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1.
Acta Biomater ; 179: 325-339, 2024 04 15.
Article in English | MEDLINE | ID: mdl-38561074

ABSTRACT

Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. SAH disrupts the blood‒brain barrier, leading to the release of iron ions from blood within the subarachnoid space, subsequently inducing neuronal ferroptosis. A recently discovered protein, known as ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10 by introducing the neuron-targeting peptide Tet1 onto the surface of liposomal CoQ10. Our objective was to determine whether this formulation could activate the FSP1 system and subsequently inhibit neuronal ferroptosis. Our findings revealed that neuron-targeted liposomal CoQ10 effectively localized to neurons at the lesion site after SAH. Furthermore, it facilitated the upregulation of FSP1, reduced the accumulation of malondialdehyde and reactive oxygen species, inhibited neuronal ferroptosis, and exerted neuroprotective effects both in vitro and in vivo. Our study provides evidence that supplementation with CoQ10 can effectively activate the FSP1 system. Additionally, we developed a neuron-targeted liposomal CoQ10 formulation that can be selectively delivered to neurons at the site of SAH. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH. STATEMENT OF SIGNIFICANCE: Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. Ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10. We find that it effectively localized to neurons at the lesion site after SAH and activated the FSP1/CoQ10 system. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH and other central nervous system diseases characterized by disruption of the blood-brain barrier.


Subject(s)
Ferroptosis , Liposomes , Neurons , Subarachnoid Hemorrhage , Ubiquinone , Ubiquinone/analogs & derivatives , Ubiquinone/pharmacology , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/metabolism , Subarachnoid Hemorrhage/pathology , Animals , Ferroptosis/drug effects , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Liposomes/chemistry , Male , Mice , Reactive Oxygen Species/metabolism , Rats, Sprague-Dawley , Mice, Inbred C57BL
2.
JAMA Netw Open ; 7(4): e247373, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38639937

ABSTRACT

Importance: Subarachnoid hemorrhage is typically diagnosed by noncontrast head computed tomography (CT); lumbar puncture is recommended if computed tomography is nondiagnostic, although CT cerebral angiography has been promoted as an alternative to lumbar puncture in this diagnostic pathway. The outcomes of this debate in practice have not been studied. Objective: To determine whether CT cerebral angiography use has increased in lieu of lumbar puncture among emergency department (ED) patients with headache, with an increase in unruptured intracranial aneurysm detection. Design, Setting, and Participants: This retrospective cohort study took place in 21 community EDs of an integrated health care system in Northern California between 2015 and 2021. Participants were adult (aged >17 years) health plan members with a chief concern of headache. Exclusions were prior diagnoses of subarachnoid hemorrhage, unruptured intracranial aneurysm, cerebral arteriovenous malformation, or cerebrospinal fluid shunt. Data were analyzed from October to November 2023. Exposures: CT cerebral angiography and/or lumbar puncture during the ED encounter. Main Outcomes and Measures: Primary and secondary outcomes were 14-day and 90-day unruptured intracranial aneurysm detection, respectively. Safety outcomes were missed diagnoses of subarachnoid hemorrhage or bacterial meningitis. The annual incidence of unruptured intracranial aneurysm detection was normalized to the incidence of subarachnoid hemorrhage (UIA:SAH ratio). Average annualized percentage changes were quantified using joinpoint regression analysis. Results: Among 198 109 included ED encounters, the mean (SD) age was 47.5 (18.4) years; 140 001 patients (70.7%) were female; 29 035 (14.7%) were Black or African American, 59 896 (30.2%) were Hispanic or Latino, and 75 602 (38.2%) were White. Per year, CT cerebral angiography use increased (18.8%; 95% CI, 17.7% to 20.3%) and lumbar punctures decreased (-11.1%; 95% CI, -12.0% to -10.4%), with a corresponding increase in the 14-day UIA:SAH ratio (3.5%; 95% CI, 0.9% to 7.4%). Overall, computed tomography cerebral angiography use increased 6-fold relative to lumbar puncture, with a 33% increase in the detection of UIA. Results were similar at 90 days and robust to sensitivity analyses. Subarachnoid hemorrhage (1004 cases) and bacterial meningitis (118 cases) were misdiagnosed in 5% and 18% of cases, respectively, with no annual trends (P = .34; z1003 = .95 and P = .74; z117 = -.34, respectively). Conclusions and Relevance: In this cohort study of ED patients with headache, increases in CT cerebral angiography use were associated with fewer lumbar punctures and higher detection of unruptured intracranial aneurysms, with no significant change in missed diagnoses of subarachnoid hemorrhage or bacterial meningitis. While this shift in diagnostic strategy appeared safe in the short-term, the long-term consequences remain unclear.


Subject(s)
Intracranial Aneurysm , Meningitis, Bacterial , Subarachnoid Hemorrhage , Adult , Humans , Female , Male , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/epidemiology , Intracranial Aneurysm/diagnostic imaging , Intracranial Aneurysm/epidemiology , Cohort Studies , Retrospective Studies , Headache/etiology , Computed Tomography Angiography , Emergency Service, Hospital , Meningitis, Bacterial/complications
3.
Altern Ther Health Med ; 30(11)2024 Nov.
Article in English | MEDLINE | ID: mdl-38401106

ABSTRACT

Objective: To assess the role of miR-30c-5p in subarachnoid hemorrhage (SAH) and its possible mechanism. Methods: We established a SAH model by injecting fresh arterial non-heparinized blood into the anterior cistern of the optic chiasm of healthy Sprague-Dawley rats. Next, we treated the rats with a miR-30c-5p inhibitor or miR-30c-5p mimics. We then assessed behavior, serum lactate dehydrogenase levels, albumin expression, neuronal degeneration, neuronal apoptosis, neuronal survival, and the cerebral edema index in the SAH model rats. We identified downstream target genes of miR-30c-5p using the Targetscan database and confirmed them via luciferase reporter assay. Finally, we assessed the effect of these targeted genes on brain injury in SAH rats through a recovery assay. Results: Our results showed that the overexpression of miR-30c-5p in brain tissue 24h after SAH prevented brain injury, reduced inflammation levels and nerve function scores, inhibited neuronal apoptosis, and improved neuronal survival. Meanwhile, inhibiting miR-30c-5p yielded opposite effects. Two genes related to the autophagy pathway, ATG5 and ATG12, were identified as miR-30c-5p downstream target genes. Silencing ATG5 and ATG12 alleviated brain injury induced by knocking down miR-30c-5p. Conclusion: Our findings suggest that miR-30c-5p protects from SAH-induced brain injury by inhibiting the ATG5/ATG12 pathway and it may serve as a new diagnostic maker or target for treatment of SAH patients.


Subject(s)
Autophagy-Related Protein 5 , MicroRNAs , Rats, Sprague-Dawley , Subarachnoid Hemorrhage , Animals , Subarachnoid Hemorrhage/complications , MicroRNAs/metabolism , MicroRNAs/genetics , Rats , Autophagy-Related Protein 5/genetics , Autophagy-Related Protein 5/metabolism , Male , Brain Injuries , Autophagy-Related Protein 12/metabolism , Autophagy-Related Protein 12/genetics , Disease Models, Animal , Signal Transduction , Autophagy , Apoptosis , Intracranial Aneurysm/genetics , Intracranial Aneurysm/complications
4.
Turk Neurosurg ; 34(1): 148-159, 2024.
Article in English | MEDLINE | ID: mdl-38282594

ABSTRACT

AIM: To evaluate the effects of the combination of nimodipine and dexamethasone in subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: In this study, 35 female adult Wistar Albino rats were randomly assigned to four groups: Sham (n=8), SAH with no treatment (n=9), SAH with nimodipine (n=9, oral gavage, 12 mg/kg, BID) treatment, and SAH with combined therapy with nimodipine and dexamethasone (n=9, intraperitoneally, 1mg/kg, BID). The "cisterna magna double injection of autologous blood" model was used. The animals were euthanized 5 days after the first injection. RESULTS: Of the total, five rats died before euthanasia. The SAH+Nontreatment group showed the worst score in neurological examinations, and the most severe histopathological findings were noted in terms of vasospasm. The SAH+Nimodipine group showed the best neurological score and the closest histopathological results to those of the Sham group, whereas adding dexamethasone to nimodipine treatment (the SAH+Nimodipine+Dexamethasone group) worsened the neurological and histopathological outcomes. CONCLUSION: We thus concluded that the therapeutic effects of nimodipine were impaired when combined with dexamethasone. We thus hypothesized that dexamethasone possibly induces the CYP3A4-enzyme that metabolizes nimodipine. However, it should be noted that our results are based on laboratory findings obtained on a small sample, therefore further studies with drug-drug interaction on a larger sample size through CYP3A4-enzyme and clinical confirmation are warranted.


Subject(s)
Subarachnoid Hemorrhage , Vasospasm, Intracranial , Female , Rats , Animals , Nimodipine/pharmacology , Subarachnoid Hemorrhage/drug therapy , Vasodilator Agents/pharmacology , Cytochrome P-450 CYP3A/therapeutic use , Rats, Wistar , Dexamethasone/therapeutic use , Vasospasm, Intracranial/drug therapy , Vasospasm, Intracranial/etiology
5.
Transl Stroke Res ; 15(2): 476-494, 2024 04.
Article in English | MEDLINE | ID: mdl-36781743

ABSTRACT

Early brain injury (EBI) is the leading cause of poor prognosis for patients suffering from subarachnoid hemorrhage (SAH), particularly learning and memory deficits in the repair phase. A recent report has involved calcium/calmodulin-dependent protein kinase II (CaMKII) in the pathophysiological process underlying SAH-induced EBI. Alpha-asarone (ASA), a major compound isolated from the Chinese medicinal herb Acorus tatarinowii Schott, was proven to reduce secondary brain injury by decreasing CaMKII over-phosphorylation in rats' model of intracerebral hemorrhage in our previous report. However, the effect of ASA on SAH remains unclear, and the role of CaMKII in both acute and recovery stages of SAH needs further investigation. In this work, we first established a classic SAH rat model by endovascular perforation and intraperitoneally administrated different ASA doses (10, 20, and 40 mg/kg) 2 h after successful modeling. Then, the short- and long-term neurobehavioral performances were blindly evaluated to confirm ASA's efficacy against SAH. Subsequently, we explored ASA's therapeutic mechanism in both acute and recovery stages using histopathological examination, TUNEL staining, flow cytometry, Western-blot, double-immunofluorescence staining, and transmission electron microscopy (TEM) observation. Finally, KN93, a selective CaMKII inhibitor, was applied in oxyhemoglobin-damaged HT22 cells to explore the role of CaMKII in ASA's neuroprotective effect. The results demonstrated that ASA alleviated short- and long-term neurological dysfunction, reduced mortality and seizure rate within 24 h, and prolonged 14-day survival in SAH rats. Histopathological examination showed a reduction of neuronal damage and a restoration of the hippocampal structure after ASA treatment in both acute and recovery phases of SAH. In the acute stage, the Western-blot and flow cytometer analyses showed that ASA restored E/I balance, reduced calcium overload and CaMKII phosphorylation, and inhibited mitochondrion-involved apoptosis, thus preventing neuronal damage and apoptosis underlying EBI post-SAH. In the recovery stage, the TEM observation, double-immunofluorescence staining, and Western-blot analyses indicated that ASA increased the numbers of synapses and enhanced synaptic plasticity in the ipsilateral hippocampi, probably by promoting NR2B/CaMKII interaction and activating subsequent CREB/BDNF/TrkB signaling pathways. Furthermore, KN93 notably reversed ASA's neuroprotective effect on oxyhemoglobin-damaged HT22 cells, confirming CaMKII a potential target for ASA's efficacy against SAH. Our study confirmed for the first time that ASA ameliorated the SAH rats' neurobehavioral deterioration, possibly via modulating CaMKII-involved pathways. These findings provided a promising candidate for the clinical treatment of SAH and shed light on future drug discovery against SAH.


Subject(s)
Allylbenzene Derivatives , Anisoles , Benzenesulfonamides , Benzylamines , Brain Injuries , Neuroprotective Agents , Subarachnoid Hemorrhage , Humans , Rats , Animals , Rats, Sprague-Dawley , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/pathology , Calcium/therapeutic use , Oxyhemoglobins/therapeutic use , Brain Injuries/etiology
6.
J Cereb Blood Flow Metab ; 44(3): 317-332, 2024 03.
Article in English | MEDLINE | ID: mdl-38017387

ABSTRACT

Aneurysmal subarachnoid hemorrhage (SAH) carries significant mortality and morbidity, with nearly half of SAH survivors having major cognitive dysfunction that impairs their functional status, emotional health, and quality of life. Apart from the initial hemorrhage severity, secondary brain injury due to early brain injury and delayed cerebral ischemia plays a leading role in patient outcome after SAH. While many strategies to combat secondary brain injury have been developed in preclinical studies and tested in late phase clinical trials, only one (nimodipine) has proven efficacious for improving long-term functional outcome. The causes of these failures are likely multitude, but include use of therapies targeting only one element of what has proven to be multifactorial brain injury process. Conditioning is a therapeutic strategy that leverages endogenous protective mechanisms to exert powerful and remarkably pleiotropic protective effects against injury to all major cell types of the CNS. The aim of this article is to review the current body of evidence for the use of conditioning agents in SAH, summarize the underlying neuroprotective mechanisms, and identify gaps in the current literature to guide future investigation with the long-term goal of identifying a conditioning-based therapeutic that significantly improves functional and cognitive outcomes for SAH patients.


Subject(s)
Brain Injuries , Brain Ischemia , Subarachnoid Hemorrhage , Vasospasm, Intracranial , Humans , Subarachnoid Hemorrhage/therapy , Subarachnoid Hemorrhage/drug therapy , Quality of Life , Nimodipine , Brain Ischemia/drug therapy , Brain Injuries/complications , Vasospasm, Intracranial/etiology
7.
World Neurosurg ; 183: e432-e439, 2024 03.
Article in English | MEDLINE | ID: mdl-38154680

ABSTRACT

BACKGROUND: This study investigates the impact of general anesthesia (GA) versus conscious sedation/local anesthesia (CS/LA) on the outcome of patients with minor stroke and isolated M2 occlusion undergoing immediate mechanical thrombectomy (iMT). METHODS: The databases of 16 comprehensive stroke centers were retrospectively screened for consecutive patients with isolated M2 occlusion and a baseline National Institutes of Health Stroke Scale score ≤5 who received iMT. Propensity score matching was used to estimate the effect of GA versus CS/LA on clinical outcomes and procedure-related adverse events. The primary outcome measure was a 90-day modified Rankin Scale (mRS) score of 0-1. Secondary outcome measures were a 90-day mRS score of 0-2 and all-cause mortality, successful reperfusion, procedural-related symptomatic subarachnoid hemorrhage, intraprocedural dissections, and new territory embolism. RESULTS: Of the 172 patients who were selected, 55 received GA and 117 CS/LA. After propensity score matching, 47 pairs of patients were available for analysis. We found no significant differences in clinical outcome, rates of efficient reperfusion, and procedural-related complications between patients receiving GA or LA/CS (mRS score 0-1, P = 0.815; mRS score 0-2, P = 0.401; all-cause mortality, P = 0.408; modified Treatment in Cerebral Infarction score 2b-3, P = 0.374; symptomatic subarachnoid hemorrhage, P = 0.082; intraprocedural dissection, P = 0.408; new territory embolism, P = 0.462). CONCLUSIONS: In patients with minor stroke and isolated M2 occlusion undergoing iMT, the type of anesthesia does not affect clinical outcome or the rate of procedural-related complications. Our results agree with recent data showing no benefit of one specific anesthesiologic procedure over the other and confirm their generalizability also to patients with minor baseline symptoms.


Subject(s)
Brain Ischemia , Embolism , Endovascular Procedures , Stroke , Subarachnoid Hemorrhage , Humans , Brain Ischemia/etiology , Anesthesia, Local/adverse effects , Conscious Sedation/methods , Subarachnoid Hemorrhage/complications , Retrospective Studies , Treatment Outcome , Stroke/etiology , Anesthesia, General/methods , Thrombectomy/methods , Endovascular Procedures/methods , Embolism/complications
8.
J Ethnopharmacol ; 322: 117583, 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38122912

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Subarachnoid hemorrhage (SAH) triggers a cascade of events that lead to early brain injury (EBI), which contributes to poor outcomes and appears within 3 days after SAH initiation. EBI involves multiple process including neuronal death, blood-brain barrier (BBB) injury and inflammation response. Microglia are cluster of immune cells originating in the brain which respond to SAH by changing their states and releasing inflammatory molecules through various signaling pathways. M0, M1, M2 are three states of microglia represent resting state, promoting inflammation state, and anti-inflammation state respectively, which can be modulated by pharmacological strategies. AIM OF THE STUDY: After identified potential active ingredients and targets of Sanhua Decoction (SHD) for SAH, we selected aloe-emodin (AE) as a potential ingredient modulating microglia activation states. MATERIALS AND METHODS: Molecular mechanisms, targets and pathways of SHD were reveal by network pharmacology technique. The effects of AE on SAH were evaluated in vivo by assessing neurological deficits, neuronal apoptosis and BBB integrity in a mouse SAH model. Furthermore, BV-2 cells were used to examine the effects of AE on microglial polarization. The influence of AE on microglia transformation was measured by Iba-1, TNF-α, CD68, Arg-1 and CD206 staining. The signal pathways of neuronal apoptosis and microglia polarization was measured by Western blot. RESULTS: Network pharmacology identified potential active ingredients and targets of SHD for SAH. And AE is one of the active ingredients. We also confirmed that AE via NF-κB and PKA/CREB pathway inhibited the microglia activation and promoted transformation from M1 phenotype to M2 at EBI stage after SAH. CONCLUSIONS: AE, as one ingredient of SHD, can alleviate the inflammatory response and protecting neurons from SAH-induced injury. AE has potential value for treating SAH-induced nerve injury and is expected to be applied in clinical practice.


Subject(s)
Aloe , Brain Injuries , Emodin , Subarachnoid Hemorrhage , Mice , Animals , Microglia , Emodin/pharmacology , Emodin/therapeutic use , Neuroinflammatory Diseases , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/metabolism , Inflammation/drug therapy , Inflammation/metabolism , NF-kappa B/metabolism , Brain Injuries/metabolism
9.
J Ethnopharmacol ; 319(Pt 3): 117335, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-37863400

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Early brain damage (EBI) following subarachnoid hemorrhage (SAH) is a long-lasting condition with a high occurrence. However, treatment options are restricted. Wu-zhu-yu Decoction (WZYD) can treat headaches and vomiting, which are similar to the early symptoms of subarachnoid hemorrhage (SAH). However, it is yet unknown if WZYD can reduce EBI following SAH and its underlying mechanisms. AIM OF THE STUDY: This study aimed to investigate whether WZYD protects against EBI following SAH by inhibiting oxidative stress through activating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling via Sirtuin 6 (SIRT6)-mediated histone H3 lysine 56 (H3K56) deacetylation. MATERIALS AND METHODS: In the current investigation, the principal components of WZYD were identified using high-performance liquid chromatography-diode array detection (HPLC-DAD). The SAH model in rats using the internal carotid artery plug puncture approach and the SAH model in primary neurons using hemoglobin incubation were developed. WZYD with different doses (137 mg kg-1, 274 mg kg-1, 548 mg kg-1) and the positive drug-Nimodipine (40 mg kg-1) were intragastrically administered in SAH model rats, respectively. The PC12 cells were cultured with corresponding medicated for 24h. In our investigation, neurological scores, brain water content, Evans blue leakage, Nissl staining, TUNEL staining, oxidative stress, expression of apoptosis-related proteins, and Nrf2/HO-1 signaling were evaluated. The interaction between SIRT6 and Nrf2 was detected by co-immunoprecipitation. SIRT6 knockdown was used to confirm its role in WZYD's neuroprotection. RESULTS: The WZYD treatment dramatically reduced cerebral hemorrhage and edema, and enhanced neurological results in EBI following SAH rats. WZYD administration inhibited neuronal apoptosis via reducing the expression levels of Cleaved cysteinyl aspartate specific proteinase-3(Cleaved Caspase-3), cysteinyl aspartate specific proteinase-3(caspase-3), and Bcl-2, Associated X Protein (Bax) and increasing the expression of B-cell lymphoma-2(Bal2). It also decreased reactive oxygen species and malondialdehyde levels and increased Nrf2 and HO-1 expression in the rat brain after SAH. In vitro, WZYD attenuated hemoglobin-induced cytotoxicity, oxidative stress and apoptosis in primary neurons. Mechanistically, WZYD enhanced SIRT6 expression and H3K56 deacetylation, activated Nrf2/HO-1 signaling, and promoted the interaction between SIRT6 and Nrf2. Knockdown of SIRT6 abolished WZYD-induced neuroprotection. CONCLUSIONS: WZYD attenuates EBI after SAH by activating Nrf2/HO-1 signaling through SIRT6-mediated H3K56 deacetylation, suggesting its therapeutic potential for SAH treatment.


Subject(s)
Brain Injuries , Neuroprotective Agents , Sirtuins , Subarachnoid Hemorrhage , Rats , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antioxidants/metabolism , NF-E2-Related Factor 2/metabolism , Caspase 3 , Rats, Sprague-Dawley , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/metabolism , Aspartic Acid/pharmacology , Aspartic Acid/therapeutic use , Brain Injuries/drug therapy , Apoptosis , Hemoglobins/pharmacology , Hemoglobins/therapeutic use , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use
10.
Medicine (Baltimore) ; 102(39): e34789, 2023 Sep 29.
Article in English | MEDLINE | ID: mdl-37773855

ABSTRACT

BACKGROUND: A systematic review and network meta-analysis (NMA) were conducted to explore the optimal administration route of nimodipine for treatment subarachnoid hemorrhage. METHODS: Electronic databases (Pubmed, Embase, Web of Science and Cochrane databases) were systematically searched to identify randomized controlled trials evaluating different administration route of nimodipine (intravenous and enteral) versus placebo for treatment subarachnoid hemorrhage. Outcomes included case fatality at 3 months, poor outcome measured at 3 months (defined as death, vegetative state, or severe disability), incidence of delayed cerebral ischemia (DCI), delayed ischemic neurological deficit. A random-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as odds ratios (ORs) and 95% credible intervals. The NMA was performed using R Software with a GeMTC package. A Bayesian NMA was performed and relative ranking of agents was assessed using surface under the cumulative ranking (SUCRA) probabilities. RESULTS: Nine randomized controlled trials met criteria for inclusion and finally included in this NMA. There was no statistically significant between intravenous and enteral in terms of case fatality, the occurrence of DCI, delayed ischemic neurologic deficit and poor outcomes (P > .05). Both intravenous and enteral could reduce case fatality, the occurrence of DCI, delayed ischemic neurologic deficit and poor outcomes (P < .05). The SUCRA shows that enteral ranked first, intravenous ranked second and placebo ranked the last for case fatality, the occurrence of DCI and poor outcomes. The SUCRA shows that intravenous ranked first, enteral ranked second and placebo ranked the last for delayed ischemic neurologic deficit. CONCLUSIONS: It is possible that both enteral and intravenous nimodipine have comparable effectiveness in preventing poor outcomes, DCI, and delayed ischemic neurological deficits. However, further investigation may be necessary to determine the exact role of intravenous nimodipine in current clinical practice.


Subject(s)
Brain Ischemia , Subarachnoid Hemorrhage , Humans , Nimodipine , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Network Meta-Analysis , Bayes Theorem , Administration, Intravenous , Brain Ischemia/drug therapy , Cerebral Infarction/drug therapy
11.
Eur Rev Med Pharmacol Sci ; 27(14): 6843-6849, 2023 07.
Article in English | MEDLINE | ID: mdl-37522695

ABSTRACT

BACKGROUND: Subarachnoid hemorrhage (SAH) causes a high percentage of deaths and rehabilitation failures. Despite endovascular and surgery treatment algorithms, there is still no consensus on the guidelines for monitoring and neuroprotective treatment of patients. CASE REPORT: We report a case of a patient with SAH treated endovascularly. The patient was hospitalized in the intensive care unit and monitored using Near Infrared Spectroscopy (NIRS) and Optic Nerve Diameters Assessment (ONDS). CONCLUSIONS: Early and high-dose Cerebrolysin was used safely as neuroprotective treatment intravenously. The treatment using Cerebrolysin and additional monitoring was beneficial for the patient.


Subject(s)
Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/drug therapy , Amino Acids , Spectroscopy, Near-Infrared , Neuroprotection
12.
Phytomedicine ; 119: 154997, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37523836

ABSTRACT

BACKGROUND: Several clinical and experimental studies have shown that therapeutic strategies targeting oxidative damage are beneficial for subarachnoid hemorrhage (SAH). A brain-permeable flavonoid, dihydromyricetin (DHM), can modulate redox/oxidative stress and has cerebroprotective effects in several neurological disorders. The effects of DHM on post-SAH early brain injury (EBI) and the underlying mechanism have yet to be clarified. PURPOSE: This work investigated a potential role for DHM in SAH, together with the underlying mechanisms. METHODS: Cerebroprotection by DHM was studied using a SAH rat model and primary cortical neurons. Atorvastatin (Ato) was a positive control drug in this investigation. The effects of DHM on behavior after SAH were evaluated by performing the neurological rotarod and Morris water maze tests, as well as by examining its effects on brain morphology and on the molecular and functional phenotypes of primary cortical neurons using dichlorodihydrofluorescein diacetate (DCFH-DA), immunofluorescent staining, biochemical analysis, and Western blot. RESULTS: DHM was found to significantly reduce the amount of reactive oxygen species (ROS), suppress mitochondrial disruption, and increase intrinsic antioxidant enzymatic activity following SAH. DHM also significantly reduced neuronal apoptosis in SAH rats and improved short- and long-term neurological functions. DHM induced significant increases in peroxiredoxin 2 (Prx2) and nuclear factor erythroid 2-related factor 2 (Nrf2) expression, while decreasing phosphorylation of p38 and apoptotic signal-regulated kinase 1 (ASK1). In contrast, reduction of Prx2 expression using small interfering ribonucleic acid or by inhibiting Nrf2 with ML385 attenuated the neuroprotective effect of DHM against SAH. Moreover, DHM dose-dependently inhibited oxidative damage, decreased neuronal apoptosis, and increased the viability of primary cultured neurons in vitro. These positive effects were associated with Nrf2 activation and stimulation of Prx2 signaling, whereas ML385 attenuated the beneficial effects. CONCLUSION: These results reveal that DHM protects against SAH primarily by modulating the Prx2 signaling cascade through the Nrf2-dependent pathway. Hence, DHM could be a valuable therapeutic candidate for SAH treatment.


Subject(s)
Signal Transduction , Signal Transduction/drug effects , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/metabolism , Cytoprotection , Male , Animals , Rats , Rats, Sprague-Dawley , Cells, Cultured , Oxidative Stress/drug effects , Cell Survival/drug effects
13.
Rofo ; 195(11): 1018-1026, 2023 11.
Article in English, German | MEDLINE | ID: mdl-37467777

ABSTRACT

BACKGROUND: Evaluation of endovascular therapies for cerebral vasospasm (CVS) documented in the DeGIR registry from 2018-2021 to analyse the current clinical care situation in Germany. METHODS: Retrospective analysis of the clinical and procedural data on endovascular spasm therapies (EST) documented anonymously in the DeGIR registry. We analysed: pre-interventional findings of CTP and consciousness; radiation dose applied, interventional-technical parameters (local medication, devices, angiographic result), post-interventional symptoms, complications and mortality. RESULTS: 3584 patients received a total of 7628 EST (median age/patient: 53 [range: 13-100, IQR: 44-60], 68.2 % women) in 91 (2018), 92 (2019), 100 (2020) and 98 (2021) centres; 5388 (70.6 %) anterior circulation and 378 (5 %) posterior circulation (both involved in 1862 cases [24.4 %]). EST was performed once in 2125 cases (27.9 %), with a mean of 2.1 EST/patient. In 7476 times, purely medicated EST were carried out (nimodipine: 6835, papaverine: 401, nitroglycerin: 62, other drug not specified: 239; combinations: 90). Microcatheter infusions were documented in 1132 times (14.8 %). Balloon angioplasty (BA) (additional) was performed in 756 EST (9.9 %), other mechanical recanalisations in 154 cases (2 %) and stenting in 176 of the EST (2.3 %). The median dose area product during ET was 4069 cGycm² (drug: 4002/[+]BA: 8003 [p < 0.001]). At least 1 complication occurred in 95 of all procedures (1.2 %) (drug: 1.1 %/[+]BA: 4.2 % [p < 0.001]). Mortality associated with EST was 0.2 % (n = 18). After EST, overall improvement or elimination of CVS was found in 94.2 % of cases (drug: 93.8 %/[+]BA: 98.1 % [p < 0.001]). In a comparison of the locally applied drugs, papaverine eliminated CVS more frequently than nimodipine (p = 0.001). CONCLUSION: EST have a moderate radiation exposure and can be performed with few complications. Purely medicated EST are predominantly performed, especially with nimodipine. With (additional) BA, radiation exposure, complication rates and angiographic results are higher or better. When considering drug EST alone, there is evidence for an advantage of papaverine over nimodipine, but a different group size has to be taken into account. In the analysis of EST, the DeGIR registry data are suitable for answering more specific questions, especially due to the large number of cases; for this purpose, further subgroupings should be sought in the data documentation. KEY POINTS: · In Germany, there are currently no guidelines for the endovascular treatment of cerebral vasospasm following spontaneous subarachnoid hemorrhage.. · In addition to oral nimodipine administration endovascular therapy is used to treat cerebral vasospasm in most hospitals.. · This is the first systematic evaluation of nationwide registry data on endovascular treatment of cerebral vasopasm in Germany.. · This real-world data shows that endovascular treatment for cerebral vasospasm has a moderate radiation exposure and can be performed with few complications overall. With (additional) balloon angioplasty, radiation exposure, complication rates and angiographic therapy results are higher or better.. CITATION FORMAT: · Neumann A, Weber W, Küchler J et al. Evaluation of DeGIR registry data on endovascular treatment of cerebral vasospasm in Germany 2018-2021: an overview of the current care situation. Fortschr Röntgenstr 2023; 195: 1018 - 1026.


Subject(s)
Endovascular Procedures , Subarachnoid Hemorrhage , Vasospasm, Intracranial , Humans , Female , Male , Nimodipine/therapeutic use , Papaverine/therapeutic use , Vasodilator Agents/therapeutic use , Vasospasm, Intracranial/therapy , Vasospasm, Intracranial/drug therapy , Retrospective Studies , Routinely Collected Health Data , Subarachnoid Hemorrhage/drug therapy , Endovascular Procedures/methods , Treatment Outcome
14.
J Korean Med Sci ; 38(21): e161, 2023 May 29.
Article in English | MEDLINE | ID: mdl-37270916

ABSTRACT

BACKGROUND: Subarachnoid hemorrhage (SAH) patients have oxidative stress results in inflammation, tissue degeneration and neuronal damage. These deleterious effects cause aggravation of the perihematomal edema (PHE), vasospasm, and even hydrocephalus. We hypothesized that antioxidants may have a neuroprotective role in acute aneurysmal SAH (aSAH) patients. METHODS: We conducted a prospective, multicenter randomized (single blind) trial between January 2017 and October 2019, investigating whether antioxidants (acetylcysteine and selenium) have the potential to improve the neurologic outcome in aSAH patients. The antioxidant patient group received antioxidants of acetylcysteine (2,000 mg/day) and selenium (1,600 µg/day) intravenously (IV) for 14 days. These drugs were administrated within 24 hours of admission. The non-antioxidant patient group received a placebo IV. RESULTS: In total, 293 patients were enrolled with 103 patients remaining after applying the inclusion and exclusion criteria. No significant differences were observed in the baseline characteristics between the antioxidant (n = 53) and non-antioxidant (n = 50) groups. Among clinical factors, the duration of intensive care unit (ICU) stay was significantly shortened in patients who received antioxidants (11.2, 95% confidence interval [CI], 9.7-14.5 vs. 8.3, 95% CI, 6.2-10.2 days, P = 0.008). However, no beneficial effects were observed on radiological outcomes. CONCLUSION: In conclusion, antioxidant treatment failed to show the reduction of PHE volume, mid-line shifting, vasospasm and hydrocephalus in acute SAH patients. A significant reduction in ICU stay was observed but need more optimal dosing schedule and precise outcome targets are required to clarify the clinical impacts of antioxidants in these patients. TRIAL REGISTRATION: Clinical Research Information Service Identifier: KCT0004628.


Subject(s)
Hydrocephalus , Selenium , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Acetylcysteine/therapeutic use , Selenium/therapeutic use , Prospective Studies , Single-Blind Method , Treatment Outcome , Hydrocephalus/etiology , Hydrocephalus/complications
15.
Neurocrit Care ; 39(1): 104-115, 2023 08.
Article in English | MEDLINE | ID: mdl-37308727

ABSTRACT

BACKGROUND: Nimodipine is recommended to prevent delayed cerebral ischemia in patients with spontaneous subarachnoid hemorrhage (SAH). Here, we studied hemodynamic side effects of different nimodipine formulations (per os [PO] and intravenous [IV]) in patients with SAH undergoing continuous blood pressure monitoring. METHODS: This observational cohort study includes consecutive patients with SAH (271 included in the IV group, 49 in the PO group) admitted to a tertiary care center between 2010 and 2021. All patients received prophylactic IV or PO nimodipine. Hemodynamic responses were evaluated based on median values within the first hour after continuous IV nimodipine initiation or PO nimodipine application (601 intakes within 15 days). Significant changes were defined as > 10% drop in systolic blood pressure (SBP) or diastolic blood pressure from baseline (median values 30 min before nimodipine application). With the use of multivariable logistic regression, risk factors associated with SBP drops were identified. RESULTS: Patients were admitted with a median Hunt & Hess score of 3 (2-5; IV 3 [2-5], PO 1 [1-2], p < 0.001) and were 58 (49-69) years of age. Initiation of IV nimodipine was associated with a > 10% SBP drop in 30% (81/271) of patients, with a maximum effect after 15 min. A start or increase in noradrenaline was necessary in 136/271 (50%) patients, and colloids were administered in 25/271 (9%) patients within 1 h after IV nimodipine initiation. SBP drops > 10% occurred after 53/601 (9%) PO nimodipine intakes, with a maximum effect after 30-45 min in 28/49 (57%) patients. Noradrenaline application was uncommon (3% before and 4% after nimodipine PO intake). Hypotensive episodes to an SBP < 90 mm Hg were not observed after IV or PO nimodipine application. In multivariable analysis, only a higher SBP at baseline was associated with a > 10% drop in SBP after IV (p < 0.001) or PO (p = 0.001) nimodipine application, after adjusting for the Hunt & Hess score on admission, age, sex, mechanical ventilation, days after intensive care unit admission, and delayed cerebral ischemia. CONCLUSIONS: Significant drops in SBP occur in one third of patients after the start of IV nimodipine and after every tenth PO intake. Early recognition and counteracting with vasopressors or fluids seems necessary to prevent hypotensive episodes.


Subject(s)
Brain Ischemia , Hypotension , Subarachnoid Hemorrhage , Humans , Nimodipine , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/drug therapy , Blood Pressure , Hypotension/drug therapy , Brain Ischemia/etiology , Cerebral Infarction/complications , Norepinephrine
16.
Neurocrit Care ; 39(1): 218-228, 2023 08.
Article in English | MEDLINE | ID: mdl-37349601

ABSTRACT

BACKGROUND: Aneurismal subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke that, despite improvement through therapeutic interventions, remains a devastating cerebrovascular disorder that has a high mortality rate and causes long-term disability. Cerebral inflammation after SAH is promoted through microglial accumulation and phagocytosis. Furthermore, proinflammatory cytokine release and neuronal cell death play key roles in the development of brain injury. The termination of these inflammation processes and restoration of tissue homeostasis are of utmost importance regarding the possible chronicity of cerebral inflammation and the improvement of the clinical outcome for affected patients post SAH. Thus, we evaluated the inflammatory resolution phase post SAH and considered indications for potential tertiary brain damage in cases of incomplete resolution. METHODS: Subarachnoid hemorrhage was induced through endovascular filament perforation in mice. Animals were killed 1, 7 and 14 days and 1, 2 and 3 months after SAH. Brain cryosections were immunolabeled for ionized calcium-binding adaptor molecule-1 to detect microglia/macrophages. Neuronal nuclei and terminal deoxyuridine triphosphate-nick end labeling staining was used to visualize secondary cell death of neurons. The gene expression of various proinflammatory mediators in brain samples was analyzed by quantitative polymerase chain reaction. RESULTS: We observed restored tissue homeostasis due to decreased microglial/macrophage accumulation and neuronal cell death 1 month after insult. However, the messenger RNA expression levels of  interleukin 6  and  tumor necrosis factor α were still elevated at 1 and 2 months post SAH, respectively. The gene expression of interleukin 1ß reached its maximum on day 1, whereas at later time points, no significant differences between the groups were detected. CONCLUSIONS: By the herein presented molecular and histological data we provide an important indication for an incomplete resolution of inflammation within the brain parenchyma after SAH. Inflammatory resolution and the return to tissue homeostasis represent an important contribution to the disease's pathology influencing the impact on brain damage and outcome after SAH. Therefore, we consider a novel complementary or even superior therapeutic approach that should be carefully rethought in the management of cerebral inflammation after SAH. An acceleration of the resolution phase at the cellular and molecular levels could be a potential aim in this context.


Subject(s)
Brain Injuries , Subarachnoid Hemorrhage , Mice , Animals , Subarachnoid Hemorrhage/drug therapy , Inflammation/etiology , Inflammation/metabolism , Brain/metabolism , Brain Injuries/metabolism , Cytokines/metabolism , Disease Models, Animal
17.
Stroke ; 54(7): 1930-1942, 2023 07.
Article in English | MEDLINE | ID: mdl-37232189

ABSTRACT

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating form of stroke frequently affecting young to middle-aged adults, with an unmet need to improve outcome. This special report focusses on the development of intrathecal haptoglobin supplementation as a treatment by reviewing current knowledge and progress, arriving at a Delphi-based global consensus regarding the pathophysiological role of extracellular hemoglobin and research priorities for clinical translation of hemoglobin-scavenging therapeutics. After aneurysmal subarachnoid hemorrhage, erythrocyte lysis generates cell-free hemoglobin in the cerebrospinal fluid, which is a strong determinant of secondary brain injury and long-term clinical outcome. Haptoglobin is the body's first-line defense against cell-free hemoglobin by binding it irreversibly, preventing translocation of hemoglobin into the brain parenchyma and nitric oxide-sensitive functional compartments of cerebral arteries. In mouse and sheep models, intraventricular administration of haptoglobin reversed hemoglobin-induced clinical, histological, and biochemical features of human aneurysmal subarachnoid hemorrhage. Clinical translation of this strategy imposes unique challenges set by the novel mode of action and the anticipated need for intrathecal drug administration, necessitating early input from stakeholders. Practising clinicians (n=72) and scientific experts (n=28) from 5 continents participated in the Delphi study. Inflammation, microvascular spasm, initial intracranial pressure increase, and disruption of nitric oxide signaling were deemed the most important pathophysiological pathways determining outcome. Cell-free hemoglobin was thought to play an important role mostly in pathways related to iron toxicity, oxidative stress, nitric oxide, and inflammation. While useful, there was consensus that further preclinical work was not a priority, with most believing the field was ready for an early phase trial. The highest research priorities were related to confirming haptoglobin's anticipated safety, individualized versus standard dosing, timing of treatment, pharmacokinetics, pharmacodynamics, and outcome measure selection. These results highlight the need for early phase trials of intracranial haptoglobin for aneurysmal subarachnoid hemorrhage, and the value of early input from clinical disciplines on a global scale during the early stages of clinical translation.


Subject(s)
Subarachnoid Hemorrhage , Adult , Middle Aged , Humans , Animals , Mice , Sheep , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/complications , Haptoglobins/therapeutic use , Consensus , Nitric Oxide , Inflammation/complications , Hemoglobins
18.
Neurocrit Care ; 39(1): 70-80, 2023 08.
Article in English | MEDLINE | ID: mdl-37138158

ABSTRACT

BACKGROUND: Dysnatremia occurs commonly in patients with aneurysmal subarachnoid hemorrhage (aSAH). The mechanisms for development of sodium dyshomeostasis are complex, including the cerebral salt-wasting syndrome, the syndrome of inappropriate secretion of antidiuretic hormone, diabetes insipidus. Iatrogenic occurrence of altered sodium levels plays a role, as sodium homeostasis is tightly linked to fluid and volume management. METHODS: Narrative review of the literature. RESULTS: Many studies have aimed to identify factors predictive of the development of dysnatremia, but data on associations between dysnatremia and demographic and clinical variables are variable. Furthermore, although a clear relationship between serum sodium serum concentrations and outcomes has not been established-poor outcomes have been associated with both hyponatremia and hypernatremia in the immediate period following aSAH and set the basis for seeking interventions to correct dysnatremia. While sodium supplementation and mineralocorticoids are frequently administered to prevent or counter natriuresis and hyponatremia, evidence to date is insufficient to gauge the effect of such treatment on outcomes. CONCLUSIONS: In this article, we reviewed available data and provide a practical interpretation of these data as a complement to the newly issued guidelines for management of aSAH. Gaps in knowledge and future directions are discussed.


Subject(s)
Hypernatremia , Hyponatremia , Inappropriate ADH Syndrome , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/therapy , Subarachnoid Hemorrhage/epidemiology , Hyponatremia/etiology , Hyponatremia/prevention & control , Sodium , Inappropriate ADH Syndrome/etiology , Inappropriate ADH Syndrome/therapy , Hypernatremia/etiology , Hypernatremia/prevention & control
19.
Altern Ther Health Med ; 29(4): 200-204, 2023 May.
Article in English | MEDLINE | ID: mdl-36947650

ABSTRACT

Objective: This retrospective case-control study aimed to investigate the relationship between cerebrospinal fluid (CSF) biomarkers and subarachnoid hemorrhage (SAH) and cerebral hemorrhage (CH) and to determine whether these biomarkers can predict the risk of hemorrhage. Methods: Patients diagnosed with SAH and CH at Chongqing University Central Hospital between January 2020 and April 2022 were included in this study. CSF-adenosine deaminase (ADA), CSF-lactate (Lac), and CSF-lactate dehydrogenase (LDH) were measured, and their associations with hemorrhage risk were analyzed using multivariable logistic regression models. The predictive value of these biomarkers was evaluated using receiver operating characteristic (ROC) analysis. Results: A total of 114 SAH patients, 105 CH patients, and 53 healthy controls were included in this study. The multivariable analysis revealed that hypertension, CSF-ADA, and CSF-Lac were independent risk factors for SAH, while hypertension and CSF-LDH were independent risk factors for CH. The ROC analysis demonstrated that the combination of CSF-ADA and CSF-Lac had the highest predictive value for SAH (area under the curve = 0.938), while CSF-LDH had the highest predictive value for CH (area under the curve = 0.946). Conclusion: CSF biomarkers, specifically CSF-ADA, CSF-Lac, and CSF-LDH, are valuable predictors of SAH and CH. These biomarkers may assist in diagnosing and managing hemorrhagic stroke in clinical settings.


Subject(s)
Cerebral Hemorrhage , Subarachnoid Hemorrhage , Humans , Case-Control Studies , Retrospective Studies , Biomarkers , Cerebral Hemorrhage/diagnosis , Cerebral Hemorrhage/complications , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/diagnosis , Lactic Acid/cerebrospinal fluid
20.
J Biochem Mol Toxicol ; 37(5): e23317, 2023 May.
Article in English | MEDLINE | ID: mdl-36872850

ABSTRACT

Early brain injury (EBI) is associated with the adverse prognosis of subarachnoid hemorrhage (SAH) patients. The key bioactive component of the Chinese herbal medicine Artemisia asiatica Nakai (Asteraceae) is eupatilin. Recent research reports that eupatilin suppresses inflammatory responses induced by intracranial hemorrhage. This work is performed to validate whether eupatilin can attenuate EBI and deciphers its mechanism. A SAH rat model was established by intravascular perforation in vivo. At 6 h after SAH in rats, 10 mg/kg eupatilin was injected into the rats via the caudal vein. A Sham group was set as the control. In vitro, BV2 microglia was treated with 10 µM Oxyhemoglobin (OxyHb) for 24 h, followed by 50 µM eupatilin treatment for 24 h. The SAH grade, brain water content, neurological score, and blood-brain barrier (BBB) permeability of the rats were measured 24 h later. The content of proinflammatory factors was detected via enzyme-linked immunosorbent assay. Western blot analysis was conducted to analyze the expression levels of TLR4/MyD88/NF-κB pathway-associated proteins. In vivo, eupatilin administration alleviated neurological injury, and decreased brain edema and BBB injury after SAH in rats. Eupatilin markedly reduced the levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), and suppressed the expression levels of MyD88, TLR4, and p-NF-κB p65 in the SAH rats' cerebral tissues. Eupatilin treatment also reduced the levels of IL-1ß, IL-6, and TNF-α, and repressed the expression levels of MyD88, TLR4, and p-NF-κB p65 in OxyHb-induced BV2 microglia. Additionally, pyrrolidine dithiocarbamate or resatorvid enhanced the suppressive effects of eupatilin on OxyHb-induced inflammatory responses in BV2 microglia. Eupatilin ameliorates SAH-induced EBI via modulating the TLR4/MyD88/NF-κB pathway in rat model.


Subject(s)
Brain Injuries , Subarachnoid Hemorrhage , Rats , Animals , NF-kappa B/metabolism , Subarachnoid Hemorrhage/drug therapy , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/metabolism , Myeloid Differentiation Factor 88/metabolism , Signal Transduction , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/metabolism , Toll-Like Receptor 4/metabolism , Interleukin-6/metabolism , Brain Injuries/metabolism
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