Neuritin attenuates early brain injury in rats after experimental subarachnoid hemorrhage

Objectives: Early brain injury (EBI) is central to the pathological progress of subarachnoid hemorrhage (SAH). In this study, we determined if neuritin protects the brain against EBI in rats and discussed the role of apoptosis pathway mediated by endoplasmic reticulum stress in this neuroprotective route. Methods: A total of 96 male Sprague Dawley rats were divided into control, sham, SAH and SAH + neuritin groups. The rat SAH model was induced by injection 0.3 mL of nonheparinized arterial blood into the prechiasmatic cistern. Mortality assay, neurological scores, brain water content measurement, Evans blue dye assay, TUNEL stain assay and Western blot analysis were performed. Results: Neuritin significantly improved the neurological scores, brain water content, blood-brain barrier (BBB) and apoptosis compared with the control and sham groups within 24 h after SAH. TUNEL staining assay results demonstrated that apoptosis was ameliorated, MMP-9 expression was reduced, whereas GRP78, CHOP, caspase-12 and ASK1 levels were markedly preserved after neuritin application. Conclusions: Our study demonstrated that neuritin plays a neuroprotective role on EBI after SAH by attenuating BBB disruption, brain edema and apoptosis.     

Nuclear receptor nur77 promotes cerebral cell apoptosis and induces early brain injury after experimental subarachnoid hemorrhage in rats

Nur77 is a potent proapoptotic member of the nuclear receptor superfamily that is expressed predominantly in brain tissue. It has been demonstrated that Nur77 mediates apoptosis in multiple organs. Nur77‐mediated early brain injury (EBI) involves a conformational change in BCL‐2 and triggers cytochrome C (cytoC) release resulting in cellular apoptosis. This study investigates whether Nur77 can promote cerebral cell apoptosis after experimentally induced subarachnoid hemorrhage (SAH) in rats. Sprague Dawley rats were randomly assigned to three groups: 1) untreated group, 2) treatment control group, and 3) SAH group. The experimental SAH group was divided into four subgroups, corresponding to 12 hr, 24 hr, 48 hr, and 72 hr after experimentally induced SAH. It remains unclear whether Nur77 can play an important role during EBI after SAH as a proapoptotic protein in cerebral cells. Cytosporone B (Csn‐B) was used to demonstrate that Nur77 could be enriched and used to aggravate EBI after SAH. Rats treated with Csn‐B were given an intraperitoneal injection (13 mg/kg) 30 min after experimentally induced SAH. We found that Nur77 promotes cerebral cell apoptosis by mediating EBI and triggering a conformational change in BCL‐2, resulting in cytoC release. Nur77 activity, along with cerebral cell apoptosis, peaked at 24 hr after SAH onset. After induction of SAH, an injection of Csn‐B, an agonist for Nur77, enhanced the expression and function of Nur77. In summary, we have demonstrated the proapoptotic effect of Nur77 within cerebral cells, an effect that can be further exacerbated with Csn‐B stimulation. © 2014 Wiley Periodicals, Inc.     

蛛网膜下腔出血后早期脑损伤的研究进展

蛛网膜下腔出血(SAH)是由多种脑血管疾病引起的一种复杂的临床综合征,可对中枢神经系统产生灾难性打击,其高致残率、病死率显著影响了患者的神经认知功能恢复,加重家庭和社会经济负担。其中颅内动脉瘤破裂出血是SAH最常见的病因(85%)。近年来,多项研究表明早期脑损伤(EBI)是导致蛛网膜下腔出血预后不良的重要因素。脑表面或脑底部血管破裂后,血液进入蛛网膜下腔的血液引起机体强烈的神经炎症反应,表现为小胶质细胞活化,外周免疫细胞募集,微循环障碍,血脑屏障破坏和神经细胞凋亡。本研究总结了目前已知的有关EBI的病理生理机制,同时讨论了蛛网膜下腔出血后EBI的潜在治疗靶点。     

黄体酮减轻大鼠蛛网膜下腔出血后早期脑损伤

目的 探讨黄体酮对蛛网膜下腔出血(SAH)后早期脑损伤(EBI)中细胞凋亡、血脑屏障(BBB)稳定性、脑水肿和死亡率方面的保护作用.方法 66只大鼠被随机分为假手术组、SAH+溶剂组、SAH+黄体酮组.于SAH模型制成后1h、6h和12h分别给予黄体酮(16毫克/千克体重)或等体积的溶剂.在SAH后24h分析不同组间大鼠在死亡率、神经功能评分、脑水肿、细胞凋亡、caspase-3及基质金属蛋白酶-9(MMP-9)表达水平的差异.结果 与SAH+溶剂组比较,黄体酮治疗显著降低了大鼠的死亡率、细胞凋亡程度以及caspase-3水平与MMP-9的表达水平,减轻了脑水肿和伊文思蓝的渗出,提高了神经功能评分.结论 黄体酮可通过抑制细胞凋亡和稳定BBB减轻SAH后EBI.     

Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage

The nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway is a key regulator for modulating inflammation and oxidative damage, which are involved in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that Nrf2-ARE pathway play neural protective roles in traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage models; however, it has not been investigated whether, and to what degree, the Nrf2-ARE pathway is induced by SAH, and the role of the Nrf2-ARE pathway in development of EBI following SAH remains unknown. Experiment 1 sought to investigate the time course of Nrf2-ARE activation in the cortex in the early stage of SAH. In experiment 2, we assessed the effect of sulforaphane (SUL; a specific Nrf2 activator) on regulation of the Nrf2-ARE pathway in the SAH model and evaluated the impact of SUL on EBI after SAH. The rat SAH model was used injection of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern over 20 sec. As a result, Nrf2 and its target gene product, heme oxygenase-1 (HO-1), were up-regulated in the cortex after SAH and peaked at 24 hr post-SAH. After intraperitoneal SUL administration, the elevated expression of Nrf2-ARE-related factors such as Nrf2, HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase-α1 (GST-α1) was detected in the cortex at 48 hr following blood injection. In the SUL-treated group, early brain damage such as brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and motor deficits was significantly ameliorated compared with vehicle-treated SAH rats. Our results suggest that the Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.     

p38丝裂原活化蛋白激酶在实验性蛛网膜下腔出血后早期脑损伤中的作用

目的探讨p38丝裂原活化蛋白激酶(p38MAPK)在蛛网膜下腔出血(SAH)后早期脑损伤(EBI)中的作用。方法成年雄性SD大鼠随机分配至对照组、SAH组及p38MAPK干预组,每组18只。采用血管内穿刺法制作SAH模型,干预组于术前30 min经侧脑室注射p38MAPK特异性抑制剂SB203580,造模后24 h处死。观察各组大鼠脑含水量和神经功能评分,RT-PCR及免疫组化检测脑组织p38MAPK表达。结果与对照组相比,SAH组大鼠脑含水量(t=-196.35,P0.01)及p38 MAPK的mRNA水平(t=-24.75,P0.01)均明显升高,神经功能评分明显减低(t=201.08,P0.01)。与SAH组相比,干预组脑含水量(t=75.67,P0.01)及p38 MAPK的mRNA水平(t=9.43,P0.01)均明显下降,神经功能评分明显升高(t=-81.68,P0.01)。免疫组化示SAH组及干预组均有p38MAPK表达,但干预组较SAH组表达水平明显下降(t=-3.37,P0.01)。结论 p38 MAPK在EBI形成机制中起重要作用,有望成为防治EBI的药物作用新靶点。     

大鼠蛛网膜下腔出血后早期脑损伤模型的建立

目的 建立一种微创、重复性好的大鼠蛛网膜下腔出血后早期脑损伤动物模型.方法 采用视交叉前池注血法建立蛛网膜下腔出血( SAH)后早期脑损伤(EBI)动物模型.在脑立体定位仪引导下将导管插入视交叉前池,注入300μl自体动脉血建立SAH后EBI模型.进行神经功能学评分,采用激光多普勒血流量仪(LDF)测定局部脑血流量(rCBF),解剖观察前循环周围血液分布情况,应用透射电子显微镜观察海马区神经细胞超微结构变化.结果 大部分大鼠在SAH后有神经行为学异常,48 h后逐渐恢复正常.SAH后不同时间点的rCBF均低于对照组.模型组大鼠颅脑解剖发现前循环蛛网膜下腔有大量的血液和血凝块.透射电子显微镜观察:与对照组比较,SAH组神经细胞线粒体和内质网肿胀,核染色质凝聚、趋边.结论 此动物模型稳定可靠,重复性高,适合进行临床前循环动脉瘤性蛛网膜下腔出血后早期脑损伤病理生理研究.     

Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage

Apigenin (API) is a naturally occurring plant flavone that exhibits powerful antioxidant and antiapoptosis. Oxidative stress plays an important role in the pathogenesis of early brain injury (EBI) following subarachnoid hemorrhage (SAH). The potential anti-oxidative and anti-apoptosis effects of API on EBI following SAH, however, have not been elucidated. The aim of this study was to assess whether API alleviates EBI after SAH via its anti-oxidative and anti-apoptotic effects. The endovascular puncture model was used to induce SAH and all the rats were subsequently sacrificed at 24 h after SAH. Our data demonstrated that administration of API could significantly alleviate EBI (including neurological deficiency, brain edema, blood–brain barrier permeability, and cortical cell apoptosis) after SAH in rats. Meanwhile, API treatment reduced the reactive oxygen species (ROS) level and the concentration of malondialdehyde (MDA) and myeloperoxidase (MPO), elevated the ratio of glutathione (GSH) and oxidized glutathione (GSSG), and increased the amount of super-oxide dismutase (SOD) and hydrogen peroxide in brain cortex at 24 h following SAH. Moreover, API treatment inhibited SAH-induced the expression of Bax and caspase-3, significantly reduced neuronal apoptosis. Collectively, API exerts its neuroprotective effect likely through the dual activities of anti-oxidation and anti-apoptosis, at least partly. These data provide a basic platform to consider API may be safely used as a potential drug for treatment of SAH.     

Acyl-CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis

AimsAcyl‐CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post‐SAH EBI using a rat model of SAH.MethodsThe rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin‐1 and Liproxstatin‐1) to investigate the role of ferroptosis in EBI.ResultsWe found that ACSL4 levels in brain tissue increased significantly in post‐SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood‐brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis.ConclusionsACSL4 exacerbated SAH‐induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post‐SAH EBI.     

信号转导与蛛网膜下腔出血早期脑损伤

蛛网膜下腔出血(subarachnoid hemorrhage,SAH)是一种破坏性脑血管疾病,导致高死亡率和致残率,在临床上,大多数死亡发生在SAH发病后的几个小时以内,并且许多幸存者遗留认知缺陷,永久影响其功能状态和生活质量.     

G蛋白偶联受体30在大鼠蛛网膜下腔出血后对神经炎症和血脑屏障破坏的影响

目的 探讨G蛋白偶联受体30（GPR30）在大鼠蛛网膜下腔出血（SAH）早期脑损伤（EBI）过程中对神经炎症和血脑屏障（BBB）破坏的影响。方法 36只雄性大鼠随机分为6组（n = 6/组）：假手术（Sham）组,SAH（3 h、6 h、12 h、24 h、72 h）组。此外,72只大鼠随机分为4组（n = 18/组）：Sham组、SAH组、SAH联合过表达GPR30慢病毒阴性载体（SAH+Lv-NC）组、SAH联合过表达GPR30慢病毒载体（SAH+Lv-GPR30）组。通过血管内穿孔建立SAH模型,于SHA大鼠脑室内注射Lv-GPR30。通过神经学评分、脑组织含水量（BWC）检测、伊文思蓝（EBP）染色、苏木精和伊红（HE）染色来分析GPR30对EBI的影响;采用蛋白质印迹法（Western blotting）和实时荧光定量PCR（qRT-PCR）分析各种蛋白质和转录水平;通过酶联免疫吸附测定法（ELISA）分别测定肿瘤坏死因子α（TNF-α）、白细胞介素6（IL-6）、白细胞介素1β（IL-1β）、白细胞介素10（IL-10）水平。结果 SAH大鼠脑内注射Lv-GPR30后脑组织中GPR30的表达增加,并改善了大鼠神经功能、神经炎症、BBB破坏和脑水肿程度。过表达GPR30抑制SAH大鼠脑组织中基质金属蛋白肽酶9（MMP-9）和基质金属蛋白肽酶2（MMP-2）的表达,以及炎症因子TNF-α、IL-6、IL-1β表达水平,同时提高IL-10的表达水平。结论 GPR30能减轻SAH大鼠的神经炎症和BBB破坏。 [国际神经病学神经外科学杂志, 2024, 51(2): 29-34]     

盐酸戊乙奎醚蛛网膜下腔出血给药缓解脑血管痉挛

背景与目的: 胆碱受体阻断剂具有抗炎、拮抗氧自由基诱导的细胞应激打击、保护缺血损伤等非胆碱受体阻断的药理作用,还可以缓解蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)和脑损伤[1-3],但以往的胆碱受体阻断剂因其某些不良反应限制了此类药在SAH方面的相关研究和应用。盐酸戊乙奎醚（Penehycldine Hydrochloride Injection,PHC）是我国自主研发的新型胆碱受体阻断剂,能弥补前述不足。本实验旨在动物模型中研究新型抗胆碱药PHC处理后,是否能改善SAH后损伤发挥其保护作用及不同用药方式效果比较。 盐酸戊乙奎醚是中国自主研发的新型胆碱受体阻断剂,给蛛网膜下腔出血动物模型肌注和枕大池注射盐酸戊乙奎醚,可缓解兔基底动脉痉挛,枕大池给药效果更好,且明显降低脑脊液中神经元特异性烯醇化酶和S-100β蛋白的表达。对蛛网膜下腔出血兔海马CA1区存活神经元数量、超氧化物歧化酶活性和丙二醛含量没有影响。提示盐酸戊乙奎醚对蛛网膜下腔出血的治疗作用与氧化应激无关,枕大池注射给药疗效可能更好。结果:在光镜下观察,药物治疗的两个组基底动脉痉挛有所缓解。术前检测的一般情况观察资料在各组间没有差异。与SAH和SAH+vehicle组相比,SAH+CM组的CC值明显降低,并有统计学差异(P＜0.05)。与SAH 和 SAH+Vehicle组相比, SAH+IM 和 SAH+CM组脑脊液NSE、S-100β浓度降低明显,有统计学差异(P＜0.05)。在SAH,SAH+IM,SAH+Vehicle,SAH+CM各组间,SOD活性、MDA含量、CA1区存活神经元数无统计学差异。 结论：盐酸戊乙奎醚能缓解动物模型蛛网膜下腔出血后的脑血管痉挛及保护脑细胞的损伤,并且局部给药有更好的疗效。 关键词：蛛网膜下腔出血;脑血管痉挛;盐酸戊乙奎醚;脑损伤     

Iron and early brain injury after subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) affects approximately 27,000 Americans per year. Although delayed cerebral vasospasm is of high clinical significance, mortality within the first 2 days may approach 30%. In this issue of the Journal of Cerebral Blood Flow and Metabolism, Lee et al have studied the role of iron in early brain injury after experimental SAH. They found that iron chelation with deferoxamine reduced mortality and oxidative DNA damage, and lessened the induction of iron-handling proteins. Taken together, these results highlight the deleterious potential of blood breakdown products and provide an insight into future intervention.     

An early neuroprotective effect of atorvastatin against subarachnoid hemorrhage

Atorvastatin has been shown to reduce early brain edema and neuronal death after subarachnoid hemorrhage,but its mechanism is not clear.In this study,rat models of subarachnoid hemorrhage were established by autologous blood injection in the cisterna magna.Rat models were intragastrically administered 20 mg/kg atorvastatin 24 hours before subarachnoid hemorrhage,12 and 36 hours after subarachnoid hemorrhage.Compared with the controls,atorvastatin treatment demonstrated that at 72 hours after subarachnoid hemorrhage,neurological function had clearly improved;brain edema was remarkably relieved;cell apoptosis was markedly reduced in the cerebral cortex of rats;the number of autophagy-related protein Beclin-1-positive cells and the expression levels of Beclin-1 and LC3 were increased compared with subarachnoid hemorrhage only.The ultrastructural damage of neurons in the temporal lobe was also noticeably alleviated.The similarities between the effects of atorvastatin and rapamycin were seen in all the measured outcomes of subarachnoid hemorrhage.However,these were contrary to the results of 3-methyladenine injection,which inhibits the signaling pathway of autophagy.These findings indicate that atorvastatin plays an early neuroprotective role in subarachnoid hemorrhage by activating autophagy.The experimental protocol was approved by the Animal Ethics Committee of Anhui Medical University,China(904 Hospital of Joint Logistic Support Force of PLA;approval No.YXLL-2017-09)on February 22,2017.     

动脉瘤破裂自发性蛛网膜下腔出血后的早期脑损伤

蛛网膜下腔出血（SAH）后的早期脑损伤（EBI）指的是从初次出血那刻起到血管痉挛发生之前大脑内发生的一系列改变。最新研究认为,EBI可能才是SAH患者的主要死亡原因。它通过各种途径,包括缺血途径、凋亡途径、炎症途径等,导致细胞的死亡,血脑屏障（BBB）的破坏,脑水肿和神经元的直接损伤。未来针对EBI的治疗将为SAH患者提供一个可行性的选择。     

Role of endothelial nitric oxide synthase for early brain injury after subarachnoid hemorrhage in mice

The first few hours and days after subarachnoid hemorrhage (SAH) are characterized by cerebral ischemia, spasms of pial arterioles, and a significant reduction of cerebral microperfusion, however, the mechanisms of this early microcirculatory dysfunction are still unknown. Endothelial nitric oxide production is reduced after SAH and exogenous application of NO reduces post-hemorrhagic microvasospasm. Therefore, we hypothesize that the endothelial NO-synthase (eNOS) may be involved in the formation of microvasospasms, microcirculatory dysfunction, and unfavorable outcome after SAH. SAH was induced in male eNOS deficient (eNOS^–/–) mice by endovascular MCA perforation. Three hours later, the cerebral microcirculation was visualized using in vivo 2-photon-microscopy. eNOS^–/– mice had more severe SAHs, more severe ischemia, three time more rebleedings, and a massively increased mortality (50 vs. 0%) as compared to wild type (WT) littermate controls. Three hours after SAH eNOS^–/– mice had fewer perfused microvessels and 40% more microvasospasms than WT mice. The current study indicates that a proper function of eNOS plays a key role for a favorable outcome after SAH and helps to explain why patients suffering from hypertension or other conditions associated with impaired eNOS function, have a higher risk of unfavorable outcome after SAH.     

虾青素对小鼠蛛网膜下腔出血早期脑损伤的保护机制的研究

目的研究虾青素对小鼠蛛网膜下腔出血(SAH)早期脑损伤的保护机制。方法 ICR雄性小鼠采用随机数字法随机分为四组:蛛网膜下腔出血组、假手术组、蛛网膜下腔出血+溶剂组(DMSO)、蛛网膜下腔出血+虾青素组。通过建立小鼠视交叉注血方法建立蛛网膜下腔出血模型,于手术后24 h记录神经功能评分,并应用末端脱氧核苷酸转移酶介导的生物素脱氧尿嘧啶核苷酸缺口末端标记法(TUNEL)、western blot法检测脑组织中的NOX2蛋白含量、ELISA法检测TNF-a/IL-1β水平,干湿法检测脑组织中含水量。结果与对照组相比,SAH后小鼠神经功能损伤评分加重,脑水肿加重,脑组织中的NOX2蛋白及脑组织中凋亡阳性细胞数也显著增多,TNF-a/IL-1β值明显升高;应用虾青素干预以后,小鼠神经功能改善,脑组织凋亡阳性细胞明显减少。同时,虾青素能够降低SAH后小鼠脑组织中NOX2蛋白,TNF-a/IL-1β水平值也明显降低。结论虾青素对s AH后早期脑损伤(EBI)具有保护作用,其作用机制可能与其抗氧化性有关。     

蛛网膜下腔出血的脑损伤机制及相关生物标志物研究进展

蛛网膜下腔出血（SAH）是一种严重的急性出血性脑卒中,具有极高的致死率和致残率。出血后发生脑损伤的机制主要包括早期脑损伤和迟发性脑缺血,最终会导致预后不良。目前,治疗并减轻脑损伤的措施有限。在此,笔者回顾了SAH动物模型及SAH后脑损伤的病理机制,并总结了相关的生物标志物在脑损伤及预后不良中的作用,以期为SAH的药物研发及临床治疗方案制订提供思路。 [国际神经病学神经外科学杂志, 2023, 50(3): 51-59]     

虾青素对小鼠蛛网膜下腔出血早期脑损伤的保护机制的研究

目的 研究虾青素对小鼠蛛网膜下腔出血（SAH）早期脑损伤的保护机制。方法 ICR雄性小鼠采用随机数字法随机分为四组：蛛网膜下腔出血组、假手术组、蛛网膜下腔出血+溶剂组（DMSO）、蛛网膜下腔出血+虾青素组。通过建立小鼠视交叉注血方法建立蛛网膜下腔出血模型，于手术后24 h记录神经功能评分，并应用末端脱氧核苷酸转移酶介导的生物素脱氧尿嘧啶核苷酸缺口末端标记法（TUNEL）、western blot法检测脑组织中的NOX2蛋白含量、ELISA法检测TNF-a/IL-1β水平，干湿法检测脑组织中含水量。结果 与对照组相比，SAH后小鼠神经功能损伤评分加重，脑水肿加重，脑组织中的NOX2蛋白及脑组织中凋亡阳性细胞数也显著增多，TNF-a/IL-1β值明显升高；应用虾青素干预以后，小鼠神经功能改善，脑组织凋亡阳性细胞明显减少。同时，虾青素能够降低SAH后小鼠脑组织中NOX2蛋白，TNF-a/IL-1β水平值也明显降低。结论 虾青素对sAH后早期脑损伤（EBI）具有保护作用，其作用机制可能与其抗氧化性有关。     

Hemoglobin and iron handling in brain after subarachnoid hemorrhage and the effect of deferoxamine on early brain injury

The purpose of this study was to investigate hemoglobin and iron handling after subarachnoid hemorrhage (SAH), examine the relationship between iron and neuroglial cell changes, and determine whether deferoxamine (DFX) can reduce SAH-induced injury. The SAH was induced in Sprague-Dawley rats (n=110) using an endovascular perforation technique. Animals were treated with DFX (100 mg/kg) or vehicle 2 and 6 hours after SAH induction followed by every 12 hours for 3 days. Rats were killed at 6 hours, Days 1 and 3 to determine nonheme iron and examine iron-handling proteins using Western blot and immunohistochemistry. 8-Hydroxyl-2′-deoxyguanosine and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining were performed to assess oxidative DNA damage and neuronal cell death. After SAH, marked heme-oxygenase-1 (HO-1) upregulation at Day 3 (P<0.01) was accompanied by elevated nonheme iron (P<0.01), transferrin (Tf) (P<0.01), Tf receptor (P<0.05), and ferritin levels (P<0.01). Deferoxamine treatment reduced SAH-induced mortality (12% versus 29%, P<0.05), brain nonheme iron concentration, iron-handling protein expression, oxidative stress, and neuronal cell death at Day 3 (P<0.01) after SAH. These results suggest that iron overload in the acute phase of SAH causes oxidative injury leading to neuronal cell death. Deferoxamine effectively reduced oxidative stress and neuronal cell death, and may be a potential therapeutic agent for SAH.