依达拉奉对血管性痴呆大鼠海马突触可塑性的影响

目的：探讨依达拉奉(edaravone,Eda)对血管性痴呆(vascular dementia,VD)大鼠海马CA1区神经元突触可塑性的调节作用及分子机制。方法：成年雄性SD大鼠30只,随机分成3组：假手术组、VD组、VD+Eda组,每组10只。应用Morris水迷宫(Morris water maze,MWM)测试各组大鼠的空间认知功能。MWM后,分别记录每只大鼠海马CA1区神经元长时程增强(long-term potentiation, LTP)并进行分析比较;电生理记录后,大鼠断头取脑,制备脑冰冻切片,免疫组织化学测定海马CA1区神经生长相关蛋白-43(GAP-43)的表达情况。结果：VD组大鼠有明显的空间认知障碍;Eda治疗后,VD+Eda组大鼠的空间认知障碍得到显著改善。VD+Eda组兴奋性突触后电位(excitatory postsynaptic potential,EPSP)斜率增加百分比显著高于VD组(P<0.05)。VD组GAP-43的表达量显著低于假手术组(P<0.01),VD+Eda组GAP-43的表达量显著高于VD组(P<0.05)。结论：依达拉奉可通过提高VD大鼠海马CA1区的突触可塑性改善空间认知障碍,其机制与依达拉奉上调VD大鼠海马CA1区GAP-43的表达有关。     

骨髓间充质干细胞移植联合依达拉奉治疗大鼠脑梗死

背景：依达拉奉具有清除自由基和抑制脂质过氧化反应的作用,能够改善中枢神经系统损伤区的微环境。 目的：观察骨髓间充质干细胞移植联合依达拉奉治疗大鼠脑梗死的效果。 方法：采用线栓法建立大鼠大脑中动脉阻塞模型,随机分为3组,对照组经尾静脉注射细胞培养液,骨髓间充质干细胞组经尾静脉注射2.0×109 L^-1的骨髓间充质干细胞悬液,依达拉奉+骨髓间充质干细胞组经尾静脉注射2.0×109 L^-1骨髓间充质干细胞悬液同时经腹腔注射依达拉奉3 mg/(kg•d),连续5 d。移植后行神经功能缺损评分,应用RT-PCR测定脑梗死组织水通道蛋白9及水通道蛋白4 mRNA的表达,并经全脑冷冻切片苏木精-伊红染色及荧光显微镜观察细胞自然存活及分布情况。 结果与结论：移植后24 h,3 d各组间神经功能缺损评分差异无显著性意义(P > 0.05),移植后2周,依达拉奉+骨髓间充质干细胞组大鼠神经功能缺损评分低于骨髓间充质干细胞组及对照组(P < 0.05-0.01)。骨髓间充质干细胞组大鼠脑梗死周围组织水通道蛋白9 及水通道蛋白4 mRNA的表达高于依达拉奉+骨髓间充质干细胞组,却低于对照组(P < 0.05)。依达拉奉+骨髓间充质干细胞组CM-Dil阳性细胞和神经元数量多于骨髓间充质干细胞组及对照组(P < 0.05)。提示移植的骨髓间充质干细胞可移行至大鼠脑梗死灶周围并存活,分化为神经元样细胞。联合注射用依达拉奉治疗可明显改善脑梗死大鼠的神经学功能。     

AngⅡ在脑缺血大鼠大脑皮质中的表达及依达拉奉对其干预的影响

目的:研究大鼠局灶性脑缺血后AngⅡ在脑组织中的表达变化规律及应用自由基清除剂-依达拉奉干预治疗对脑组织中AngⅡ表达的影响,探讨脑缺血后脑内AngⅡ表达的生物学作用及依达拉奉对缺血性脑损伤的保护作用。方法:采用微创开颅法建立大鼠大脑中动脉闭塞(MCAO)模型,分为正常对照组、假手术组、脑缺血组和药物干预组。应用免疫组织化学及尼氏染色方法分别观察脑缺血后和依达拉奉干预后AngⅡ在脑内的表达和神经元的变化。结果:在缺血半暗区可见大量AngⅡ阳性细胞,以缺血后1周数目最多,且免疫阳性反应最强,与对照组相比有显著性差异(P<0.05);尼氏染色显示,缺血半暗区可见大量变性坏死神经元,其中以1周组数量最多,与对照组相比有统计学意义(P<0.05);经依达拉奉干预后半暗区AngⅡ阳性细胞数量、光密度值及变性坏死神经元数量明显减少,与对照组比较有统计学差异,以治疗后3 d最为显著(P<0.01)。结论:①大鼠局灶性脑缺血后缺血半暗区AngⅡ表达增强,可能与缺血后神经元的病理变化有一定联系;②脑损伤后,依达拉奉可能通过抑制AngⅡ的表达而减少神经元的坏死,发挥脑保护作用。     

Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis

ABSTRACT

Introduction

To date, riluzole and edaravone are the only two drugs that have successfully passed clinical trials for the treatment of Amyotrophic Lateral Sclerosis (ALS). Unfortunately, both drugs exhibit very modest effects. Most other drugs have failed at phase III to show significant effects in phase III when tested in larger cohorts. This pattern necessitates improvements in the approach to ALS pharmacotherapy.     

Edaravone,a scavenger for multiple reactive oxygen species,reacts with singlet oxygen to yield 2-oxo-3-(phenylhydrazono)-butanoic acid

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a synthetic antioxidant used as a drug to treat acute ischemic stroke in Japan and amyotrophic lateral sclerosis in Japan and the USA. Its pharmacological mechanism is thought to be scavenging of reactive oxygen species, which are intimately related with these diseases. Recently, the singlet oxygen (‍¹O₂) has attracted attention among reactive oxygen species. In this study, we investigated the reactivity of edaravone toward ¹O₂ and identified its reaction products. Edaravone showed a reactivity toward ¹O₂ greater than those of uric acid, histidine, and tryptophan, which are believed to be ‍¹O₂ scavengers in vivo. And we confirmed that 2-oxo-3-(phenylhydrazono)-butanoic acid was formed as an oxidation product. We propose a plausible mechanism for 2-oxo-3-(phenylhydrazono)-butanoic acid production by ‍¹O₂-induced edaravone oxidation. Since 2-oxo-3-(phenylhydrazono)-butanoic acid has already been identified as a radical-initiated oxidation product, free radical-induced oxidation should be seriously reconsidered. We also found that edaravone can react with not only hypochlorous anions but also ‍¹O₂ that are formed from myeloperoxidase. This result suggests that edaravone treatment can be beneficial against myeloperoxidase-related injuries such as inflammation.     

Effects of intravenous thrombolysis with alteplase combined with edaravone on cerebral hemodynamics and T lymphocyte level in patients with acute cerebral infarction

Our study aimed to investigate the effect of intravenous thrombolysis with alteplase and edaravone on cerebral hemodynamics and T lymphocyte level in patients harboring acute cerebral infarction.There involved a total of 118 patients with acute cerebral infarction from November 2017 to May 2019 in our hospital were randomly divided into 2 groups: the observation group (59 patients were treated with intravenous thrombolysis with alteplase combined with edaravone) and the control group (59 patients were treated with intravenous thrombolysis of alteplase). The clinical effect, neurological function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index of the 2 groups were observed and compared.Before the treatment, there were no significant differences in neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes between the 2 groups (P > .05). After the treatment, the neurological function, cerebral hemodynamic indexes, T-lymphocyte level, oxygen free radical scavenging level and oxidative stress indexes of the 2 groups were significantly improved. In addition, the observation group exerted greater beneficial effect in terms of the clinical effect, neurologic function, cerebral hemodynamic index, T lymphocyte level, oxygen free radical scavenging level and oxidative stress index than those of the control group (P < .05).The intravenous thrombolysis with alteplase and edaravone is effective in the treatment of acute cerebral infarction, which also provides better results in terms of improving the clinical efficacy and prognosis of patients and might be an alternative option for clinical practice.     

尤瑞克林联合依达拉奉治疗急性脑梗死的Meta分析

目的：评价尤瑞克林联合依达拉奉治疗急性脑梗死的疗效。方法计算机检索中国学术期刊全文数据库（CNKI）、PubMed数据库、万方数据库、维普期刊资源数据库2009年1月-2013年9月,使用尤瑞克林联合依达拉奉治疗急性脑梗死的随机对照试验（RCT）,采用Stata12.0软件进行Meta分析。结果共检出30篇符合标准的RCT文献,共纳入11个随机对照试验,合计828例患者,联合用药组414例,标准对照组414例,Meta分析结果显示：尤瑞克林联合依达拉奉治疗急性脑梗死有效率与常规治疗比较,其差异有统计学意义（P〈0.001）,OR值,95%CI为4.00（2.62,6.11）。结论与常规治疗相比,尤瑞克林联合依达拉奉治疗急性脑梗死在改善症状、降低病残率、促进神经功能恢复方面疗效明显。     

依达拉奉治疗病毒性心肌炎心力衰竭的研究

目的 研究依达拉奉治疗病毒性心肌炎心力衰竭的效果及其抗氧自由基的作用.方法 病毒性心肌炎患者41例随机分为两组.观察组给予依达拉奉治疗,对照组给予辅酶Q10治疗,观察用药前后患者心功能分级(NYHA分级),左室射血分数(LVEF)和脑利钠肽(BNP)指标变化.通过检测治疗前后血清超氧化物歧化酶(SOD)、丙二醛(MDA)了解依达拉奉的抗氧化作用.结果 治疗后观察组NYHA分级(2.1±0.2)级,较对照组(2.3±0.3)级下降(P<0.05),LVEF(40.3±4.3)%较对照组(37.9±5.9)%上升(P<0.05),BNP(741±33)ng/L较对照组(1 273±38)ng/L下降(P<0.01).依达拉奉组患者SOD活性上升高于对照组(P<0.01); MDA下降高于对照组(P<0.05).结论 依达拉奉治疗病毒性心肌炎心力衰竭临床疗效满意.     

Protective effect of edaravone,a free‐radical scavenger,on ischaemia‐reperfusion injury in the rat testis

OBJECTIVE

To investigate the effect of edaravone, a radical scavenger, on ischaemia‐reperfusion (I‐R) injury in the testes.

MATERIALS AND METHODS

Eight‐week‐old male Sprague‐Dawley rats were allocated to one of four groups: a no‐drug group subjected to induction of 30‐min of ischaemia and 60‐min reperfusion; two drug groups administered edaravone at 1 or 10 mg/kg intraperitoneal and then subjected to 30‐min ischaemia and 60‐min reperfusion; and a sham‐operated control group administered edaravone at 10 mg/kg intraperitoneal. To induce testicular I‐R, the right testis was exposed outside of the body and the testicular artery was clamped with a small clip for 30 min. Blood flow and nitric oxide (NO) release were monitored in real time simultaneously with a laser Doppler flowmeter and an NO‐selective electrode, respectively. After death the tissue levels of NO₂‐NO₃ (a marker of NO production), malondialdehyde (a marker of lipid peroxidation), 8‐hydroxydeoxyguanosine (a marker of oxidative DNA damage), myeloperoxidase (a marker of neutrophil infiltration), and heat‐shock protein 70 (HSP 70) and its mRNA were measured. The testicular tissue was also analysed histologically.

RESULTS

Clamping the testicular artery resulted in a decrease of blood flow to 0–5% of the basal level measured before clamping. NO release was increased during clamping and gradually recovered to the basal level on removing the clip. Interestingly, the peak of NO release in rats of the no‐drug group occurred at the start of reperfusion, while that in the high‐dose drug group occurred several minutes later. The levels of NO₂‐NO₃, malondialdehyde, 8‐hydroxydeoxyguanosine, myeloperoxidase and HSP 70 and its mRNA, and histological variables, were significantly greater in the no‐drug I‐R group than in the control, and these variables were ameliorated by treatment with edaravone.

CONCLUSION

These results indicate that edaravone reduces the oxidative stress and prevents the testicular damage induced by I‐R.     

Edaravone, a radical scavenger, inhibits mitochondrial permeability transition pore in rat brain

Edaravone, a radical scavenger, prevents ischemia/reperfusion injury in the brain, but the detailed mechanism is not known. This study examines the effect of edaravone on mitochondrial permeability transition pore (PTP) in rat brain. Edaravone at 10 - 100 microM inhibited Ca(2+)- and H(2)O(2)-induced swelling of mitochondria isolated from rat brain. Addition of Ca(2+) generated reactive oxygen species (ROS) in isolated mitochondria. Edaravone (10 - 100 microM) inhibited Ca(2+)-induced generation of ROS. These results suggest that edaravone inhibits opening of mitochondrial PTP in the brain, and they imply that inhibition of mitochondrial PTP may account for the neuroprotective effect of edaravone.