Department of Physiology and Pharmacology, State University of New York-Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA.
Neurosci Lett. 2010 Apr 5;473(2):67-71. doi: 10.1016/j.neulet.2009.10.021. Epub 2009 Oct 12.
The sodium-potassium ATPase (Na/K ATPase) is a major ionic transporter in the brain and is responsible for the maintenance of the Na(+) and K(+) gradients across the cell membrane. Cardiotonic steroids such as ouabain, digoxin and marinobufagenin are well-characterized inhibitors of the Na/K ATPase. Recently, cardiotonic steroids have been shown to have additional effects at concentrations below their IC(50) for pumping. The cardiotonic steroids ouabain, digoxin, and marinobufagenin all show an inverted U-shaped dose-response curve with inhibition of pumping at concentrations near their IC(50), while increasing Na/K ATPase activity at doses below their IC(50). This stimulatory effect of cardiotonic steroids was observed in vitro in hippocampal slice cultures as well as in the hippocampus in vivo. Increased Na/K ATPase activity has been shown to protect slice culture neurons from hypoxia-hypoglycemia. Ouabain protected slice culture neurons from experimental ischemia at concentrations that increased Na/K ATPase. This protective effect was observed when ouabain was dosed 30min before, or 2h following experimental ischemia. Ouabain no longer protected against experimental ischemia if the increase of Na/K ATPase was blocked. These data suggest that the protective effect of ouabain was due to increased Na/K ATPase activity. The demonstration of a neuroprotective effect of cardiotonic steroids could potentially assist in the treatment of stroke since digoxin, one of the cardiotonic steroids examined in this study, has approval by the Food and Drug Administration and can be safely administered at the concentrations that increase Na/K ATPase activity.
钠钾 ATP 酶（Na/K ATPase）是大脑中主要的离子转运体，负责维持细胞膜两侧的钠离子和钾离子梯度。地高辛、哇巴因和蟾蜍灵等强心甾类化合物是 Na/K ATPase 的典型抑制剂。最近，强心甾类化合物在低于其泵作用 IC50 的浓度下显示出其他额外的作用。强心甾类化合物哇巴因、地高辛和蟾蜍灵均显示出抑制泵作用的倒 U 型剂量反应曲线，而在低于其 IC50 的剂量下增加 Na/K ATPase 活性。这种强心甾类化合物的刺激作用在海马切片培养物以及体内海马体中均有观察到。增加的 Na/K ATPase 活性已被证明可保护切片培养神经元免受缺氧低糖的影响。哇巴因在增加 Na/K ATPase 的浓度下可保护切片培养神经元免受实验性缺血的影响。在实验性缺血之前或之后 30 分钟给予哇巴因时观察到这种保护作用。如果阻断 Na/K ATPase 的增加，则哇巴因不再对实验性缺血起保护作用。这些数据表明，哇巴因的保护作用归因于 Na/K ATPase 活性的增加。强心甾类化合物的神经保护作用的证明可能有助于中风的治疗，因为在本研究中检查的强心甾类化合物之一地高辛已获得食品和药物管理局的批准，并且可以在增加 Na/K ATPase 活性的浓度下安全给药。
