemorragia Subaracnóidea , Triterpenos , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/patologia , Animais , Proteína Desglicase DJ-1/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Apoptose/efeitos dos fármacos , Triterpenos/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Ácido BetulínicoRESUMO
Clazosentan prevents vasospasms after aneurysmal subarachnoid hemorrhage (SAH). However, clinical data on patients with SAH with ruptured vertebral artery dissecting aneurysms (VADAs) are limited. We report the case of a 49-year-old male patient with mild-grade (WFNS grade 1) thick and diffuse (modified Fisher grade 3) SAH who underwent endovascular trapping of a ruptured VADA, resulting in a poor functional outcome with a modified Rankin Scale score of 4 due to severe symptomatic vasospasm refractory to clazosentan, requiring repeated rescue endovascular therapies and chronic communicating hydrocephalus. A retrospective analysis of the clot density in the basal and Sylvian cisterns, assessed by the Hounsfield unit (HU) values of serial CT scans, in this patient showed persistent higher values, distinct from another VADA case that showed a decline in HU values with a good clinical course. These results imply the limited effectiveness of clazosentan in cases of thick and diffuse SAH after a ruptured VADA, even in good-clinical-grade patients treated with less invasive modalities. The HU values may become a simple quantitative marker for predicting symptomatic vasospasms and chronic hydrocephalus.
Assuntos
Dioxanos , Piridinas , Pirimidinas , Hemorragia Subaracnóidea , Sulfonamidas , Tetrazóis , Vasoespasmo Intracraniano , Humanos , Masculino , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Pessoa de Meia-Idade , Dioxanos/uso terapêutico , Sulfonamidas/uso terapêutico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/complicações , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/diagnóstico por imagem , Pirimidinas/uso terapêutico , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Dissecação da Artéria Vertebral/complicações , Dissecação da Artéria Vertebral/tratamento farmacológico , Aneurisma Roto/complicações , Estudos Retrospectivos , Procedimentos Endovasculares/métodosRESUMO
Subarachnoid hemorrhage (SAH) is a devastating stroke caused by ruptured intracranial aneurysms, leading to blood accumulation around the brain. Early brain injury (EBI) within 72 h post-SAH worsens prognosis, primarily due to intense neuroinflammation. Microglia, pivotal in central nervous system defense and repair, undergo M1 to M2 polarization post-SAH, with M1 exacerbating neuroinflammation. Propofol (PPF), an anesthetic with anti-inflammatory properties, shows promise in mitigating neuroinflammation in SAH by modulating microglial activation. It likely acts through microRNAs like miR-140-5p, which attenuates microglial activation and inflammation by targeting TREM-1 and the NF-κB pathway. Understanding these mechanisms could lead to new therapeutic approaches for SAH-related EBI. In this study, BV-2 cell was used to establish in vitro model of SAH, and the expression of miR-140-5p and TREM-1 was detected after modeling. Microglial activity, apoptosis, the inflammatory pathway and response, oxidative damage, and M1/M2 polarization of microglia were evaluated by drug administration or transfection according to experimental groups. Finally, the targeting relationship between miR-140-5p and TREM-1 was verified by dual luciferase reporter assays, and the effect of PPF on the miR-140-5p/TREM-1/NF-κB signaling cascade was evaluated by RTâqPCR or Western blotting. PPF effectively mitigates apoptosis, neuroinflammation, oxidative damage, and M1 microglial polarization in SAH. In SAH cells, PPF upregulates miR-140-5p and downregulates TREM-1. Mechanistically, PPF boosts miR-140-5p expression, while TREM-1, a downstream target of miR-140-5p, inhibits NF-κB signaling by regulating TREM-1, promoting M1 to M2 microglial polarization. Reduced miR-140-5p or increased TREM-1 counters PPF's therapeutic impact on SAH cells. In conclusion, PPF plays a neuroprotective role in SAH by regulating the miR-140-5p/TREM-1/NF-κB signaling axis to inhibit neuroinflammation and M1 polarization of microglia.
Assuntos
MicroRNAs , Microglia , NF-kappa B , Propofol , Transdução de Sinais , Hemorragia Subaracnóidea , Receptor Gatilho 1 Expresso em Células Mieloides , MicroRNAs/metabolismo , MicroRNAs/genética , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Microglia/metabolismo , Microglia/efeitos dos fármacos , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Propofol/farmacologia , Camundongos , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Linhagem Celular , Modelos Animais de DoençasRESUMO
Subarachnoid hemorrhage (SAH) is a life-threatening acute hemorrhagic cerebrovascular disease, with early brain injury (EBI) being the main cause of high mortality and severe neurological dysfunction. Oxidative stress plays a crucial role in the pathogenesis of EBI. In this study, we synthesized antioxidant stress nanoparticles based on self-assembled oleanolic acid (OA) using the solvent volatilization method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM) techniques were employed to analyze and understand the self-assembly mechanism of oleic acid nanoparticles (OA NPs). The TUNEL assay, Nissl staining, and brain water content measurements were conducted to investigate the impact of OA NPs on cortical neuronal injury. Additionally, Western blot analysis was performed to investigate the antioxidant stress mechanism of OA NPs. The result showed that OA NPs exhibited a spherical structure with an average diameter of 168 nm. The application of OA NPs in SAH has been found to contribute to the reduction of keap1 protein levels and an increase in the nuclear level of Nrf2. As a result, the transcription of antioxidant stress proteins, including HO1 and NQO1, is triggered. The activation of the antioxidant stress pathway by OA NPs ultimately leads to a decrease in neuron damage and an improvement in neurological dysfunction. In conclusion, we successfully designed and synthesized OA NPs that can efficiently target the site of SAH. These nanoparticles have demonstrated their potential as antioxidants for the treatment of SAH, offering significant clinical applications.
Assuntos
Antioxidantes , Nanopartículas , Ácido Oleanólico , Estresse Oxidativo , Hemorragia Subaracnóidea , Hemorragia Subaracnóidea/tratamento farmacológico , Ácido Oleanólico/farmacologia , Ácido Oleanólico/administração & dosagem , Nanopartículas/química , Antioxidantes/farmacologia , Antioxidantes/administração & dosagem , Animais , Estresse Oxidativo/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ratos , Masculino , Ratos Sprague-Dawley , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Tamanho da Partícula , CamundongosAssuntos
Apoptose , Atorvastatina , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Hemorragia Subaracnóidea , Animais , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/patologia , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Apoptose/efeitos dos fármacos , Ratos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/etiologia , Ratos Sprague-Dawley , Masculino , HumanosRESUMO
Subarachnoid hemorrhage due to rupture of intracranial aneurysms has a poor outcome, making this disease being the social problem. Inflammation evoked by the increase in intracranial pressure and the clot in the subarachnoid space after the onset of SAH exacerbates neuronal death and vasospasm, resulting in the poor outcome and severe aftereffects. Here, FROUNT mediates CCR2 and CCR5 signaling as an intracellular molecule binding to these chemoattractant receptors which facilitate the migration of inflammatory cells, such as macrophages, in situ to trigger inflammation there. Animal model of subarachnoid hemorrhage was established in rats through intrathecal injection of autologous blood. The effect of the FROUNT inhibitor, disulfiram, on survival rate, neuronal death in hippocampus or vasospasm was then examined. The intrathecal administration of disulfiram significantly suppressed the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils toward the clot in the cistern in situ. In this condition, disulfiram ameliorated the death of animals after the onset of subarachnoid hemorrhage in rats. In addition, disulfiram suppressed both the two major events after subarachnoid hemorrhage, the neuronal death in hippocampus and vasospasm. The pharmacological inhibition of CCR2 and CCR5 signaling by disulfiram could thus be the therapeutic strategy to improve the outcome of subarachnoid hemorrhage.
Assuntos
Dissulfiram , Ratos Sprague-Dawley , Hemorragia Subaracnóidea , Animais , Dissulfiram/farmacologia , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismo , Masculino , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/metabolismo , Receptores CCR2/metabolismo , Receptores CCR2/antagonistas & inibidores , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Receptores CCR5/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Ratos , Prognóstico , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Antígenos de Diferenciação Mielomonocítica/metabolismoRESUMO
This letter commends the article by Luzzi et al. on alternative neuroprotection strategies for aneurysmal subarachnoid hemorrhage (SAH). It highlights the pharmacological advantages of nicardipine, cilostazol, and clazosentan over nimodipine in managing cerebral vasospasm and delayed cerebral ischemia. Emphasizing the need for personalized medicine, it advocates for integrating genetic screening and advanced monitoring techniques to tailor treatments to individual patient profiles. This approach could significantly improve clinical outcomes by optimizing drug efficacy and minimizing adverse effects.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Nicardipino/uso terapêutico , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêutico , Dioxanos/uso terapêutico , Vasodilatadores/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas , Sulfonamidas , TetrazóisRESUMO
BACKGROUND: Reactive astrocytes participate in various pathophysiology after subarachnoid hemorrhage (SAH), including neuroinflammation, glymphatic-lymphatic system dysfunction, brain edema, BBB disruption, and cell death. Astrocytes transform into two new reactive phenotypes with changed morphology, altered gene expression, and secretion profiles, termed detrimental A1 and beneficial A2. This study investigates the effect of 67LR activation by PEDF-34, a PEDF peptide, on neuroinflammation and astrocyte polarization after the experimental SAH. METHODS: A total of 318 male adult Sprague-Dawley rats were used in experiments in vivo, of which 272 rats were subjected to the endovascular perforation model of SAH and 46 rats underwent sham surgery. 67LR agonist (PEDF-34) was administrated intranasally 1 h after SAH. 67LR-specific inhibitor (NSC-47924) and STAT1 transcriptional activator (2-NP) were injected intracerebroventricularly 48 h before SAH. Short- and long-term neurological tests, brain water content, immunostaining, Nissl staining, western blot, and ELISA assay were performed. In experiments in vitro, primary astrocyte culture with hemoglobin (Hb) stimulation was used to mimic SAH. The expression of the PEDF-34/67LR signaling pathway and neuro-inflammatory cytokines were assessed using Western blot, ELISA, and immunohistochemistry assays both in vivo and in vitro. RESULTS: Endogenous PEDF and 67LR expressions were significantly reduced at 6 h after SAH. 67LR was expressed in astrocytes and neurons. Intranasal administration of PEDF-34 significantly reduced brain water content, pro-inflammatory cytokines, and short-term and long-term neurological deficits after SAH. The ratio of p-JNK/JNK and p-STAT1/STAT1 and the expression of CFB and C3 (A1 astrocytes marker), significantly decreased after PEDF-34 treatment, along with fewer expression of TNF-α and IL-1ß at 24 h after SAH. However, 2-NP (STAT1 transcriptional activator) and NSC-47924 (67LR inhibitor) reversed the protective effects of PEDF-34 in vivo and in vitro by promoting A1 astrocyte polarization with increased inflammatory cytokines. CONCLUSION: PEDF-34 activated 67LR, attenuating neuroinflammation and inhibiting astrocyte A1 polarization partly via the JNK/STAT1 pathway, suggesting that PEDF-34 might be a potential treatment for SAH patients.
Assuntos
Astrócitos , Fatores de Crescimento Neural , Doenças Neuroinflamatórias , Fator de Transcrição STAT1 , Serpinas , Hemorragia Subaracnóidea , Animais , Masculino , Ratos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Polaridade Celular , Células Cultivadas , Sistema de Sinalização das MAP Quinases , Fatores de Crescimento Neural/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/metabolismo , Ratos Sprague-Dawley , Serpinas/metabolismo , Transdução de Sinais , Fator de Transcrição STAT1/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/metabolismoAssuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Humanos , Nimodipina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , NeuroproteçãoRESUMO
The clinical management of aneurysmal subarachnoid hemorrhage (SAH)-associated vasospasm remains a challenge in neurosurgical practice, with its prevention and treatment having a major impact on neurological outcome. While considered a mainstay, nimodipine is burdened by some non-negligible limitations that make it still a suboptimal candidate of pharmacotherapy for SAH. This narrative review aims to provide an update on the pharmacodynamics, pharmacokinetics, overall evidence, and strength of recommendation of nimodipine alternative drugs for aneurysmal SAH-associated vasospasm and delayed cerebral ischemia. A PRISMA literature search was performed in the PubMed/Medline, Web of Science, ClinicalTrials.gov, and PubChem databases using a combination of the MeSH terms "medical therapy," "management," "cerebral vasospasm," "subarachnoid hemorrhage," and "delayed cerebral ischemia." Collected articles were reviewed for typology and relevance prior to final inclusion. A total of 346 articles were initially collected. The identification, screening, eligibility, and inclusion process resulted in the selection of 59 studies. Nicardipine and cilostazol, which have longer half-lives than nimodipine, had robust evidence of efficacy and safety. Eicosapentaenoic acid, dapsone and clazosentan showed a good balance between effectiveness and favorable pharmacokinetics. Combinations between different drug classes have been studied to a very limited extent. Nicardipine, cilostazol, Rho-kinase inhibitors, and clazosentan proved their better pharmacokinetic profiles compared with nimodipine without prejudice with effective and safe neuroprotective role. However, the number of trials conducted is significantly lower than for nimodipine. Aneurysmal SAH-associated vasospasm remains an area of ongoing preclinical and clinical research where the search for new drugs or associations is critical.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêutico , Nicardipino/uso terapêutico , Dioxanos/uso terapêutico , Vasodilatadores/uso terapêutico , Pirimidinas/uso terapêutico , Piridinas , Sulfonamidas , TetrazóisRESUMO
This critique discusses neuroprotective strategies for aneurysmal subarachnoid hemorrhage (SAH), excluding Nimodipine, emphasizing alternatives like verapamil, albumin, and cilostazol. While these options show potential, their efficacy lacks robust confirmation from randomized controlled trials (RCTs), relying mainly on observational studies and small trials. The letter underscores the need for comprehensive safety assessments and long-term outcome studies to enhance practical application. Highlighting ongoing trials and emerging therapies like clazosentan and TAK-044, it advocates for future research directions focused on large-scale RCTs and combination therapies, such as cilostazol and Nimodipine, which have demonstrated synergistic benefits in reducing delayed cerebral ischemia (DCI) and improving patient outcomes.
Assuntos
Isquemia Encefálica , Fármacos Neuroprotetores , Nimodipina , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/etiologia , Nimodipina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/prevenção & controle , Neuroproteção/efeitos dos fármacos , Cilostazol/uso terapêuticoRESUMO
BACKGROUND: Subarachnoid hemorrhage (SAH) is a severe cerebrovascular disease, often leading to neuroinflammation and neuronal damage. Activation of the Nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is closely associated with post-SAH neuroinflammation, while activation of Nicotinamide Adenine Dinucleotide (NAD)-dependent deacetylase sirtuin-1 (SIRT1) has neuroprotective effects. This study aimed to investigate the impact of injectable Collagen Binding Domain-Brain Derived Neurotrophic Factor (CBD-BDNF) on neuroinflammation and neuronal damage following SAH. METHODS: After establishing the SAH model, experimental animals were divided into three groups: sham surgery group (Sham), SAH group, and SAH+neuroregenerative scaffold (CBD-BDNF treatment) group. Behavioral performance was evaluated using neurofunctional deficit, beam balance, and Y-maze tests. Expression of inflammatory factors and essential proteins was quantitatively analyzed using Enzyme-Linked Immunosorbent Assay (ELISA) kits and immunoblotting. Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) staining was used to assess cell apoptosis. To further investigate the mechanism of action of CBD-BDNF on SIRT1, the model animals were treated with EX527 (SIRT1 inhibitor) for comparative studies. RESULTS: Neurological deficit tests, CBD-BDNF improves functional outcomes after SAH. Compared to the SAH group, the SAH+neuroregenerative scaffold group showed significantly increased expression of SIRT1 protein and significantly decreased expression of NLRP3, Apoptosis-associated speck-like protein containing a CARD (ASC), and c-caspase-1. The inflammatory cytokines Interleukin-1 beta (IL-1ß), IL-6, and IL-18 levels also significantly decreased in the SAH+neuroregenerative scaffold group. Additionally, animals in the SAH+neuroregenerative scaffold group showed better neurofunctional recovery in neurofunctional deficit and beam balance tests. The number of apoptotic cells significantly decreased in the SAH+neuroregenerative scaffold group compared to the SAH group. However, when SIRT1 was inhibited with EX527, the aforementioned neuroprotective effects were reversed, indicating the involvement of CBD-BDNF through SIRT1 activation. CONCLUSION: This study demonstrates that injectable CBD-BDNF can significantly alleviate neuroinflammation and neuronal damage resulting from SAH by blocking NLRP3 inflammasome activation and promoting SIRT1 expression. These findings provide a new therapeutic strategy for neuroprotection after SAH and reveal the mechanism of action of CBD-BDNF as a potential therapeutic agent. Future research will further explore the long-term efficacy and safety of CBD-BDNF.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Sirtuína 1 , Hemorragia Subaracnóidea , Sirtuína 1/metabolismo , Sirtuína 1/antagonistas & inibidores , Animais , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/patologia , Hemorragia Subaracnóidea/complicações , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Doenças Neuroinflamatórias/tratamento farmacológico , Doenças Neuroinflamatórias/etiologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Modelos Animais de Doenças , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamassomos/metabolismo , Ratos , Apoptose/efeitos dos fármacos , Colágeno/metabolismo , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Aneurysmal subarachnoid hemorrhage (aSAH) patients are given calcium channel blockers (CCBs) to prevent brain vessel vasospasm. We hypothesized that preinjury antihypertensive use may protect against vasospasm. It remains unclear whether the timing of in-hospital CCB initiation affects the vasospasm risk in this population. METHODS: This retrospective cohort study included aSAH patients (≥18 y/o) at a Comprehensive Stroke Center (1/18-11/21). Patients taking prehospital antihypertensives [CCBs, Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin II receptor blockers (ARBs)] were compared to those who were not. Results were stratified by patients receiving vasospasm prophylaxis ('in-hospital CCBs') ≤1.2 h of arrival vs. >1.2 h from arrival. Outcomes included vasospasm, hospital length of stay (LOS), and mortality. RESULTS: Of 251 patients, 18% were taking prehospital antihypertensives. Patients were comparable in baseline characteristics. There was no difference in the rate of vasospasm when compared by prehospital antihypertensive use. For those on prehospital antihypertensives, the time to in-hospital CCBs was significantly longer for patients who developed vasospasm than for those who did not (1.2 vs. 4.9 h, respectively, p = 0.02). For those on prehospital antihypertensives, receipt of in-hospital CCBs within 1.2 h of arrival was associated with a significantly lower vasospasm rate (6% vs. 39%, p = 0.03) and LOS (14 vs. 20 d, p = 0.01) when compared to receiving in-hospital CCBs > 1.2 h of arrival, respectively. The mortality rate (50% vs. 26%, p = 0.06) was statistically similar between groups, respectively. These results were not observed among patients who were not on prehospital antihypertensives. The timing to in-hospital CCB initiation had no effect on vasospasm (p = 0.23), death (p = 0.08), or LOS (p = 0.31) for patients not on prehospital antihypertensives. CONCLUSIONS: Enhancing the efficiency of in-hospital CCB initiation for patients on prehospital antihypertensives may decrease the occurrence of vasospasm and lead to a shorter LOS.
Assuntos
Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina , Bloqueadores dos Canais de Cálcio , Hemorragia Subaracnóidea , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/prevenção & controle , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/uso terapêutico , Idoso , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Resultado do Tratamento , Adulto , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Tempo de Internação/estatística & dados numéricos , Fatores de TempoRESUMO
Regulation of the redox system by branched-chain amino acid transferase 1 (BCAT1) is of great significance in the occurrence and development of diseases, but the relationship between BCAT1 and subarachnoid hemorrhage (SAH) is still unknown. Ferroptosis, featured by iron-dependent lipid peroxidation accompanied by the depletion of glutathione peroxidase 4 (GPX4), has been implicated in the pathological process of early brain injury after subarachnoid hemorrhage. This study established SAH model by endovascular perforation and adding oxyhemoglobin (Hb) to HT22 cells and delved into the mechanism of BCAT1 in SAH-induced ferroptotic neuronal cell death. It was found that SAH-induced neuronal ferroptosis could be inhibited by BCAT1 overexpression (OE) in rats and HT22 cells, and BCAT1 OE alleviated neurological deficits and cognitive dysfunction in rats after SAH. In addition, the effect of BCAT1 could be reversed by the Ly294002, a specific inhibitor of the PI3K pathway. In summary, our present study indicated that BCAT1 OE alleviated early brain injury EBI after SAH by inhibiting neuron ferroptosis via activation of PI3K/AKT/mTOR pathway and the elevation of GPX4. These results suggested that BCAT1 was a promising therapeutic target for subarachnoid hemorrhage.
Assuntos
Lesões Encefálicas , Ferroptose , Fosfatidilinositol 3-Quinases , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Hemorragia Subaracnóidea , Serina-Treonina Quinases TOR , Animais , Masculino , Camundongos , Ratos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/etiologia , Cromonas/farmacologia , Modelos Animais de Doenças , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Morfolinas/farmacologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/patologia , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genéticaRESUMO
BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurosurgical emergency with a high mortality rate. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) are delayed products of early brain injury (EBI), which may constitute the principal determinant of an unfavorable patient prognosis. Consequently, the mitigation of DCI and CVS assumes paramount significance in the pursuit of enhanced patient outcomes. However, except for oral nimodipine, there is no effective therapy available in the current guideline. Hence, the exigency arises to proffer novel treatment paradigms. The diversity of hydrogen therapeutic targets has been largely reported in basic research, unveiling its latent capacity to ameliorate EBI in aSAH patients. METHODS: Early Hydrogen-Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA), a single-center, prospective, open-labeled, randomized controlled clinical trial, endeavors to evaluate the efficacy and safety of hydrogen-oxygen gas mixture inhalation therapy in aSAH patients. A cohort of 206 patients will be randomized to either hydrogen-oxygen gas mixture inhalation group (8 h per day, 3 L/min, hydrogen concentration of 67%, oxygen concentration of 33%) or oxygen inhalation group (8 h per day, 3 L/min, oxygen concentration of 33%) within 72 h after aSAH and treated for 7 days in the ICU ward. The primary outcomes are the incidence of DCI and CVS during hospitalization. DISCUSSION: The HOMA aims to evaluate the effectiveness of hydrogen-oxygen gas mixture inhalation therapy in preventing DCI or CVS and improving outcomes in aSAH patients. Notably, this is the first large-scale trial of hydrogen therapy in aSAH patients. Given that the Chinese population represents a significant portion of the global population and the increasing incidence of stroke due to aging, optimizing patient care is vital. Given the current challenges in aSAH patient outcomes, initiating more prospective clinical trials is essential. Recent research has shown hydrogen's therapeutic potential, aligning with EBI in aSAH, driving our exploration of hydrogen therapy's mechanisms in post-aneurysm rupture damage. ETHICS AND DISSEMINATION: The protocol for the HOMA study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (KY 2022-020-02). All results of the present study will be published in peer-reviewed journals and presented at relevant conferences. TRIAL REGISTRATION: ClinicalTrials.gov NCT05282836. Registered on March 16, 2022.
Assuntos
Hidrogênio , Oxigenoterapia , Oxigênio , Ensaios Clínicos Controlados Aleatórios como Assunto , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/tratamento farmacológico , Estudos Prospectivos , Hidrogênio/administração & dosagem , Oxigenoterapia/efeitos adversos , Oxigênio/administração & dosagem , Resultado do Tratamento , Fatores de Tempo , Adulto , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/tratamento farmacológico , Pessoa de Meia-Idade , Feminino , Masculino , Idoso , Administração por Inalação , Isquemia Encefálica/prevenção & controle , Isquemia Encefálica/tratamento farmacológico , Adulto JovemRESUMO
BACKGROUND: Thyroid hormones were reported to exert neuroprotective effects after ischemic stroke by reducing the burden of brain injury and promoting post-ischemic brain remodeling. OBJECTIVE: We aimed to analyze the value of thyroid hormone replacement therapy (THRT) due to pre-existing hypothyroidism on the clinical course and outcome of aneurysmal subarachnoid hemorrhage (SAH). METHODS: SAH individuals treated between January 2003 and June 2016 were included. Data on baseline characteristics of patients and SAH, adverse events and functional outcome of SAH were recorded. Study endpoints were cerebral infarction, in-hospital mortality and unfavorable outcome at 6 months. Associations were adjusted for outcome-relevant confounders. RESULTS: 109 (11%) of 995 individuals had THRT before SAH. Risk of intracranial pressure- or vasospasm-related cerebrovascular events was inversely associated with presence of THRT (p = 0.047). In multivariate analysis, THRT was independently associated with lower risk of cerebral infarction (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.41-0.99, p = 0.045) and unfavorable outcome (aOR = 0.50, 95% CI = 0.28-0.89, p = 0.018), but not with in-hospital mortality (aOR = 0.69, 95% CI = 0.38-1.26, p = 0.227). CONCLUSION: SAH patients with THRT show lower burden of ischemia-relevant cerebrovascular events and more favorable outcome. Further experimental and clinical studies are required to confirm our results and elaborate the mechanistic background of the effect of THRT on course and outcome of SAH.
Assuntos
Terapia de Reposição Hormonal , Hemorragia Subaracnóidea , Hormônios Tireóideos , Humanos , Hemorragia Subaracnóidea/tratamento farmacológico , Feminino , Masculino , Pessoa de Meia-Idade , Terapia de Reposição Hormonal/métodos , Idoso , Hormônios Tireóideos/uso terapêutico , Resultado do Tratamento , Mortalidade Hospitalar , Adulto , Hipotireoidismo/tratamento farmacológico , Estudos Retrospectivos , Infarto Cerebral/prevenção & controle , Infarto Cerebral/etiologia , Infarto Cerebral/tratamento farmacológico , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/prevenção & controle , Vasoespasmo Intracraniano/tratamento farmacológicoRESUMO
BACKGROUND/OBJECTIVES: Epileptiform activity (EA), including seizures and periodic patterns, worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized control trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, and complex physiology of acute brain injury, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine the feasibility of RCTs evaluating EA treatment. METHODS: In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework, we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. RESULTS: Sample sizes ranged from 500 for levetiracetam 7 mg/kg versus placebo, to >4000 for levetiracetam 15 versus 7 mg/kg to achieve 80% power (5% type I error). For propofol 1 mg/kg/h versus placebo, 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. CONCLUSIONS: Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and propose use of this simulation-based RCT paradigm to assess the feasibility of future trials of anti-seizure treatment in acute brain injury.
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Anticonvulsivantes , Levetiracetam , Convulsões , Humanos , Anticonvulsivantes/administração & dosagem , Levetiracetam/administração & dosagem , Convulsões/tratamento farmacológico , Convulsões/etiologia , Adulto , Pessoa de Meia-Idade , Masculino , Feminino , Propofol/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/complicações , Idoso , Projetos de PesquisaRESUMO
Subarachnoid hemorrhage (SAH) is a neurological condition with high mortality and poor prognosis, and there are currently no effective therapeutic drugs available. Poly (ADP-ribose) polymerase 1 (PARP-1) dependent cell death pathway-parthanatos is closely associated with stroke. We investigated improvements in neurological function, oxidative stress, blood-brain barrier and parthanatos-related protein expression in rats with SAH after intraperitoneal administration of PARP-1 inhibitor (AG14361). Our study found that the expression of parthanatos-related proteins was significantly increased after SAH. Immunofluorescence staining showed increased expression of apoptosis-inducing factor (AIF) in the nucleus after SAH. Administration of PARP-1 inhibitor significantly reduced malondialdehyde (MDA) level and the expression of parthanatos-related proteins. Immunofluorescence staining showed that PARP-1 inhibitor reduced the expression of 8-hydroxy-2' -deoxyguanosine (8-OHdG) and thus reduced oxidative stress. Moreover, PARP-1 inhibitor could inhibit inflammation-associated proteins level and neuronal apoptosis, protect the blood-brain barrier and significantly improve neurological function after SAH. These results suggest that PARP-1 inhibitor can significantly improve SAH, and the underlying mechanism may be through inhibiting parthanatos pathway.
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Barreira Hematoencefálica , Lesões Encefálicas , Morte Celular , Parthanatos , Poli(ADP-Ribose) Polimerase-1 , Hemorragia Subaracnóidea , Animais , Masculino , Ratos , Fator de Indução de Apoptose/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Lesões Encefálicas/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/patologia , Morte Celular/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Parthanatos/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ratos Sprague-Dawley , Hemorragia Subaracnóidea/metabolismo , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/patologiaRESUMO
Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a singular pathological entity necessitating early diagnostic approaches and both prophylactic and curative interventions. This retrospective before-after study investigates the effects of a management strategy integrating perfusion computed tomography (CTP), vigilant clinical monitoring and standardized systemic administration of milrinone on the occurrence of delayed cerebral infarction (DCIn). The "before" period included 277 patients, and the "after" one 453. There was a higher prevalence of Modified Fisher score III/IV and more frequent diagnosis of vasospasm in the "after" period. Conversely, the occurrence of DCIn was reduced with the "after" management strategy (adjusted OR 0.48, 95% CI [0.26; 0.84]). Notably, delayed ischemic neurologic deficits were less prevalent at the time of vasospasm diagnosis (24 vs 11%, p = 0.001 ), suggesting that CTP facilitated early detection. In patients diagnosed with vasospasm, intravenous milrinone was more frequently administered (80 vs 54%, p < 0.001 ) and associated with superior hemodynamics. The present study from a large cohort of aSAH patients suggests, for one part, the interest of CTP in early diagnosis of vasospasm and DCI, and for the other the efficacy of CT perfusion-guided systemic administration of milrinone in both preventing and treating DCIn.
Assuntos
Infarto Cerebral , Milrinona , Hemorragia Subaracnóidea , Tomografia Computadorizada por Raios X , Vasoespasmo Intracraniano , Humanos , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico por imagem , Milrinona/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/prevenção & controle , Infarto Cerebral/etiologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Idoso , Vasoespasmo Intracraniano/etiologia , Vasoespasmo Intracraniano/tratamento farmacológico , Vasoespasmo Intracraniano/diagnóstico por imagem , Vasoespasmo Intracraniano/prevenção & controle , Adulto , Administração IntravenosaRESUMO
BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe event often complicated by cerebral vasospasm (CV). This study aimed to assess the efficacy and safety of clazosentan, an endothelin receptor antagonist, in reducing CV, delayed cerebral ischemia (DCI), and the need for rescue therapy in aSAH patients, while evaluating its impact on functional outcomes and mortality. METHODS: We conducted a literature search across multiple databases to identify relevant studies evaluating the effects of clazosentan in aSAH patients. Both cohort studies and randomized controlled trials (RCTs) were included. The primary outcomes were vasospasm incidence, moderate to severe vasospasm, DCI, and the need for rescue therapy. Secondary outcomes included functional outcomes, mortality, and adverse events. The data were pooled as Risk ratios (R/R) with 95 % confidence intervals (CI) using RevMan 5.4 software. RESULTS: A total of 11 studies, including 10 published and one unpublished, comprising 8,469 patients were included in the meta-analysis. Clazosentan significantly reduced the incidence of vasospasm (R/R = 0.49: 0.34-0.70), moderate to severe vasospasm (R/R = 0.53: 0.46-0.61), DCI (R/R = 0.70: 0.59-0.82), and the need for rescue therapy (R/R = 0.65: 0.52-0.83) compared to placebo. However, no significant improvement in functional outcomes or mortality rates was observed. Clazosentan was associated with increased rates of pulmonary adverse events (R/R = 1.89: 1.64-2.18), hypotension (R/R = 2.47: 1.79-3.42), and anemia (R/R = 1.49: 1.23-1.79) but no increased risk of hepatobiliary adverse events or cerebral hemorrhage. CONCLUSIONS: Clazosentan demonstrates efficacy in reducing vasospasm, moderate to severe vasospasm, DCI, and the need for rescue therapy in aSAH patients, but does not significantly improve functional outcomes or mortality rates. While associated with specific adverse events, clazosentan may be a valuable adjunctive therapy in the management of aSAH, particularly in a high-risk population for vasospasm.