Combination treatment of hypothermia and mesenchymal stromal cells amplifies neuroprotection in primary rat neurons exposed to hypoxic-ischemic-like injury in vitro: role of the opioid system.
Combination treatment of hypothermia and mesenchymal stromal cells amplifies neuroprotection in primary rat neurons exposed to hypoxic-ischemic-like injury in vitro: role of the opioid system.
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DOI：
10.1371/journal.pone.0047583
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Borlongan CV
中科院分区：
文献类型：
--
作者：
Kaneko Y;Tajiri N;Su TP;Wang Y;Borlongan CV
本研究旨在揭示低温联合干细胞移植改善新生儿缺氧缺血性损伤的治疗方案和作用机制。将原代大鼠神经元暴露于氧-葡萄糖剥夺（OGD），其在体外产生缺氧缺血样损伤，然后在25°C（严重低温）、34°C（中度低温）和37°C（常温）下孵育，随后与或不与间充质基质细胞（MSC）共培养。中度低温和MSC的联合治疗显著改善了OGD暴露后的细胞存活和线粒体活性。δ阿片样物质人胚肾细胞（HEK 293）暴露于中度低温减弱了OGD介导的细胞改变，这在过表达δ阿片样物质受体的HEK 293细胞中更为明显。此外，在原代大鼠神经元中向34°C低温和干细胞处理中添加δ阿片肽显示出针对OGD的协同神经保护作用，其比中度低温和MSC的双重组合显著更稳健，并且被阿片受体拮抗剂纳洛酮显著降低，但未完全消除，这完全涉及神经保护的配体-受体机制。对非阿片类药物治疗信号传导途径的进一步研究揭示了伴随所观察到的治疗益处的生长因子介导和抗凋亡功能。这些结果支持低温和干细胞联合治疗体外缺氧缺血样损伤，这可能对目前使用独立低温或干细胞治疗新生儿脑病的临床试验产生直接影响。
This study was designed to reveal the therapeutic regimen and mechanism of action underlying hypothermia treatment in combination with stem cell transplantation for ameliorating neonatal hypoxic-ischemic-like injury. Primary rat neurons were exposed to oxygen-glucose deprivation (OGD), which produced hypoxic-ischemic-like injury in vitro, then incubated at 25°C (severe hypothermia), 34°C (moderate hypothermia), and 37°C (normothermia) with or without subsequent co-culture with mesenchymal stromal cells (MSCs). Combination treatment of moderate hypothermia and MSCs significantly improved cell survival and mitochondrial activity after OGD exposure. The exposure of delta opioid human embryonic kidney cells (HEK293) to moderate hypothermia attenuated OGD-mediated cell alterations, which were much more pronounced in HEK293 cells overexpressing the delta opioid receptor. Further, the addition of delta opioid peptide to 34°C hypothermia and stem cell treatment in primary rat neurons showed synergistic neuroprotective effects against OGD which were significantly more robust than the dual combination of moderate hypothermia and MSCs, and were significantly reduced, but not completely abolished, by the opioid receptor antagonist naltrexone altogether implicating a ligand-receptor mechanism of neuroprotection. Further investigations into non-opioid therapeutic signaling pathways revealed growth factor mediation and anti-apoptotic function accompanying the observed therapeutic benefits. These results support combination therapy of hypothermia and stem cells for hypoxic-ischemic-like injury in vitro, which may have a direct impact on current clinical trials using stand-alone hypothermia or stem cells for treating neonatal encephalopathy.
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DOI：
10.1126/science.1201940
发表时间：
2011-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Green DR;Galluzzi L;Kroemer G
通讯作者：
Kroemer G
影响因子：
8.3
作者：
Borlongan, CV;Hadman, M;Sanberg, PR
通讯作者：
Sanberg, PR
影响因子：
17.1
作者：
Baud, Olivier;Gressens, Pierre
通讯作者：
Gressens, Pierre
鼻内递送绕过靶向治疗剂到中枢神经系统并治疗神经退行性疾病的血脑屏障。
影响因子：
2.4
作者：
Hanson LR;Frey WH 2nd
通讯作者：
Frey WH 2nd
影响因子：
3.6
作者：
Borlongan CV;Weiss MD
通讯作者：
Weiss MD