Institute of Molecular Medicine and Genetics, Medical College of Georgia, Georgia Health Sciences University, Augusta, Georgia 30912, USA.
J Neurochem. 2011 May;117(4):703-11. doi: 10.1111/j.1471-4159.2011.07239.x. Epub 2011 Apr 6.
Stem cell-based approaches provide hope as a potential therapy for neurodegenerative diseases and stroke. One of the major scientific hurdles for stem cell therapy is the poor survival rate of the newly formed or transplanted neural stem cells. In this study, we found that low-dose treatment with the Heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heavily investigated anti-cancer drug, prevented neural progenitor cells from either naturally-occurring or stress-induced apoptosis, although it induced apoptosis at higher doses. This stress adaptation effect mediated by low-dose 17-AAG is accompanied by activation of multiple cell survival pathways, including the stress response pathway (induction of Hsp70), the MAPK pathway, and the PI3K/Akt pathway. When administered in vivo, 17-AAG led to Akt and glycogen synthase kinase 3β phosphorylation, and more 5-bromo-2'-deoxyuridine positive cells in the mouse brain. These findings could have profound implications in stem cell therapy for neurodegenerative diseases and stroke.
基于干细胞的方法为神经退行性疾病和中风的潜在治疗提供了希望。干细胞治疗的主要科学障碍之一是新形成或移植的神经干细胞的存活率低。在这项研究中，我们发现，低剂量的热休克蛋白 90（Hsp90）抑制剂 17-烯丙基-17-脱甲氧基格尔德霉素（17-AAG）治疗，一种经过大量研究的抗癌药物，可以防止神经祖细胞发生自然发生或应激诱导的细胞凋亡，尽管在较高剂量下它会诱导细胞凋亡。这种由低剂量 17-AAG 介导的应激适应效应伴随着多种细胞存活途径的激活，包括应激反应途径（诱导 Hsp70）、MAPK 途径和 PI3K/Akt 途径。在体内给药时，17-AAG 导致 Akt 和糖原合酶激酶 3β的磷酸化，以及小鼠大脑中更多的 5-溴-2'-脱氧尿苷阳性细胞。这些发现可能对神经退行性疾病和中风的干细胞治疗产生深远影响。
