SOD2
神经保护
SIRT3
神经干细胞
神经发生
干细胞
医学
干细胞疗法
线粒体
药理学
冲程(发动机)
超氧化物歧化酶
内科学
生物
氧化应激
锡尔图因
移植
细胞生物学
生物化学
机械工程
乙酰化
工程类
基因
作者
Jea-Young Lee,Vanessa Castelli,Narender Kumar,Régine Sitruk-Ware,Cesario V. Borlongan
标识
DOI:10.1016/j.freeradbiomed.2022.03.020
摘要
Ischemic stroke remains a significant unmet need causing massive mortality and morbidity due to few treatment options with limited therapeutic window. The progestin Nestorone® (segesterone acetate) displays high affinity for the progesterone receptor in exerting its potent birth control and hormone replacement therapy. Accumulating evidence implicates a new utility of Nestorone in affording neuroprotection in a variety of central nervous system diseases, including stroke. However, the mechanism of action mediating Nestorone's neuroprotection in stroke remains unknown. Here, we showed that stand-alone treatments of Nestorone or human amniotic fluid-derived stem cells (hAFSc), but more pronounced with their combined treatment, led to significant improvements in behavioral function and reductions in infarction and peri-infarct cell loss in adult rats with ischemic stroke. We detected significantly lower levels of pro-inflammatory signals (OX6 and IBA1) coupled with enhanced levels of stem cell proliferation (Ki67) and differentiation (DCX and MAP2) in both brain and spleen of stroke rats that received stand-alone or combined treatments of Nestorone and hAFSc. In concert, the in vitro oxygen-glucose deprivation stroke model revealed that neural stem cells treated with Nestorone exhibited increased stem cell proliferation and differentiation that was accompanied by rescue of the mitochondrial respiratory activity characterized by reduced mitochondrial reactive oxygen species, increased ATP, elevated mitochondrial deacetylase Sirtuin 3 (SIRT3), and a normalized ratio of acetyl-superoxide dismutase 2 (Ac-SOD2)/SOD2, suggesting the key role of mitochondrial metabolism and oxidative protection in Nestorone's therapeutic effects in stroke.
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