1 ISCHAEMIC STROKE OUTCOME, DISABILITY AND TREATMENTS

Despite significant improvements in acute stroke management, stroke is still the second world-leading cause of death (6.6 million people) and the third world-leading cause of disability (143 million disability-adjusted life years lost).¹

Therapies to improve outcomes after ischaemic stroke are currently exclusively based on successful thrombolysis or thrombectomy. However, despite significant progress to extend the therapeutic window of these treatments, only a minority of stroke patients qualify for them because of therapeutic time window restrictions or other contraindications. Furthermore, even though these treatments prevent further ischaemic neuronal death by restoring blood flow, they do not exert any direct effects on neuronal survival, resulting in a substantial portion of injured tissue that remains damaged.

Different acute neuroprotective strategies have been shown to be highly efficacious in animal models of stroke. However, to date, no neuroprotectant has been available to improve human stroke outcome. The reasons for this unsuccessful translation depend on numerous factors, such as differences in dosage and/or timing of drug administration in animal versus human trials, the use of experimental models dissimilar to the clinical setting (e.g., rodents without the typical comorbidities of stroke patients, such as diabetes and hypertension), and clinically unfeasible routes of drug administration.² The matter is further complicated by the complexity of stroke pathology, with a myriad of processes resulting in cell death such as excitotoxicity, free radical and cytokine-mediated cytotoxicity and pro-inflammatory cellular cascades.³ This complexity makes it difficult to design effective neuroprotective strategies targeting several aspects of stroke pathology simultaneously. Moreover, mice lack human genetic diversity and different mice strains may respond differently to treatment. For these reasons, clinical translation still appears to be a distant possibility. Recently, however, progress has been made in the understanding of ischaemia–reperfusion injury and in the identification of preventive mechanisms of oxidative stress through upregulation of antioxidant effectors, with promising results in some clinical trials.³

中文翻译：

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糖尿病和中风基于登记的研究的必要性：了解糖尿病治疗是否改善中风后结果的独特机会

1 缺血性中风的结果、残疾和治疗

尽管急性中风管理取得了重大进展，中风仍然是世界第二大死亡原因（660 万人）和世界第三大残疾原因（损失 1.43 亿残疾调整生命年）。¹

目前，改善缺血性中风后预后的治疗完全基于成功的溶栓或血栓切除术。然而，尽管在延长这些治疗的治疗窗方面取得了重大进展，但由于治疗时间窗限制或其他禁忌症，只有少数中风患者符合这些治疗的条件。此外，尽管这些治疗通过恢复血流来防止进​​一步的缺血性神经元死亡，但它们不会对神经元存活产生任何直接影响，导致大部分受伤组织仍然受损。

不同的急性神经保护策略已被证明在中风动物模型中非常有效。然而，迄今为止，还没有神经保护剂可以改善人类中风的结果。这种不成功翻译的原因取决于许多因素，例如动物与人体试验中给药剂量和/或给药时间的差异，使用与临床环境不同的实验模型（例如，没有中风患者典型合并症的啮齿类动物） ，如糖尿病和高血压），以及临床上不可行的给药途径。²中风病理学的复杂性使问题变得更加复杂，有多种过程导致细胞死亡，例如兴奋性毒性、自由基和细胞因子介导的细胞毒性以及促炎性细胞级联反应。³这种复杂性使得很难同时针对中风病理学的多个方面设计有效的神经保护策略。此外，小鼠缺乏人类遗传多样性，不同品系的小鼠对治疗的反应可能不同。由于这些原因，临床转化似乎仍然是一个遥远的可能性。然而，最近，在对缺血再灌注损伤的理解以及通过上调抗氧化效应物识别氧化应激预防机制方面取得了进展，并在一些临床试验中取得了有希望的结果。³