Bergado, Jorge

The activities of the enzymes glutathione reductase (GRD), glutathione peroxidase (GPX), and glutathione S-transferase (GST) were studied in several rat brain areas following the aspirative transection of the septohippocampal pathway (Fimbria fornix) and the administration of nerve growth factor (NGF) or cytochrome c. One group of animals remained untreated. This lesion resulted in a decreased hippocampal GRD and septal GST activities, as well as, in an increase in GPX activity from the frontal cortex, striatum, and septum. NGF prevented the lesion-induced changes in hippocampal GRD and septal GPX. These findings show that the insult resulting from the aspiration of the fimbria fornix bundle involves modifications in glutahione related enzymes, and therefore, in the antioxidant status of brain tissue. These changes in glutathione matabolism could be a consequence of the oxidative damage to GRD and GST proteins or represent a compensatory response of GPX to the oxidative threat. The restoring effects of NFG on altered enzyme activities are possibly linked to its known neuroprotective action.

Glutathione serves the function of providing reducing equivalents for the maintenance of oxidant homeostasis, and besides it plays roles in intra- and intercellular signaling in the brain. Our purpose was to test the effects of depleting tissue glutathione by diethylmaleate (5.3 mmol/kg, intraperitoneal) on brain antioxidant metabolism, nerve growth factor levels, and cognitive performance in rats. Six hours after the treatment, glutathione level in the hippocampus dropped down to 30% of the mean value of vehicle-treated animals and glutathione peroxidase activity also declined. Twenty-four hours after the injection the values had been partially restored. Moreover, the hippocampal and cortical levels of nerve growth factor protein did not change in response to diethylmaleate treatment. Glutathione depletion did not influence the performance of animals in the step-through passive avoidance test, but impairs acquisition in the Morris water maze when given before training. However, when diethylmaleate was administered after acquisition in the same paradigm, it did not affect the retention tested at the following day. Our results suggest that glutathione status is important during acquisition, but not for retention, of spatial memory in maze tasks and they support the hypothesis of the oxidant/antioxidant equilibrium as a key piece acting in the regulation of brain function.