甘露醇和替莫唑胺联合使用可提高慢性中风模型中干细胞治疗的效果。
The combination of mannitol and temozolomide increases the effectiveness of stem cell treatment in a chronic stroke model.
机构信息
Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
Department of Obstetrics and Gynecology, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea.
出版信息
Cytotherapy. 2018 Jun;20(6):820-829. doi: 10.1016/j.jcyt.2018.04.004.
BACKGROUND
The blood-brain barrier (BBB) presents a significant challenge to the therapeutic efficacy of stem cells in chronic stroke. Various methods have been developed to increase BBB permeability, but these are associated with adverse effects and are, therefore, not clinically applicable. We recently identified that combination drug treatment of mannitol and temozolomide improved BBB permeability in vitro. Here, we investigated whether this combination could increase the effectiveness of stem cell treatment in an animal model of chronic ischemic stroke.
METHODS
Chronic stroke was induced in rats by middle cerebral artery occlusion (MCAo). After then, rats were administered human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) by intravenous injection with or without combination drug treatment of mannitol and temozolomide. To evaluate the therapeutic efficacy, behavioral and immunohistochemical tests were performed, and the differences among control, stem cell only, combination drug only and stem cell with combination drug treatment were analyzed.
RESULTS
Although no hUC-MSCs were detected in any group, treatment with stem cells and combination drug of mannitol and temozolomide increased the intracerebral delivery of hCD63-positive microvesicles compared with stem cell only treatment. Furthermore, treatment with stem cells and drug combination ameliorated behavioral deficits and increased bromodeoxyuridine-, doublecortin- and Reca-1-positive cells in the perilesional area as compared with other groups.
DISCUSSION
The combination drug treatment of mannitol and temozolomide allowed for the efficient delivery of hUC-MSC-derived microvesicles into the brain in a chronic stroke rat model. This attenuated behavioral deficits, likely by improving neural regeneration and angiogenesis. Thus, combination drug treatment of mannitol and temozolomide could be a novel therapeutic option for patients with chronic ischemic stroke.
背景
血脑屏障（BBB）对慢性中风中干细胞的治疗效果构成了重大挑战。已经开发出各种方法来增加 BBB 的通透性，但这些方法都伴随着不良反应，因此在临床上不可用。我们最近发现甘露醇和替莫唑胺联合药物治疗可增加体外 BBB 的通透性。在这里，我们研究了这种联合用药是否可以提高慢性缺血性中风动物模型中干细胞治疗的效果。
方法
通过大脑中动脉闭塞（MCAo）在大鼠中诱导慢性中风。然后，通过静脉注射给予大鼠人脐带间充质基质细胞（hUC-MSCs），并用或不用甘露醇和替莫唑胺联合药物治疗。为了评估治疗效果，进行了行为和免疫组织化学测试，并分析了对照组、仅干细胞治疗组、仅联合药物治疗组和干细胞联合药物治疗组之间的差异。
结果
尽管在任何组中都未检测到 hUC-MSCs，但与仅干细胞治疗相比，用干细胞和甘露醇与替莫唑胺联合药物治疗增加了 hCD63 阳性微泡的脑内递送。此外，与其他组相比，用干细胞和药物联合治疗改善了行为缺陷，并增加了梗塞周边区域的溴脱氧尿苷、双皮质素和 Reca-1 阳性细胞。
讨论
甘露醇和替莫唑胺联合药物治疗允许 hUC-MSC 衍生的微泡在慢性中风大鼠模型中有效地递送到大脑。这减轻了行为缺陷，可能通过改善神经再生和血管生成。因此，甘露醇和替莫唑胺联合药物治疗可能是慢性缺血性中风患者的一种新的治疗选择。
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