Impact of aging and comorbidities on ischemic stroke outcomes in preclinical animal models: A translational perspective.
Impact of aging and comorbidities on ischemic stroke outcomes in preclinical animal models: A translational perspective.
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DOI：
10.1016/j.expneurol.2020.113494
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发表时间：
2021-01
影响因子：
5.3
通讯作者：
Paul S
中科院分区：
文献类型：
--
作者：
Candelario-Jalil E;Paul S
缺血性脑卒中是一种高度复杂和破坏性的神经系统疾病。由于缺血性损伤导致的流向脑区域的血流的突然损失导致对该区域的严重损伤，导致形成梗塞组织，也称为缺血核心。这被梗死周围区域或半暗带包围，表示功能受损但可能可挽救的组织。因此，半影组织是神经保护策略的主要目标，以通过及时的治疗干预来最大限度地减少缺血性脑损伤的程度。鉴于重组组织纤溶酶原激活剂或机械血栓切除术的再灌注治疗的局限性，将联合收割机再灌注治疗与神经保护策略相结合以进一步减少缺血性脑损伤的进展具有很高的热情。到目前为止，大量的候选神经保护药物已被确定为潜在的治疗方法的基础上，在啮齿动物缺血性中风模型的研究非常有前途的结果。然而，在临床试验中，这些干预措施都没有显示出对中风患者的治疗益处。在这篇综述文章中，我们讨论了迫切需要利用缺血性卒中的临床前模型，更准确地模拟中风患者的临床条件，包括老年动物和动物中风模型与合并症。我们还概述了最近的发现，这些发现强调了幼年动物和老年动物之间中风结局的显着差异，以及高血压、糖尿病、肥胖和高脂血症等主要共病如何显着增加大脑对缺血性损伤的脆弱性，最终导致更差的功能结果。从这些早期研究中可以明显看出，在药物开发的早期阶段包括衰老和合并症的动物模型可以促进识别在中风临床试验中成功可能性很高的神经保护策略。
Ischemic stroke is a highly complex and devastating neurological disease. The sudden loss of blood flow to a brain region due to an ischemic insult leads to severe damage to that area resulting in the formation of an infarcted tissue, also known as the ischemic core. This is surrounded by the peri-infarct region or penumbra that denotes the functionally impaired but potentially salvageable tissue. Thus, the penumbral tissue is the main target for the development of neuroprotective strategies to minimize the extent of ischemic brain damage by timely therapeutic intervention. Given the limitations of reperfusion therapies with recombinant tissue plasminogen activator or mechanical thrombectomy, there is high enthusiasm to combine reperfusion therapy with neuroprotective strategies to further reduce the progression of ischemic brain injury. Till date, a large number of candidate neuroprotective drugs have been identified as potential therapies based on highly promising results from studies in rodent ischemic stroke models. However, none of these interventions have shown therapeutic benefits in stroke patients in clinical trials. In this review article, we discussed the urgent need to utilize preclinical models of ischemic stroke that more accurately mimic the clinical conditions in stroke patients by incorporating aged animals and animal stroke models with comorbidities. We also outlined the recent findings that highlight the significant differences in stroke outcome between young and aged animals, and how major comorbid conditions such as hypertension, diabetes, obesity and hyperlipidemia dramatically increase the vulnerability of the brain to ischemic damage that eventually results in worse functional outcomes. It is evident from these earlier studies that including animal models of aging and comorbidities during the early stages of drug development could facilitate the identification of neuroprotective strategies with high likelihood of success in stroke clinical trials.
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