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首页> 外文学位 >Alterations in JAK/STAT signaling pathway and blood-brain barrier function: Mechanisms underlying worsened outcome following stroke in the aged rat.
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Alterations in JAK/STAT signaling pathway and blood-brain barrier function: Mechanisms underlying worsened outcome following stroke in the aged rat.

机译：JAK / STAT信号传导途径和血脑屏障功能的改变：老年大鼠中风后预后恶化的潜在机制。

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摘要

Effective interventions and therapeutic strategies for stroke victims are few. Investigative focus on the discovery of neuroprotective drugs has drawn attention from gaining a deeper understanding of stroke pathophysiology and mechanisms underlying ultimate neuronal and functional loss. In this study we have described a method for improving the precision and accuracy of clot placement within the middle cerebral artery (MCA) of rats, creating thromboembolic method of occlusion relevant to the majority of strokes seen clinically and included the use of aged animals. We evaluated the pathologic and physiologic differences of stroke in young, adult and elderly female rats, demonstrating an association between animal age and the degree of resultant neuronal damage and functional deficit. The response of supporting cells and structures to ischemia, upon which neuronal survival is critically dependent, is essential in our attempt to reduce severity of acute brain damage. We have examined the role of blood-brain barrier function in stroke progression, demonstrating that aged rats suffer larger infarcts with increased BBB disruption, greater neuronal damage, and reduced functional recovery. Moreover, BBB disruption in the absence of significant neuronal damage suggests a potential mechanism by which alteration in BBB integrity, during stroke, contributes to a greater degree of subsequent neuronal injury. Finally we have examined signaling pathways implicated in cellular response to ischemic injury in young and aged animals. Activation of the janus kinase (JAK) and signal transduction and activator of transcription pathway is rapid following stroke, and the reponse was attenuated in the aged brain. Our data demonstrate early activation of the JAK/STAT signal during stroke in all animals. The phosphorylation of STAT3 in young animals persists, while it is absent in aged animals by 72h post-occlusion. As STAT3 phosphrylation/activation has been demonstrated to promote survival mechanisms, this could unlerlie the inability of aged animals to compensate for neuronal insult. These data emphasize the need for inclusion of aged animals in preclinical evaluation of potential stroke therapies. An accurate MCAO model, which mimics the stroke population and allows for effective, reliable reperfusion, is imperative for the successful translation of therapeutic strategies and improved stroke outcomes in elderly patients.
机译：针对中风患者的有效干预措施和治疗策略很少。对神经保护药物的研究重点已引起人们对中风病理生理学和最终神经元和功能丧失的潜在机制的深入了解，从而引起了人们的关注。在这项研究中，我们描述了一种提高大鼠中脑动脉（MCA）内血块放置的精确度和准确性的方法，该方法创建了与临床上大多数卒中相关的血栓栓塞方法，包括使用老年动物。我们评估了年轻，成年和老年雌性大鼠中风的病理学和生理学差异，证明了动物年龄与导致的神经元损害程度和功能缺陷之间的关联。支持细胞和结构对局部缺血的反应，神经元的存活严重依赖于局部缺血，这在我们减少急性脑损伤严重程度的尝试中至关重要。我们已经检查了血脑屏障功能在中风进展中的作用，表明老年大鼠遭受更大的梗塞，血脑屏障破坏增加，神经元损伤增加，功能恢复降低。此外，在没有明显神经元损伤的情况下，BBB破坏提示中风期间BBB完整性改变可能导致更大程度的后续神经元损伤的潜在机制。最后，我们已经检查了涉及幼年和老年动物对缺血性损伤的细胞应答的信号通路。脑卒中后，janus激酶（JAK）的激活以及信号转导和转录途径的激活很快，并且在衰老的大脑中反应减弱。我们的数据表明，所有动物在卒中过程中均会早期激活JAK / STAT信号。 STAT3的磷酸化在幼小动物中持续存在，而在闭塞后72h在老年动物中则不存在。由于已证明STAT3磷酸化/激活可以促进生存机制，因此这可能无法解决老年动物无法补偿神经元损伤的问题。这些数据强调了在可能的中风疗法的临床前评估中需要纳入老年动物。模仿中风人群并允许有效，可靠的再灌注的准确的MCAO模型，对于成功转换治疗策略和改善老年患者的中风结果至关重要。

著录项

  • 作者

    DiNapoli, Vincent A.;

  • 作者单位

    West Virginia University.;

  • 授予单位 West Virginia University.;
  • 学科 Biology Molecular.; Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 164 p.
  • 总页数 164
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;神经科学;
  • 关键词

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