Expanding the therapeutic window for stroke treatment.

扩大中风治疗的治疗窗口。

• 批准号: 7526955
• 负责人: Keith R Pennypacker
• 金额: $ 16.08万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7526955
• 关键词: ASIC channel; Adult; Agonist; Alteplase; Anti-Anxiety Agents; Anti-Inflammatory Agents; Anti-inflammatory; Area; Behavioral; Blood Cells; Brain Injuries; Calcium; Cause of Death; Cell Death; Cells; Cessation of life; Clinical; Clinical Trials; Cognitive; Condition; Cytotoxin; Data; Depressed mood; Disease; Dose; Elevation; Europe; Goals; Health; Hospitals; Hour; Human; Immune; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Innovative Therapy; Ischemia; Ischemic Stroke; Laboratories; Ligands; Measures; Microglia; Middle Cerebral Artery Occlusion; Modeling; Motor; Neuronal Injury; Neurons; New Agents; Operative Surgical Procedures; Opipramol; Outcome; Pathologic; Pharmaceutical Preparations; Production; Property; Rattus; Receptor Activation; Recovery; Research; Research Project Grants; Stroke; Techniques; Testing; Therapeutic; Time; Translating; Umbilical Cord Blood; United States; Week; Work; base; behavior test; cytokine; day; design; disability; improved; insight; interest; killings; migration; neuroprotection; novel; post stroke; receptor; research study; sigma receptors; stroke therapy; therapeutic effectiveness; therapeutic target

DESCRIPTION (provided by applicant): Stroke is a major health problem in the US with 800,000 people killed or debilitated each year. Currently, there is only one treatment, which needs to be administered within the first three hours of stroke onset. Our laboratory is examining treatments that would extend this therapeutic window. Our studies have shown that effective post-stroke treatment must possess both neuroprotective and anti-inflammatory properties. We have found that activation of sigma receptors decrease infarct area by over 80% when delivered 24 hours post- stroke in the rat. These receptors decrease neuronal death by depressing ischemia-induced intracellular calcium elevations, increased neuroexcitability and acid-sensing ion channel activation. Sigma receptors activation is also anti-inflammatory by blocking activation, migration and release of inflammatory cytotoxins from microglia. The goal of this proposal is to extend our initial findings that sigma receptor activation is a useful stroke treatment at timepoints beyond the current three hour window. The initial studies will determine the proper dose and therapeutic window for these compounds following an ischemic insult. The proposed study examines behavioral recovery promoted by sigma receptor activation at delayed time points following an ischemic insult. Moreover, we will test the sigma receptor ligand opipramol in our stroke model. Opipramol has been used clinically for over 40 years in Europe, which would accelerate its progression to clinical trials. Sigma receptor agonists are potential compounds to treat stroke many hours to days after onset to arrest the expansion of ischemic area through increasing neurosurvival and blocking the inflammatory response. Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. Since there have been no advances in stroke therapies, innovative approaches are needed to discover new agents to combat this pathologic condition. We have found that systemic administration of DTG, a sigma receptor agonist, has neuroprotective and anti-inflammatory properties that protects against stroke-induced brain injury at 24 hours post-stroke in rats. This proposal will further examine the therapeutic capability of DTG in stroked rats. Another sigma receptor agonist, opipramol, will also be examined for its therapeutic effectiveness in stroke. Opipramol has been used in humans for over 40 years as an anxiolytic agent.

描述(申请人提供)：中风是美国的一个主要健康问题，每年有80万人死亡或虚弱。目前，只有一种治疗方法，需要在中风发病后的前三个小时内进行。我们的实验室正在研究延长这一治疗窗口的治疗方法。我们的研究表明，有效的中风后治疗必须同时具有神经保护和抗炎特性。我们发现，在卒中后24小时给药时，激活Sigma受体可使大鼠脑梗塞面积减少80%以上。这些受体通过抑制缺血诱导的细胞内钙升高、增加神经兴奋性和酸敏离子通道激活来减少神经元死亡。Sigma受体的激活也通过阻止小胶质细胞中炎性细胞毒素的激活、迁移和释放来抗炎。这项建议的目的是扩大我们的初步发现，即在当前三小时窗口之外的时间点激活sigma受体是一种有用的中风治疗方法。初步研究将确定这些化合物在缺血性损伤后的适当剂量和治疗窗口。这项拟议的研究考察了在缺血性损伤后延迟时间点激活Sigma受体促进的行为恢复。此外，我们将在我们的中风模型中测试Sigma受体配体阿片帕莫尔。奥比拉莫在欧洲的临床使用已有40多年，这将加速其进入临床试验的进程。Sigma受体激动剂是一种潜在的化合物，可在发病数小时至数天后治疗中风，通过增加神经存活和阻断炎症反应来阻止缺血区的扩大。 在美国，中风是一个主要的健康问题，只有一种FDA批准的治疗方法，治疗窗口有限。由于中风疗法没有进展，因此需要创新的方法来发现新的药物来对抗这种病理状况。我们发现，全身应用Sigma受体激动剂DTG具有神经保护和抗炎特性，可以在大鼠中风后24小时保护中风诱导的脑损伤。这项建议将进一步检验DTG对中风大鼠的治疗能力。另一种Sigma受体激动剂阿片受体激动剂也将被检测其对中风的治疗效果。奥比拉莫作为一种抗焦虑药物在人类身上已经使用了40多年。