Subirós Nelvys, Pérez-Saad Héctor M, Berlanga Jorge A, Aldana Lizet, García-Illera Gerardo, Gibson Claire L, García-Del-Barco Diana
a Biomedical Research Division , Center for Genetic Engineering and Biotechnology , Havana , Cuba.
b Group of Stability and Reference Materials , Quality Control Division, Center for Genetic Engineering and Biotechnology , Havana , Cuba.
Neurol Res. 2016 Mar;38(3):187-95. doi: 10.1179/1743132815Y.0000000089. Epub 2016 Apr 19.
Stroke continues to be a leading cause of mortality and morbidity worldwide, and novel therapeutic options for ischaemic stroke are urgently needed. In this context, drug combination therapies seem to be a viable approach, which has not been fully explored in preclinical studies.
In this work, we assessed the dose-response relationship and therapeutic time window, in global brain ischaemia, of a combined therapeutic approach of recombinant human epidermal growth factor (EGF) and growth hormone-releasing peptide-6 (GHRP-6).
Mongolian gerbils underwent 15 minutes occlusion of both common carotid arteries. Four different doses of rhEGF, GHRP-6 and these combined agents were intraperitoneally administered immediately after the onset of reperfusion. Having identified a better response with both agents, rhEGF+GHRP-6 were administered at 2, 4, 6, 8 or 24 hours after the onset of reperfusion to assess the time window of effectiveness. Animals were evaluated daily for neurological deficits. Three days post-occlusion, the animals were sacrificed and 2,3,5-triphenyltetrazolium chloride was used to quantify infarcted tissues.
The coadministration of rhEGF and GHRP-6 at doses of 100 and 600 μg/kg, respectively, administered up to 4 hours following the ischaemic insult, significantly improved survival and neurological outcome, and reduced infarct volume compared with vehicle treatment. These results are considered as an additional proof of concept as supporting a combined therapeutic approach and justify the further development of this preclinical research.
中风仍然是全球范围内导致死亡和发病的主要原因，缺血性中风急需新的治疗选择。在这种情况下，联合药物治疗似乎是一种可行的方法，但在临床前研究中尚未得到充分探索。
在这项研究中，我们评估了重组人表皮生长因子（EGF）和生长激素释放肽-6（GHRP-6）联合治疗方法在全脑缺血中的剂量反应关系和治疗时间窗。
蒙古沙鼠双侧颈总动脉闭塞15分钟。再灌注开始后立即腹腔注射四种不同剂量的重组人表皮生长因子、生长激素释放肽-6及其联合制剂。在确定两种药物均有更好的反应后，在再灌注开始后2、4、6、8或24小时给予重组人表皮生长因子+生长激素释放肽-6，以评估有效性的时间窗。每天评估动物的神经功能缺损。闭塞后三天，处死动物，用2,3,5-三苯基四氮唑氯化物定量梗死组织。
与载体治疗相比，分别以100和600μg/kg的剂量联合给予重组人表皮生长因子和生长激素释放肽-6，在缺血损伤后4小时内给药，显著提高了存活率和神经功能结局，并减少了梗死体积。这些结果被视为支持联合治疗方法的概念验证的补充证据，并证明了这项临床前研究进一步开展的合理性。
