Electrophysiology of cerebral ischemia.

Organized brain activity requires the coordinated firing of vast numbers of nerve cells. To maintain this, all these cells must be adequately polarized, their axons capable of conducting action potentials and releasing transmitters at an even greater numbers of synapses. Hence the often dire consequences of any interruption in the normal supply of O(2) and glucose. Initially, though both cognitive and synaptic functions are soon suppressed, membrane potentials in the brain change little -- indeed, many neurons are hyperpolarized -- and all these effects are fully reversible when glucose and/or O(2) supplies are restored. The early events, suppression of synaptic and cognitive function, sharply reduce the brain's needs of energy, enabling it to maintain the minimal metabolism required for survival. Even this minimum cannot be sustained for more than a few minutes: if ischemia is prolonged, a slowly progressive depolarization (mainly caused by glutamate release) suddenly accelerates owing to the activation of several inward currents. The resulting near-total depolarization and large increase in Ca(2+) influx -- as well as Ca(2+) release from internal stores (including mitochondria) -- leads to a rapid rise in cytoplasmic [Ca(2+)]. As long as this does not reach the critical level that triggers the irreversible processes leading to cell death, restoring energy supplies reactivates the membrane pumps that re-establish normal ionic gradients and membrane potentials, and thus make possible the return of synaptic and cognitive functions, Rapid advances in knowledge suggest a wide spectrum of agents potentially capable of delaying or even preventing irreversible outcomes of brain ischemia.