EFECTO NEUROPROTECTOR DEL 17ALFA-ETINIL ESTRADIOL FRENTE AL DAÑO PROVOCADO POR EL ÁCIDO QUINOLÍNICO Y SU RELACIÓN CON LA CAPACIDAD DE ASOCIACIÓN DE LA RATA

Abstract

Ovarian steroids are very important in normal brain function; lost of these hormones in menopause can be justified, at least in part, cognitive decline and neurodegeneration associated with Alzheimer's disease, as has been shown that both natural and synthetic estrogens help alleviate these disorders. 17-ethinyl estradiol (EE2) is 30 to 50 folds more active than 17-estradiol (E2), it is commonly used as a component of oral contraceptives and is widely used in treatment of menopause and posmenopause symptoms. Neuroprotective action oh this hormone has been poorly explored, recently it was observed that it exerts similar effects to those produced by E2 versus neuronal damage induced by kainic acid (KA). In contrast, EE2 but not E2, exerts a partial neuroprotective effect against damage induced by quinolinic acid (QUIN). In relation to this neurotoxin, it is known that at low doses it produces a reduction in the number of cells at the hilus of hippocampus. This model of neuronal injury is widely used to quantify neuroprotective effects of various substances, including the steroid hormone used in this work. The head aim of this work was investigate underlying mechanisms of action by histological and biochemical techniques of EE2 to exert neuroprotection against injury caused by QUIN at hippocampus, as well as to explore effects of this hormone on rats abilities on two tasks of association: the trial of self-learning and elevated T maze. We used Wistar rats previously ovariectomized. It has been done a curved of EE2 dose response to damage induced by QUIN. To determine if this supposed neuroprotective effect is carried out through a genomic pathway, it is use an antagonist estrogen receptor, in which EE2 links. Hormone was simultaneously administered (i.p.) with QUIN (i.c.v.), and estrogen receptors antagonist (ICI 182,780) was given one hour and a half before the other treatments. 48 hours later animals were sacrificed and right hippocampal formation was dissected out, these were fixed to set histological study and neuronal quantification. To determine if neuroprotective effect is carried out by an antioxidant pathway, animals were sacrificed by decapitation 2 hours after treatment and both hippocampal formation were dissected out, which were kept at - 70 ° C until analysis. Finally, association ability of rats was evaluated using a self-learning associative test and elevated T maze model (LET) which evaluates a "passive avoidance" learning. Obtained data from EE2 curve dose-response to damage caused by QUIN show that only low-dose of this hormone exerts effective neuroprotective effect against neuronal loss induced by this toxin. Due to this finding, dose used for the other experiments was 4 g/Kg. There is an increase in LP after treatment with QUIN which indicating an excitotoxic damage of this neurotoxin, this effect is blocked after administration of e.e.2. Decrease in GSH concentration after administration of QUIN is due to link of this neurotoxin with their receptors, which facility Ca2+ entry into the cell by inducing a decrease in GSH synthesis, on the other hand concentration decline observed in GSSG concentration indicates that GSH carries out its role as part of the antioxidant system in cells. As a marker of REDOX environmental in this case GSH2/GSSG ratio indicates that EE2 blocked QUIN effect as oxidizing environment increase. There is an increase in LP after QUIN treatment and there is a decrease in GSSG, effects that are blocked with EE2 administration. In self-learning trial (Skinner box) there were no significant differences between groups. For this reason it can be inferred that dose of 100 nM/L of QUIN does not affect the association ability of rats. In the same line, this neurotoxin induces a significant neuronal loss and administration of EE2 does not prevent this effect. In elevated T maze values of risk index eliminated the possibility that which it was seeing can be an anxiolytic effect and not a learning process. Data of this test shows that group treated with QUIN acquired before the passive avoidance criterion to group treated only with vehicles, similar to the group treated with EE2, but in latency there is a significant difference between groups, therefore there is no consolidation on this learning criterion.