Effects of steroid hormones on (Na +, K +)-ATPase activity inhibition-induced amnesia on the step-through passive avoidance task in gonadectomized mice

Abstract

Inhibition of sodium-potassium adenosine 5′-triphosphatase ((Na +, K +)-ATPase) activity causes edema and cell death in the central nervous system, and impairment of learning and memory. Several sex steroid hormones have a protective effect against neuronal cell damage and the hypofunction of learning and memory. To examine the possible roles and mechanism of action of steroid hormones against amnesia induced by ouabain, an inhibitor of (Na +, K +)-ATPase, gonadectomized male mice were administrated ouabain (0.1 μg per mouse) intracisternally (i.cist.), and the learning and memory abilities of the mice were assessed by a step-through passive avoidance task. Subcutaneous (s.c.) administration of 17β-estradiol (βE2; 10 μg kg −1) or testosterone (TES; 1 mg kg −1) improved the memory impairment induced by ouabain, while administration of dihydrotestosterone (1 mg kg −1) or corticosterone (COR) (1 mg kg −1) did not. Treatment with the estradiol receptor antagonists, tamoxifen (TAM) (10 mg kg −1; s.c. or 0.1 μg; i.cist.) and 4-hydroxytamoxifen (10 mg kg −1; s.c.), or the androgen receptor antagonist, cyproterone (10 mg kg −1; s.c. or 1 μg; i.cist.), did not influence the protective effect of βE2 or TES on ouabain-induced amnesia. Moreover, we studied the effects of several free radical scavengers—17α-estradiol (10 μg kg −1; s.c.), α-tocopherol (VE: 200 mg kg −1; per os (p.o.), ascorbic acid (VC: 200 mg kg −1; p.o.), or VE+VC (200 mg kg −1 each; p.o.)—on ouabain-induced amnesia, and compared those effects with that of βE2. The administration of free radical scavengers had no significant effect on memory impairment. These results indicate that βE2 and TES ameliorate the amnesia induced by inhibition of (Na +, K +)-ATPase activity, and that the protective effect of βE2 is caused by a non-genomic, rather than a genomic effect or a radical scavenging action. Additionally, the ameliorative effect of TES does not appear to involve free radical scavenging, but its aromatization to estrogen could contribute to the non-genomic action of βE2.