Cerebral Vascular Disease Research Laboratories, Department of Neurology, University of Miami, Miller School of Medicine, Medical Campus, Locator: D4-5, 1420 N.W. 9th Avenue, Miami, FL, 33136, USA,
Transl Stroke Res. 2014 Feb;5(1):109-17. doi: 10.1007/s12975-013-0276-z. Epub 2013 Aug 6.
We previously showed that palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Solutol HS15, a clinically approved excipient because it possesses similar fatty acid compositions as PAME/SAME. Asphyxial cardiac arrest (ACA, 6 min) was performed 30 min after PAME/SAME treatment (0.02 mg/kg, IV). Solutol HS15 (2 ml/kg, IP) was injected chronically for 14 days (once daily). Histopathology of hippocampal CA1 neurons was assessed 7 days after ACA. For focal ischemia experiments, PAME, SAME, or Solutol HS15 was administered following reperfusion after 2 h of middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium staining of the brain was performed 24 h after MCAO and the infarct volume was quantified. Following ACA, the number of surviving hippocampal neurons was enhanced by PAME-treated (68%), SAME-treated (69%), and Solutol-treated HS15 (68%) rats as compared to ACA only-treated groups. Infarct volume was decreased by PAME (83%), SAME (68%), and Solutol HS15 (78%) as compared to saline (vehicle) in MCAO-treated animals. PAME, SAME, and Solutol HS15 provide robust neuroprotection in both paradigms of ischemia. This may prove therapeutically beneficial since Solutol HS15 is already administered as a solublizing agent to patients. With proper timing and dosage, administration of Solutol HS15 and PAME/SAME can be an effective therapy against cerebral ischemia.
我们之前已经表明，棕榈酸甲酯（PAME）和硬脂酸甲酯（SAME）是从交感神经节同时释放出来的，PAME 具有很强的血管舒张作用，这在脑缺血中可能很重要。由于 PAME 是与 SAME 同时释放的一种强效血管舒张剂，我们的假设是 PAME/SAME 在大鼠局灶性/全脑缺血模型中具有神经保护作用。我们还研究了 Solutol HS15 的神经保护特性，Solutol HS15 是一种临床批准的赋形剂，因为它具有与 PAME/SAME 相似的脂肪酸组成。在 PAME/SAME 处理（0.02mg/kg，IV）后 30 分钟进行窒息性心脏骤停（ACA，6 分钟）。Solutol HS15（2ml/kg，IP）每天一次连续注射 14 天。ACA 后 7 天评估海马 CA1 神经元的组织病理学。对于局灶性缺血实验，在大脑中动脉闭塞（MCAO）后再灌注后给予 PAME、SAME 或 Solutol HS15。MCAO 后 24 小时进行脑的 2,3,5-三苯基四唑染色，并定量梗死体积。与仅接受 ACA 治疗的组相比，接受 PAME 治疗（68%）、SAME 治疗（69%）和 Solutol HS15 治疗（68%）的大鼠海马神经元存活数增加。与盐水（载体）相比，在 MCAO 治疗的动物中，PAME（83%）、SAME（68%）和 Solutol HS15（78%）减少了梗死体积。PAME、SAME 和 Solutol HS15 在两种缺血模型中均提供了强大的神经保护作用。由于 Solutol HS15 已经作为增溶剂给予患者，因此这可能具有治疗益处。通过适当的时机和剂量，给予 Solutol HS15 和 PAME/SAME 可以成为治疗脑缺血的有效方法。
