Somjen G G, Aitken P G, Czéh G, Jing J, Young J N
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710.
Res Publ Assoc Res Nerv Ment Dis. 1993;71:51-65.
We began this brief review with a condensed summary of the responses of mammalian central neurons to hypoxic insult and then described our recent studies aimed at solving the biophysical basis of these responses. We distinguished three main phases of cerebral hypoxia. First, withdrawal of oxygen is rapidly followed by failure of synaptic transmission. Second, there is massive depolarization of cells, resembling the SD of Leão. Timely reoxygenation can still restore function. If, however, SD-like depolarization continues beyond a critical time, the third phase, irreversible loss of responsiveness, sets in. Cell loss is initially highly selective. Finally, upon reoxygenation, some neurons, which at first appear normal, then undergo a sequence of changes leading to delayed neuron degeneration. The principal cause of early synaptic failure is the depression of synaptic potentials. This can be attributed to reduced release of transmitter substance, in turn caused by failure of the opening of voltage-dependent calcium channels in presynaptic terminals. Calcium-channel failure is probably caused either by a rise of intracellular free calcium activity, depletion of adenosine triphosphate (ATP) levels in presynaptic terminals, or a combination of both. Conduction block in presynaptic fiber terminals can, in some situations, contribute to synaptic failure. In some (postsynaptic) neuron membranes, conductance for potassium increases, raising the firing threshold and hastening the failure of excitatory synaptic transmission. Hypoxic SD-like depolarization is a complex but stereotyped and explosive event. The longer the depolarization lasts, the smaller the chance for functional recovery after reoxygenation. The least likely to recover are those cells that undergo SD the earliest. Prolonged intracellular accumulation of free calcium, admitted into the cells by the SD-like membrane change, plays a key role in causing neuron damage (Fig. 8). Some antagonists of NMDA receptors and blockers of sodium, calcium, and potassium channels influence the onset and magnitude of SD-like hypoxic depolarization, but no known drug prevents it. The irreversible neuron damage that occurs during hypoxia should be distinguished from delayed postischemic injury that occurs after initial apparent recovery. The delayed process can proceed even in the controlled environment of isolated hippocampal tissue slices, but it can be prevented in vitro by NMDA receptor antagonist drugs. In the clinical management of cerebral ischemia not only the intrinsic neuronal degenerative process, but also the deteriorating extracellular milieu, needs to be treated, and the latter may not be improved by NMDA receptor blockade.(ABSTRACT TRUNCATED AT 400 WORDS)
我们以对哺乳动物中枢神经元对缺氧损伤反应的简要总结开始了这篇简短的综述，然后描述了我们最近旨在解决这些反应生物物理基础的研究。我们区分了脑缺氧的三个主要阶段。首先，氧气撤离后迅速出现突触传递失败。其次，细胞出现大量去极化，类似于莱昂的去极化波（SD）。及时复氧仍可恢复功能。然而，如果类SD去极化持续超过临界时间，第三阶段，即不可逆的反应丧失就会开始。细胞损失最初具有高度选择性。最后，复氧时，一些起初看似正常的神经元会经历一系列变化，导致延迟性神经元变性。早期突触失败的主要原因是突触电位的抑制。这可归因于递质释放减少，而递质释放减少又是由突触前终末电压依赖性钙通道开放失败所致。钙通道失败可能是由细胞内游离钙活性升高、突触前终末三磷酸腺苷（ATP）水平耗竭或两者共同作用引起的。在某些情况下，突触前纤维终末的传导阻滞也会导致突触失败。在一些（突触后）神经元膜中，钾电导增加，提高了放电阈值并加速了兴奋性突触传递的失败。缺氧类SD去极化是一个复杂但刻板且爆发性的事件。去极化持续时间越长，复氧后功能恢复的机会就越小。最早经历SD的细胞最不可能恢复。通过类SD膜变化进入细胞的游离钙在细胞内长期积累，在导致神经元损伤中起关键作用（图8）。一些NMDA受体拮抗剂以及钠、钙和钾通道阻滞剂会影响类SD缺氧去极化的起始和幅度，但尚无已知药物可预防它。缺氧期间发生的不可逆神经元损伤应与初始明显恢复后发生的延迟性缺血后损伤区分开来。即使在分离的海马组织切片的可控环境中，延迟过程也会发生，但在体外可通过NMDA受体拮抗剂药物预防。在脑缺血的临床治疗中，不仅需要治疗内在的神经元退行性过程，还需要治疗不断恶化的细胞外环境，而NMDA受体阻断可能无法改善后者。（摘要截选至400字）
