Eady Tiffany N, Khoutorova Larissa, Atkins Kristal D, Bazan Nicolas G, Belayev Ludmila
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, 70112, USA.
Exp Transl Stroke Med. 2012 Sep 14;4(1):19. doi: 10.1186/2040-7378-4-19.
Docosahexaenoic acid (DHA) complexed to human serum albumin (Alb) is neuroprotective after experimental stroke. Here we tested using lower concentrations of albumin as part of the complex to achieve neuroprotection. We found that lower Alb concentrations extend the therapeutic window of protection beyond 5 h after stroke onset.
Sprague-Dawley rats were received 2 h middle cerebral artery occlusion (MCAo). The behavior was evaluated on day 1, 2, 3 and 7 after MCAo. In the dose-response study, animals were given either DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (5mg/kg + 0.32, 0.63 or 1.25 g/kg) or saline, i.v. 3 h after onset of stroke (n=6-8 per group). In the therapeutic window study, DHA-Alb (5mg/kg + 1.25g/kg) was administered i.v. at either 3, 4, 5, 6 or 7 h after onset of stroke (n=7-9 per group). Alb (1.25g/kg) was given at 3 h or 5 h and saline at 3h after onset of reperfusion. Seven days after MCAo, infarct volumes and number of GFAP, ED-1, NeuN, SMI-71 positive cells and vessels were counted.
Moderate DHA-Alb doses (0.63 and 1.25 g/kg) improved neurological scores compared to albumin-treated rats on days 1, 2, 3 and 7. All DHA-Alb doses (0.32, 0.63 and 1.25 g/kg) markedly reduced cortical (by 65-70%), striatal (by 52-63%) and total infarct volumes (by 60-64%) compared to native Alb group. In the therapeutic window study DHA-Alb led to improved neurological score and significant reductions of infarct volumes (especially in the cortical or penumbral region), even when treatment was initiated as late as 7 hours after onset of MCAo.
The DHA-Alb complex affords high-grade neurobehavioral neuroprotection in focal cerebral ischemia, equaling or exceeding that afforded by native Alb or DHA, at considerably moderate doses. It has a broad therapeutic window extending to 7 h after stroke onset. Taken together, these finding support the potential clinical feasibility of administering DHA-Alb therapy to patients with acute ischemic stroke.
与人类血清白蛋白（Alb）结合的二十二碳六烯酸（DHA）在实验性中风后具有神经保护作用。在此，我们测试了使用较低浓度的白蛋白作为复合物的一部分以实现神经保护。我们发现较低的Alb浓度可将保护的治疗窗口延长至中风发作后5小时以上。
对Sprague-Dawley大鼠进行2小时的大脑中动脉闭塞（MCAo）。在MCAo后的第1、2、3和7天评估行为。在剂量反应研究中，动物在中风发作后3小时静脉注射DHA（5mg/kg）、Alb（0.63g/kg）、DHA-Alb（5mg/kg + 0.32、0.63或1.25g/kg）或生理盐水（每组n = 6 - 8）。在治疗窗口研究中，在中风发作后3、4、5、6或7小时静脉注射DHA-Alb（5mg/kg + 1.25g/kg）（每组n = 7 - 9）。在再灌注后3小时给予Alb（1.25g/kg），在3小时或5小时给予生理盐水。MCAo后7天，计算梗死体积以及GFAP、ED-1、NeuN、SMI-71阳性细胞和血管的数量。
与白蛋白治疗的大鼠相比，中度DHA-Alb剂量（0.63和1.25g/kg）在第1、2、3和7天改善了神经学评分。与天然Alb组相比，所有DHA-Alb剂量（0.32、0.63和1.25g/kg）均显著降低了皮质（降低65 - 70%）、纹状体（降低52 - 63%）和总梗死体积（降低60 - 64%）。在治疗窗口研究中，即使在MCAo发作后7小时才开始治疗，DHA-Alb也能改善神经学评分并显著减少梗死体积（尤其是在皮质或半暗带区域）。
DHA-Alb复合物在局灶性脑缺血中提供高度的神经行为神经保护作用，在相当适度的剂量下等同于或超过天然Alb或DHA所提供的保护作用。它具有广泛的治疗窗口，可延长至中风发作后7小时。综上所述，这些发现支持了对急性缺血性中风患者进行DHA-Alb治疗的潜在临床可行性。
