Mitigation effect of atorvastatin on cerebral vasospasm after subarachnoid hemorrhage in rats and its effect on expression of Mitofusin-2 and BDNF

Objective:To investigate the mitigation effect of atorvastatin on cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in rats and its effect on mitochondrial fusion protein 2 (Mitofusin-2) and brain-derived neurotrophic factor (BDNF), which provides an experimental basis and a new method for the prevention and treatment of CVS after SAH.Methods:30 male SD rats were randomly divided into the sham operation group, the model group and the treatment group, with 10 rats in each group. In the model group and the treatment group, the subarachnoid hemorrhage model was made by the double injection of blood in the occipital cistern, and the sham operation group was injected with physiological saline in the same manner. The treatment group was given atorvastatin 20 mg/kg, which was dissolved in 2 mL of distilled water. The sham operation group and the model group were given 2 mL of distilled water. The body weight, mortality, neurological deficit, basilar artery inner diameter, wall thickness and smooth muscle cell apoptosis were observed in the rats 5 d after intervention. The expression levels of Mitofusin-2 and BDNF in each group were observed.Results:The body weight of the three groups was from low to high in the sham operation group, the treatment group and the model group, and the difference was statistically significant. One rat died in the sham operation group and the treatment group, respectively, 2 rats died in the model group and there was no significant difference in mortality between the three groups. The scores of the three groups of neurological function were from low to high among the model group, treatment group and sham operation group, and the difference was statistically significant. The diameter of the three groups of blood vessels was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The apoptotic rate of the three groups of vascular endothelial cells was from small to large among the model group, treatment group and sham operation group, and the difference was statistically significant. The expression levels of Mitofusin-2 were from low to high among the sham operation group, model group and treatment group, respectively.Conclusion:Atorvastatin can alleviate the occurrence of CVS after SAH and alleviate brain tissue damage, and its mechanism may be related to up-regulation of Mitofusin-2 expression.

Inhibitory effects of lidocaine on cerebral vasospasm in a rabbit model of subarachnoid hemorrhage

Following subarachnoid hemorrhage, vasoconstrictor substances, cellular apoptosis, blood coagulation, and vascular cell proliferation affect the onset of cerebral vasospasm. Previous studies from our laboratory have revealed that injection of lidocaine （2 mg） into the cisterna magna reduces cerebral vasospasm and nerve functional impairment in an animal model of subarachnoid hemorrhage. The present study determined the optimal lidocaine dose for vasospasm and brain injury by injecting different doses of lidocaine into the cisterna magna in a rabbit model of subarachnoid hemorrhage. Results showed that endothelin, tumor necrosis factor-a, and interleukin-6 levels significantly increased in plasma, and calcitonin gene-related peptide levels significantly decreased in plasma （P 〈 0.05）. The number of neurons was decreased, the number of cells expressing c-Fos increased in the hippocampus, and cross-sections and diameters of basilar arteries were reduced （P 〈 0.05）. These changes significantly improved following injection of lidocaine （1,2, 4, and 6 mg） into the cisterna magna. A dose of 6 mg lidocaine into the cisterna magna resulted in optimal effects on cerebral vasospasm and brain injury following subarachnoid hemorrhage.

Establishment of a new symptomatic cerebral vasospasm model following subarachnoid hemorrhage in rabbit

Objective To establish an experimental model of symptomatic cerebral vasospasm(CVS) after subarachnoid hemorrhage(SAH)in rabbits. Method 2 weeks after the ligation of bilateral common carotid arteries, We induced CVS by injecting arterial blood twice via a cranial hole 2 mm×2 mm and then neurological symptoms ,cerebral blood flow(rCBF) and food intake were evaluated. Results Food intake and rCBF decreased and neurological disorders were observed. Conclusion An experimental rabbit model of symptomatic CVS can be established by injecting blood via a cranial hole after bilateral common carotid arteries ligation.

Studies of the antagonistic effect of BQ-123 on cerebral vasospasm induced by intracisternal injection of endothelin-1 and subarachnoid hemorrhage

To clarify whether the endothelin A (ETA)-receptor antagonist BQ-123 can prevent the development of cerebral vasospasm (CVS) induced by endothelin (ET-1) and subarachnoid hemorrhage (SAH), which has been controversia11y reported by various authors. We have performed investigations in anesthetized Sprague-Dawley rats- Intracisternal injection (i. c. ) of ET-l (10-11, 10-10, 10-9 mol/kg) could induce acute dose-dependent CVS, furthermore, the highest dose of ET-l (lO-’ mo1/kg) had a biphasic response in CVS of a 24-hour duration. However, the CVS by ET-1 (10-9 mol/kg) could be prevented effectively by previous i. c. of BQ-123 in a dose-dependent manner (10-9, 10-8, 10-7 mol/kg), of which the i. c- of BQ-123 (10-7mol/kg) could abolish the CVS completely. i. c. of BQ-123 (10-7 mol/kg) before SAH induced by a single i. c, of 150 pl autologous fresh blood directly to the Willis circle cou1d prevent the following CVS largely, which was a biphasic response and long-lasting (duration of 72 h). We conclude that subarachnoid application of ETA-receptor antagonist can effecti vely prevent CVS induced by ET-1 and SAH, and ET-1 may be the major mediator responsible for the CVS following SAH.

Role of endothelin in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

A model of cerebral vasospasm (CVS) associated with subarachnoid hemorrhage (SAH) was prepared on male Sprague-Dawley rats by a single intracisternal injection (i. c.) of 150 μl autologous fresh blood directly to Willis circle.The process of CVS was monit

Research on the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage

目的 :进一步研究脑血管痉挛的发生机理 ,为临床治疗服务。方法 :采用 1 4只成年家犬 ,实验组 9只 ,对照组 5只 ,通过 2次枕大池注血法建立蛛网膜下腔出血 (SAH)模型。观察痉挛血管的自由基变化、血管活性、血管造影像、超微结构变化。另外 2 0只犬用来观察血管扩张剂的作用。结果 :实验组较对照组自由基含量高 ,血管活性降低 ,血管狭窄 ,管壁损害重。结论 :尼莫地平对急性痉挛有效 ,对慢性痉挛无效 ;慢性血管痉挛是以管壁结构性狭窄为特点。

Clinical Efficacy of Shenmai Injection in the Treatment of Cerebral Vasospasm after Ruptured Aneurysm Surgery

Objective: To investigate the therapeutic effect of Shenmai Injection on postoperative cerebral vasospasm in patients with ruptured aneurysms. Methods: Seventy patients undergoing craniotomy for ruptured aneurysms in our hospital were selected as study subjects and randomly divided into control (n = 33) and research (n = 37) groups, they were treated with nimodipine and nimodipine combined with Shenmai injection after operation. The blood flow velocity in the middle cerebral artery (MCA) before and at 1, 3, 7, 11 and 14 days after surgery and the incidence of cerebral vasospasm during these days were compared, and the GCS scores at 14 days postoperatively and GOS scores at 6 months postoperatively were compared between the two groups. Results: There were no statistically significant differences in the occurrence of cerebral vasospasm, GCS or GOS scores between the two groups (P > 0.05), but the period of postoperative cerebral vasospasm in the study group was significantly shorter than that in the control group. Conclusion: Shenmai injection has the effect of shortening the cycle of occurrence of cerebral vasospasm after the operation of ruptured aneurysms, promoting patients to recover as early as possible and reducing their physical and mental burden.

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

Correlation of calcitonin gene-related peptide and endothelin receptor A with subarachnoid hemorrhage

Numerous studies have demonstrated that endothelin-1 combines with endothelin receptor A, resulting in intense vasoconstriction. Although calcitonin gene-related peptide （CGRP） suppresses endothelin-1, CGRP and endothelin receptor A exhibit direct biological effects on brain tissue. The present study analyzed CGRP and endothelin receptor A expression following subarachnoid hemorrhage in rabbits using immunohistochemistry. CGRP expression was significant at 5 days after model establishment, and endothelin receptor A expression was significant at 3 days after model induction. The perimeter of the basilar artery was measured to determine the amount of cerebral vasospasm. Analytical results revealed a significantly shortened basilar artery perimeter following subarachnoid hemorrhage. Changes in the basilar artery perimeter were negatively associated with endothelin receptor A expression, but positively correlated with CGRP expression in vessels. These results suggest that following subarachnoid hemorrhage, CGRP and endothelin receptor A expressions dynamically changed in brain vessels and tissues, although these changes were not synchronous. Changes in endothelin receptor A expression exhibited a significant effect on the occurrence and development of delayed cerebral vasospasm and delayed neuronal death, while CGRP relaxed vessels and protected nerves.

Experimental investigation on the prevention of delayed cerebral vasospasm with Tong Qiao Huo Xue Tang

Objective To investigate the prevention effects and the physicochemical mechanisms of action of Tong Qiao Huo Xue Tang on delayed cerebral vasospasm(DCD) after subarachnoid hemorrhage(SAH).Methods Macaca cynomolgus were divided into two groups and underwent craniectomy,a semipermeable microdialysis catheter was placed adjacent to right middle cerebral artery (MCA).Therapeutic group were exposed to Tong Qiao Huo Xue Tang and control group to placebo via oral .Results The diameter of proximal MCA in therapeutic group changed slightly on 7th day after operation(P >0.05),whereas it decreased prominently(P< 0.05) in control group with severe vasospasm.OxyHb concentration:There’s no significant difference between the two groups on 2nd ～5th day(P >0.05),the concentration of therapeutic group(was zero after 8 days) was lower than that of control group (became zero after 12 days) on 6th ～8th day(P< 0.05).The peak value of therapeutic group (on 5th day) was lower than that of control group (on 7th day)(P< 0.05).Conclusion Tong Qiao Huo Xue Tang can prevent DCV after SAH effectively and decreasing OxyHb concentration around vessels after SAH maybe the mechanism.

Diffuse coronary artery vasospasm in a patient with subarachnoid hemorrhage: A case report

BACKGROUND Coronary artery vasospasm(CAV)is a reversible,transient form of vasoconstriction with clinical manifestations ranging from stable angina to acute coronary syndromes(ACS).Vasospasm of epicardial coronary arteries or associated micro-vasculature can lead to total or subtotal occlusion and has been demonstrated in nearly 50%of patients undergoing angiography for suspected ACS.The mechanism for CAV has been described in literature,but in a subgroup of patients presenting with intracranial hemorrhage,it appears to be multifactorial.These patients tend to have electrocardiographic changes,elevation of cardiac biomarkers of injury and neurogenic stress cardiomyopathy.CASE SUMMARY A 44-year-old woman presented with severe headaches and tonic-clonic seizures.She was found to have diffuse subarachnoid hemorrhage(SAH)requiring ventricular drain placement,coil embolization and induced hypertension.She subsequently developed chest pain with ST elevations in anterior precordial leads,elevated cardiac enzymes and apical ballooning with left ventricular ejection fraction of 35%on transthoracic echocardiogram.Coronary angiogram revealed severe diffuse triple vessel stenoses secondary to CAV seen distally.Subsequent cardiac MRI notable for apical non-viability and scar formation.CONCLUSION This case highlights a unique etiology of acute myocardial infarction in a patient with SAH leading to ST elevations,diffuse triple vessel CAV and apical scar.

INFLUENCE OF GINKGO BILOBA EXTRACT ON NITRIC OXIDE AND ENDOTHELIN-1 DURING CEREBRAL VASOSPASM IN RATS

Objective.To investigate the effects of Ginkgo biloba extracton cer ebral vasospasmafter subarachnoid hemorrhageand its influence on n itric oxideand endothelin-l .Methods.Noncraniotomy models of SAH in Wistar rats were used and animals were divided into sham-operated group ,SAH group,saline-treated group and EGb-treated group.Diameter of basilar a rtery was measured.Regional cerebral blood flow,NO and ET-1levels in blood,and calcium content in brain tissue within24hours after SAH were dete cted.Pathological examination of hippocampus CA1sub-field was also performed .Results.Sham operation did not alter the above parameters.Induction of SAH l ed to a marked spasm of basilar artery.rCBF decreased obviously and consecutive ly within24hours after SAH.Meanwhile NO level in serum decreased,ET-1level in plasma and calcium content in brain tissue significantly in-creased.Pyra midal cells in hippocampus CA1subfield were severely damaged.EGb significantly antago-nized the pathological alterations of the above parameters.Conclusion .Alterations of NO,and ET-1play an important role in the development of CV S after SAH.EGb exerts its protective effects on CVS by inhibitng the above pat hological alterations.

Experimental and clinical study on effect of endovascular dilation on symptomaticcerebral vasospasm

Objective To undertake animal experimentation and clinical study on the safety and efficacy of percutaneous transluminal angioplasty (PTA) and intraarterial papaverine (IAP) infusion for treatment of refractory symptomatic cerebral vasospasm (CVS). Methods In the experimental study, vasospasm was induced in rabbits by double injections of blood into the cisterna magna, IAP infusion was given on either the 4th day or the 7th day after occurrence of subarachnoid hemorrhage (SAH), and then neurological observation, angiography, light and electron microscopy were done. In the clinical study, since September 1996, 22 patients with refractory symptomatic CVS involving 50 vascular territories received dilation therapy by PTA and IAP within 24 hours of clinical neurological deterioration. Results In the experimental study, all the rabbits except two in the 'the 4th day' group showed angiographic dilation in all of the spastic basilar arteries, and neurological improvement; in the ' the 7th day' group angiographic dilation appeared in 4 (57. 1% ) out of 7 rabbits. After 24 hours, 1 rabbit in each group had recurrence of neurological deficits and angiographic constriction. In the clinical study after aneurysm clipping or endovascular coil embolization was done, within 72 hours of SAH all patients underwent endovascular treatment: PTA alone in 3 cases, IAP alone in 14 cases, PTA and IAP in the remaining 5 cases. All vessel segments were dilated satisfactorily after endovascular treatment. Clinical improvement was significant in 13 cases,moderate in 7, minimal or none in 2; 2 cases died on the 7th day after endovascular dilation treatment. Conclusion Endovascular dilating techniques, namely, PTA, IAP and a combination of PTA and IAP, are safe and effective for treatment of symptomatic CVS refractory to medical therapy.

New Developments in Drug Therapy and Research of Cerebral Vasospasm

In this manuscript a comprehensive coverage of recent developments in the drug therapy of vasospasm while providing the background information that neuroscientists need to understand its rationale. The range of new agents available for treatment of cerebral vasospasm is expanding rapidly along with rapid advances in pharmacology and physiology that are uncovering the mechanisms of this disease. Although there are many publications for treatment of cerebral vaso-spasm, most are focusing on different aspects of vasospasm treatment and many have limited value due to insufficient quality. Moreover, the complexity of this, in many cases deleterious condition, is enormous and the information needed to understand drug effects is accordingly often not readily available in a single source. A number of pharmacological and medical therapies are currently in use or being investigated in an attempt to reverse cerebral vasospasm, but only a few have proven to be useful. Current research efforts promise the eventual production of new medical therapies. At last, recommendations for the use of different treatment stages based on currently available clinical data are provided.

CHANGES OF ENDOTHELIN DURING CEREBRAL VASOSPASM AFTER EXPERIMENTAL SUBARACHNOID HEMORRHAGE

Laser-Doppler flowmetry was employed in the observation of regional cortical blood flow (rCBF) after experimental subarachnoid hemorrhage (SAH) in anesthetized rats and the contents of endothelin (ET) in the cerebral-spinal fluid (CSF), plasma, hypothalamus, cerebral cortex, cerebellum and medulla were simultaneously measured. There was a biphasic change of rCBF after SAH. The contents of ET in CSF, plasma and hypothalamus rose prominently in the early stage after SAH, and the ET-increase in CSF and hypothalamus was earlier than that in plasma. The changes of ET contents in CSF correlated well with that in hypothalamus. Our results suggest that ET probably is an early important factor which induces cerebral vasospasm (CVS) after SAH. The increase of ET in CSF, which may originate from the hypothalamus, might play a more important role in the development of CVS after SAH than that in plasma.

Drug treatment of cerebral vasospasm after subarachnoid hemorrhage following aneurysms

Cerebral vasospasm (CVS) is a common and severe complication of aneurysmal subarachnoid hemorrhage (aSAH). Despite the improvement in treatment of aSAH, CVS complicating aSAH has remained the main cause of death. CVS begins most often on the third day after the ictal event and reaches the maximum on the 5th–7th postictal days. Several therapeutic modalities have been employed to prevent or reverse CVS. The aim of this review is to summate all the available drug treatment modalities for vasospasm.

血清MBL、HRG、IL-23/IL-17炎症轴与动脉瘤性蛛网膜下腔出血患者介入栓塞术后脑血管痉挛和预后的关系

目的探讨血清甘露聚糖结合凝集素(MBL)、富组氨酸糖蛋白(HRG)、白细胞介素(IL)-23/IL-17炎症轴与动脉瘤性蛛网膜下腔出血(aSAH)患者介入栓塞术后脑血管痉挛(CVS)和预后的关系。方法选取2019年3月至2022年2月该院收治的195例行介入栓塞术治疗的aSAH患者,根据术后第4天数字减影血管造影检查是否发生CVS及严重程度分为无CVS组(126例)、轻度CVS组(18例)、中度CVS组(39例)和重度CVS组(12例)。比较4组术前及术后3 d血清MBL、HRG、IL-23、IL-17水平。随访6个月,根据患者预后的不同分为预后良好组(137例)和预后不良组(58例)。采用多因素Logistic回归模型分析aSAH患者预后不良的影响因素。采用受试者工作特征(ROC)曲线分析血清MBL、HRG、IL-23、IL-17水平及其联合应用模型对aSAH患者预后不良的预测价值。结果195例aSAH患者介入栓塞术后CVS发生率为35.38%。术后3 d,轻、中、重度CVS组血清MBL、IL-23、IL-17水平高于无CVS组,其中重度CVS组高于中度CVS组,中度CVS组高于轻度CVS组(P<0.05);轻、中、重度CVS组血清HRG水平低于无CVS组,其中重度CVS组低于中度CVS组,中度CVS组低于轻度CVS组(P<0.05)。术后3 d,4组血清MBL、IL-23、IL-17水平高于术前,血清HRG水平低于术前(P<0.05)。预后良好组动脉瘤直径≥6 mm、动脉瘤个数>1个、手术时间>24 h、Hunt-Hess分级Ⅲ/Ⅳ级、术后CVS患者例数占比及术后3 d血清MBL、IL-23、IL-17水平均低于预后不良组,术后3 d血清HRG水平高于预后不良组(P<0.05)。多因素Logistic回归分析显示,动脉瘤直径≥6 mm、Hunt-Hess分级Ⅲ/Ⅳ级、术后CVS、术后3 d MBL、IL-23、IL-17水平升高及HRG水平降低均是导致aSAH患者预后不良的独立危险因素(P<0.05)。ROC曲线结果显示,术后3 d血清MBL、HRG、IL-23、IL-17这4项指标对aSAH患者预后不良均有一定的预测效能。4项指标联合应用的预测模型效能较高(曲线下面积为0.853)。结论aSAH患者介入栓塞术后血清MBL、IL-23、IL-17水平升高及HRG水平下降可导致CVS发生风险增加,且与aSAH患者介入栓塞术后的预后不良有关。上述指标对aSAH患者预后不良有一定的预测效能。

脑血管痉挛诊断方法的研究进展

脑血管痉挛是蛛网膜下腔出血后的常见并发症,其定义为一种特殊类型的脑动脉收缩,具体表现为脑部动脉收缩性狭窄,常伴受累血管远端分布区的血液灌注减少。此病发病隐匿,预后不佳,依据临床症状明确诊断时病程已进展到末期,错过最佳治疗时机。因此,如何有效迅速地诊断脑血管痉挛已成为临床研究的热点问题。近年来,新兴影像学技术的发展以及更多监测手段的出现,为脑血管痉挛的诊断提供了新的方法与思路。本文主要从脑血管痉挛的影像学诊断方面作一综述。

经颅多普勒超声动态监测应用于蛛网膜下腔出血患者发生脑血管痉挛中的价值

目的探讨经颅多普勒超声动态监测应用于蛛网膜下腔出血(SAH)患者发生脑血管痉挛中的价值。方法选取2018年6月至2021年6月白银市第一人民医院收治的85例SAH患者作为观察组,另选取同期76名健康志愿者作为常规组。比较两组收缩期峰值流速(Peak)、搏动指数(PI)及平均血流速度(Mean),比较观察组发生与未发生脑血管痉挛患者的PI、Peak及Mean,分析PI、Peak、Mean单独及三者联合对SAH患者发生脑血管痉挛的诊断价值。结果观察组PI高于常规组,Peak、Mean慢于常规组,差异有统计学意义(P<0.05)。观察组发生脑血管痉挛10例,未发生脑血管痉挛75例,发生脑血管痉挛患者PI高于未发生脑血管痉挛患者,发生脑血管痉挛患者Peak、Mean慢于未发生脑血管痉挛患者,差异有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,PI、Peak、Mean是脑血管痉挛发生的危险因素(P<0.05)。PI、Peak、Mean联合诊断脑血管痉挛的灵敏度高于单独诊断(P<0.05)。结论经颅多普勒超声动态监测在SAH患者发生脑血管痉挛中的应用价值较高,PI、Peak、Mean是脑血管痉挛发生的危险因素,三者联合对脑血管痉挛的诊断灵敏度较高。

头皮脑电图波型在SAH患者发生脑血管痉挛中的应用价值

目的探讨头皮脑电图波型在蛛网膜下腔出血(SAH)患者发生脑血管痉挛中的应用价值。方法选取2019年1月至2020年1月于甘肃省白银市第一人民医院就诊的86例SAH患者作为研究对象,根据是否发生脑血管痉挛分为发生组(n=25)与未发生组(n=61)。比较两组临床资料,采用多因素Logistic回归分析SAH患者发生脑血管痉挛的影响因素。结果86例SAH患者中,发生脑血管痉挛25例,发生率为29.07%。发生组脑电图波型重度异常占比、乙酰肝素酶水平均高于未发生组,差异有统计学意义(P<0.05)。多因素Logistic回归分析结果显示,头皮脑电图波型重度异常、乙酰肝素酶水平较高是SAH患者发生脑血管痉挛的独立危险因素(P<0.05)。结论头皮脑电图波型与SAH患者发生脑血管痉挛的发生有关,在发生脑血管痉挛中的应用价值较高。