Sato Tomoaki, Tanaka Koh ichi, Ohnishi Yoshiko, Teramoto Toyonori, Irifune Masahiro, Nishikawa Takashige
Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Sakuragaoka, Kagoshima 890-8544, Japan.
Pharmacol Res. 2004 Feb;49(2):151-9. doi: 10.1016/j.phrs.2003.09.006.
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 microg 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 17beta-estradiol (betaE2; 10 microg 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 microg; 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 microg; i.cist.), did not influence the protective effect of betaE2 or TES on ouabain-induced amnesia. Moreover, we studied the effects of several free radical scavengers-17alpha-estradiol (10 microg kg(-1); s.c.), alpha-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 betaE2. The administration of free radical scavengers had no significant effect on memory impairment. These results indicate that betaE2 and TES ameliorate the amnesia induced by inhibition of (Na(+), K(+))-ATPase activity, and that the protective effect of betaE2 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 betaE2.
抑制钠钾腺苷三磷酸酶（（Na⁺，K⁺）-ATP酶）活性会导致中枢神经系统水肿和细胞死亡，以及学习和记忆受损。几种性类固醇激素对神经元细胞损伤和学习记忆功能减退具有保护作用。为了研究类固醇激素对哇巴因（一种（Na⁺，K⁺）-ATP酶抑制剂）诱导的失忆可能的作用及其作用机制，对去性腺雄性小鼠脑池内注射哇巴因（每只小鼠0.1微克），并通过穿梭箱被动回避任务评估小鼠的学习和记忆能力。皮下注射17β-雌二醇（βE2；10微克/千克）或睾酮（TES；1毫克/千克）可改善哇巴因诱导的记忆损伤，而注射二氢睾酮（1毫克/千克）或皮质酮（COR）（1毫克/千克）则没有这种作用。用雌二醇受体拮抗剂他莫昔芬（TAM）（10毫克/千克；皮下注射或0.1微克；脑池内注射）和4-羟基他莫昔芬（10毫克/千克；皮下注射），或雄激素受体拮抗剂环丙孕酮（10毫克/千克；皮下注射或1微克；脑池内注射）处理，并不影响βE2或TES对哇巴因诱导失忆的保护作用。此外，我们研究了几种自由基清除剂——17α-雌二醇（10微克/千克；皮下注射）、α-生育酚（维生素E：200毫克/千克；口服）、抗坏血酸（维生素C：200毫克/千克；口服）或维生素E + 维生素C（各200毫克/千克；口服）——对哇巴因诱导失忆的影响，并将这些影响与βE2的影响进行比较。自由基清除剂的给药对记忆损伤没有显著影响。这些结果表明，βE2和TES可改善由抑制（Na⁺，K⁺）-ATP酶活性诱导的失忆，且βE2的保护作用是由非基因组效应引起的，而非基因组效应或自由基清除作用。此外，TES的改善作用似乎不涉及自由基清除，但其向雌激素的芳香化可能有助于βE2的非基因组作用。
