ABSTRACT
Most models of hypoxia and ischemia are used for evaluating the metabolic consequences of cerebral insult. They have also been used for inducing cognitive disturbance. The pathological cascade after severe hypoxia or ischemia includes decreased ATP, influx of Ca2+ and Na+ with decrease in intracellular K+ leading to depolarization, release of glutamate, noradrenaline and acetylcholine, changes in neuronal plasticity, cell death, and cognitive impairment. Possible pharmacological mechanisms for protecting brain function include blockade of Ca2+ influx, inhibition of cell swelling, regulation of membrane potential, inhibition of neurotransmitter release and inhibition of excitatory amino-acid receptors. Among the existing models, many suffer from poor reproducibility and standardization. Two models which are more satisfactory in this respect are global transient ischemia in gerbils induced by bilateral carotid occlusion and focal ischemia in rats induced by occlusion of the middle cerebral artery. Although clear protective effects have been observed in both kinds of model (e.g., with NMDA antagonists, Ca2+ antagonists, PAF antagonists) it is frequently difficult to extrapolate these effects to disorders associated with memory impairment.
Subject(s)
Brain Ischemia/psychology , Hypoxia/psychology , Animals , Disease Models, Animal , HumansABSTRACT
Concerning the physiological cascade associated with cerebral vascular accidents, numerous studies have been devoted to a search for a key element (outside the initial fall in blood perfusion) responsible for the noxious jumble that leads to tissue necrosis. As a fundamental element of cell physiology, calcium intervenes in a number of vital functions, but when present in excessive amounts it may engender disorders by accelerating reactions which it normally regulates. Thus, in cerebral tissue, and notably in acute ischaemia, calcium is held responsible for additional phenomena of coagulation, exacerbated neurotransmitter discharge or even cell poisoning by paralysis of mitochondrial respiration. Based on these data, attempts have been made to treat cerebral vascular accidents by the so-called calcium antagonists. Experimentally or clinically, the results obtained, although divergent, show that acting on calcium movements contributes to total or partial correction of the complex physiopathology of cerebral ischaemia. A new generation of calcium antagonists is needed to oppose the fundamental disorders engendered, notably those of mitochondrial function.
