Zeynalov Emil, Jones Susan M, Elliott J Paul
Swedish Medical Center, Neurotrauma Research, Englewood, Colorado, United States of America.
Colorado Brain and Spine Institute, Englewood, Colorado, United States of America.
PLoS One. 2017 Aug 30;12(8):e0183985. doi: 10.1371/journal.pone.0183985. eCollection 2017.
Ischemic stroke is often complicated by brain edema, disruption of blood-brain barrier (BBB), and uncontrolled release of arginine-vasopressin (AVP). Conivaptan, a V1a and V2 receptor antagonist, reduces brain edema and minimizes damage to the blood-brain barrier after stroke. Most stroke patients do not receive treatment immediately after the onset of brain ischemia. Delays in therapy initiation may worsen stroke outcomes. Therefore, we designed a translational study to explore the therapeutic time window for conivaptan administration.
Mice were treated with conivaptan beginning 3, 5, or 20 hours after 60-minute focal middle cerebral artery occlusion. Treatments were administered by continuous IV infusion for a total of 48 hours. Brain edema and blood-brain barrier (BBB) disruption were evaluated at endpoint.
Conivaptan therapy initiated at 3 hours following ischemia reduced edema in the ipsilateral hemisphere, which corresponded with improvements in neurological deficits. Stroke-triggered BBB disruption was also reduced in mice when conivaptan treatments were initiated at 3 hours of reperfusion. However, 5 and 20-hour delays of conivaptan administration failed to reduce edema or protect BBB.
Timing of conivaptan administration is important for successful reduction of brain edema and BBB disruption. Our experimental data open new possibilities to repurpose conivaptan, and make an important "bench-to-bedside translation" of the results into clinical practice.
缺血性中风常伴有脑水肿、血脑屏障（BBB）破坏以及精氨酸加压素（AVP）的失控释放。考尼伐坦是一种V1a和V2受体拮抗剂，可减轻脑水肿并使中风后血脑屏障的损伤最小化。大多数中风患者在脑缺血发作后未立即接受治疗。治疗开始的延迟可能会使中风预后恶化。因此，我们设计了一项转化研究，以探索考尼伐坦给药的治疗时间窗。
小鼠在大脑中动脉闭塞60分钟后3、5或20小时开始接受考尼伐坦治疗。通过静脉持续输注给药，共48小时。在终点时评估脑水肿和血脑屏障（BBB）破坏情况。
缺血后3小时开始考尼伐坦治疗可减轻同侧半球的水肿，这与神经功能缺损的改善相对应。当在再灌注3小时开始考尼伐坦治疗时，中风引发的血脑屏障破坏在小鼠中也有所减少。然而，考尼伐坦给药延迟5小时和20小时未能减轻水肿或保护血脑屏障。
考尼伐坦给药的时机对于成功减轻脑水肿和血脑屏障破坏至关重要。我们的实验数据为考尼伐坦的重新利用开辟了新的可能性，并将结果进行了重要的“从 bench 到 bedside 的转化”应用于临床实践。
