Cellular physiology of hypoxia of the mammalian central nervous system

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)