Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices
Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices
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DOI：
10.1152/jn.00654.2004
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发表时间：
2005-02-01
影响因子：
2.5
通讯作者：
Andrew, RD
中科院分区：
文献类型：
--
作者：
Anderson, TR;Jarvis, CR;Andrew, RD
在卒中发作的2分钟内，由于Na+/K+ATPase泵的故障，大脑中最缺乏血液的区域(缺血核心)的神经元和神经胶质细胞经历了突然而严重的膜电位损失。这种缺氧性去极化(AD)代表膜离子选择性的崩溃，导致急性神经元损伤，因为神经元在缺乏氧气和葡萄糖的情况下根本无法生存复极化的能量需求。在活体和活脑片中，AD抵抗神经递质受体拮抗剂(包括谷氨酸)或离子通道阻滞剂的阻断。我们的神经保护策略是寻找对神经功能影响最小的AD阻滞剂。如果阿尔茨海默病背后的电导不是正常活跃的，它的选择性阻断不应该改变神经元的兴奋性。活体新皮质和海马区脑片透光率的成像变化揭示了AD的发病、传播和随后的树突损伤。在这里，我们确定了几个sigma-1受体配体，它们在用10-30微米的配体预处理的切片中阻断AD。阻断可防止随后的细胞肿胀、树突损伤以及记录在新皮质II/III层和海马区CA1区的诱发场电位的丧失。即使只是延缓了AD的发病，电生理恢复也有明显改善。在配体治疗下，诱发的轴突传导和突触传递保持不变。推动AD的大的非选择性电导仍未确定，但代表了抑制中风最初关键分钟期间急性神经元损伤的主要上游靶点。Sigma受体配体提供了洞察力，以更好地定义负责缺氧去极化的通道的属性。有关缺氧性去极化和扩散性抑制的视频片段可在http://anatomy.queensu.ca/faculty/andrew.cfm.(1).上观看
Within 2 min of stroke onset, neurons and glia in brain regions most deprived of blood ( the ischemic core) undergo a sudden and profound loss of membrane potential caused by failure of the Na+/K+ ATPase pump. This anoxic depolarization ( AD) represents a collapse in membrane ion selectivity that causes acute neuronal injury because neurons simply cannot survive the energy demands of repolarization while deprived of oxygen and glucose. In vivo and in live brain slices, the AD resists blockade by antagonists of neurotransmitter receptors ( including glutamate) or by ion channel blockers. Our neuroprotective strategy is to identify AD blockers that minimally affect neuronal function. If the conductance underlying AD is not normally active, its selective blockade should not alter neuronal excitability. Imaging changes in light transmittance in live neocortical and hippocampal slices reveal AD onset, propagation, and subsequent dendritic damage. Here we identify several sigma-1 receptor ligands that block the AD in slices that are pretreated with 10 - 30 muM of ligand. Blockade prevents subsequent cell swelling, dendritic damage, and loss of evoked field potentials recorded in layers II/III of neocortex and in the CA1 region of hippocampus. Even when AD onset is merely delayed, electrophysiological recovery is markedly improved. With ligand treatment, evoked axonal conduction and synaptic transmission remain intact. The large nonselective conductance that drives AD is still unidentified but represents a prime upstream target for suppressing acute neuronal damage arising during the first critical minutes of stroke. Sigma receptor ligands provide insight to better define the properties of the channel responsible for anoxic depolarization. Video clips of anoxic depolarization and spreading depression can be viewed at http://anatomy.queensu.ca/faculty/andrew.cfm.(1).