Transl Stroke Res. 2012 Jun;3(2):286-95. doi: 10.1007/s12975-012-0149-x. Epub 2012 Mar 7.
Glibenclamide improves outcomes in rat models of stroke, with treatment as late as 6 h after onset of ischemia shown to be beneficial. Because the molecular target of glibenclamide, the sulfonylurea receptor 1 (Sur1)-regulated NC(Ca-ATP) channel, is upregulated de novo by a complex transcriptional mechanism, and the principal pathophysiological target, brain swelling, requires hours to develop, we hypothesized that the treatment window would exceed 6 h. We studied a clinically relevant rat model of stroke in which middle cerebral artery occlusion (75% < reduction in LDF signal ≤90%) was produced using an intra-arterial occluder. Recanalization was obtained 4.5 h later by removing the occluder. At that time, we administered recombinant tissue plasminogen activator (rtPA; 0.9 mg/kg IV over 30 min). Immunolabeling showed modest expression of Sur1 5 h after onset of ischemia, with expression increasing 7- to 11-fold (P < 0.01) by 24 h. Rats were administered either vehicle or glibenclamide (10 μg/kg IP loading dose plus 200 ng/h by constant subcutaneous infusion) beginning 4.5 or 10 h after onset of ischemia. In rats treated at 4.5 or 10 h, glibenclamide significantly reduced hemispheric swelling at 24 h from (mean ± SEM) 14.7 ± 1.5% to 8.1 ± 1.6% or 8.8 ± 1.1% (both P < 0.01), respectively, and significantly reduced 48-h mortality from 53% to 17% or 12% (both P < 0.01), and improved Garcia scores at 48 h from 3.8 ± 0.62 to 7.6 ± 0.70 or 8.4 ± 0.74 (both P < 0.01). We conclude that, in a clinically relevant model of stroke, the treatment window for glibenclamide extends to 10 h after onset of ischemia.
格列本脲可改善中风大鼠模型的预后，即使在缺血发作后 6 小时开始治疗也有益处。由于格列本脲的分子靶标，即磺酰脲受体 1（Sur1）调节的 NC（Ca-ATP）通道，通过复杂的转录机制新上调，而主要的病理生理靶标，脑水肿，需要数小时才能发展，因此我们假设治疗窗口将超过 6 小时。我们研究了一种临床相关的中风大鼠模型，其中通过动脉内闭塞器产生大脑中动脉闭塞（LDF 信号减少 75%<≤90%）。4.5 小时后，通过取出闭塞器来实现再通。此时，我们给予重组组织型纤溶酶原激活物（rtPA；30 分钟内静脉注射 0.9mg/kg）。免疫标记显示，缺血后 5 小时Sur1 表达适度，24 小时表达增加 7-11 倍（P<0.01）。大鼠在缺血后 4.5 或 10 小时开始分别给予载体或格列本脲（10μg/kg 腹腔内负荷剂量加 200ng/h 持续皮下输注）。在 4.5 或 10 小时治疗的大鼠中，格列本脲显著降低了 24 小时的半球肿胀，从（平均值±SEM）14.7±1.5%降至 8.1±1.6%或 8.8±1.1%（均 P<0.01），显著降低了 48 小时的死亡率，从 53%降至 17%或 12%（均 P<0.01），并提高了 48 小时的 Garcia 评分，从 3.8±0.62 升至 7.6±0.70 或 8.4±0.74（均 P<0.01）。我们得出结论，在一种临床相关的中风模型中，格列本脲的治疗窗口可延长至缺血发作后 10 小时。
