engleski

Ifenprodil antagonizes amnestic effect of hypoxia in rats

Hypoxia is one of the most dangerous conditions that can damage the structural and functional integrity of cerebral tissue. It has generally been accepted that increase in intracellular Ca2+ concentration is one of the major determinants of hypoxic brain damage. The mechanisms through which Ca2+ acts to produce its devastating effects in hypoxic conditions are not completely understood. ln brief, it is proposed that under anaerobic conditions, a decline in ATP causes an interruption of Na+/K+ pump leading to prolonged membrane depolarisation. Depolarisation of the presynaptic bottom causes an influx of Ca2+ through voltage dependent calcium channels in the presynaptic terminal. The subsequent increase of presynaptic Ca2+ leads to release of glutamate, which binds to two subtypes of ionotropic postsynaptic receptors, the NMDA and kainate- quisqualate receptors. Postsynaptic depolarisation coupled with binding of glutamate relieves the Mg2+ block of the NMDA receptors associated channels and excessive entry of Ca2+ occurs. Cerebral hypoxia accompanies various clinical situations that are manifested with impairment of cognitive processes, especially memory functions. The pharmacological treatment of cognitive disturbances caused by hypoxia is still uneffective. According to the described pathophysiological events occurring in cerebral hypoxia, we hypothesized that disturbances in Ca2+ homeostasis might contribute to the memory deficits associated with cerebral hypoxia and that the pharmacological inhibition of the Ca2+ entry into the neuronal cells could antagonize cognitive deficits. This study was designed to examine the influence of various doses of the NMDA channel blocker, ifenprodil, on the retention of passive avoidance in normoxic and hypoxic conditions in rats. The study was carried out on Hannover-Wistar rats weighing 250 g. Various doses (0.03 ; 0.1 ; 0.3 or 1.0 mg/kg) of ifenprodil were administrated intraperitoneally. Thirty minutes later the passive avoidance task was performed according to the step-through procedure. Immediately after the training trial the animals were subjected to the period of oxygen deprivation hypoxia. Rats were placed into hypoxia cage and the percentage of oxygen was gradually reduced and continuously measured. The level of 3.5 V% of oxygen was reached in about twenty minutes and maintained up to the loss of righting reflex. Twenty four hours later passive avoidance retention was tested. It has been found that ifenprodil successfully antagonized the memory deficit in hypoxia exposed rats. Namely, all tested doses of mentioned drug led to a significant enhancement of the passive avoidance behavior. The results of our experiments indicate that ifenprodil possess a protective action against the impairment of passive avoidance retention caused by hypoxia in rats. Our findings indirectly confirm the hypothesis that memory decline in hypoxic conditions is associated with disturbances in Ca2+ homeostasis.

ifenprodil; hypoxia; passive avoidance; Ca2+ homeostasis; rat

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