Suda S, Katsura K I, Saito M, Kamiya N, Katayama Y
Division of Neurology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku 113-0022, Tokyo, Japan.
Division of Neurology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku 113-0022, Tokyo, Japan.
Brain Res. 2014 May 27;1565:74-81. doi: 10.1016/j.brainres.2014.04.011. Epub 2014 Apr 16.
Bone marrow derived mononuclear cell (MNC) transplantation is a potential therapy for ischemic stroke. Here, we hypothesized that valproic acid (VPA) would modulate transplantation effects of MNCs in a rat ischemic stroke model. Male Sprague-Dawley rats were subjected to transient 90min middle cerebral artery occlusion. Infarct volume, neurological outcome, and immunohistological assessments were performed 7 days after ischemia. MNCs injected 6 or 24h but not 48 or 72h after ischemia significantly reduced infarct volume and improved neurological deficits. We then tested whether the therapeutic window of MNC transplantation could be expanded through combination therapy with VPA. MNC transplantation at 48h combined with VPA injection three times at 47, 53, and 72h after ischemia significantly ameliorated infarct volume and neurological deficits compared to a vehicle group. Combination therapy reduced the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, tumor necrosis factor-α-positive cells, and von Willebrand factor-positive cells in the ischemic boundary zone. The number of engrafted MNCs that were fluorescently labeled with PKH 26, on day 7, was significantly higher after combination therapy than after that MNC transplantation alone. Our results demonstrated that combination therapy with VPA enhanced the anti-inflammatory and vasculo-protective effects against endothelial damage following ischemia, and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MNC transplantation. Together, these findings suggest that VPA may be an appropriate partner for cell-based treatment of ischemic stroke.
骨髓来源的单核细胞（MNC）移植是缺血性中风的一种潜在治疗方法。在此，我们假设丙戊酸（VPA）会调节MNCs在大鼠缺血性中风模型中的移植效果。雄性Sprague-Dawley大鼠接受90分钟的大脑中动脉短暂闭塞。在缺血7天后进行梗死体积、神经功能结果和免疫组织学评估。在缺血后6或24小时而非48或72小时注射MNCs可显著减少梗死体积并改善神经功能缺损。然后我们测试了MNC移植的治疗窗口是否可以通过与VPA联合治疗来扩大。与溶剂对照组相比，在缺血后48小时进行MNC移植并在47、53和72小时注射三次VPA可显著改善梗死体积和神经功能缺损。联合治疗减少了缺血边界区髓过氧化物酶阳性细胞、离子钙结合衔接分子1阳性细胞、肿瘤坏死因子-α阳性细胞和血管性血友病因子阳性细胞的数量。在第7天，联合治疗后用PKH 26荧光标记的植入MNCs数量显著高于单独进行MNC移植后。我们的结果表明，VPA联合治疗增强了对缺血后内皮损伤的抗炎和血管保护作用，并提高了移植细胞的存活率，从而扩大了MNC移植的治疗时间窗口。总之，这些发现表明VPA可能是基于细胞治疗缺血性中风的合适搭档。
