Reddy D S, Kulkarni S K
Department of Pharmacology, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India.
Brain Res. 1998 Jul 20;799(2):215-29. doi: 10.1016/s0006-8993(98)00419-3.
The ability of the nitric oxide (NO) synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), to modulate the attenuating effects of neurosteroids on the aging- and NMDA receptor antagonist dizocilpine-induced learning impairment, was tested in mice using two different behavioral models of long-term memory. The performance of aged mice (16 months old) in step-down type of passive-avoidance and elevated plus-maze paradigms was significantly impaired compared to that of young mice (3 months old). Neurosteroids pregnenolone sulfate (PS) and dehydroepiandrosterone sulfate (DHEAS), at 1-20 mg/kg, s.c., significantly improved the passive-avoidance and plus-maze performances in aged mice. Neurosteroids PS and DHEAS, at doses 1-20 mg/kg, s.c., significantly attenuated dizocilpine (0.1 mg/kg, i.p.)-induced amnesia, without producing any promnestic effects alone in adult mice. In both cognitive tasks, the effects exhibited by the neurosteroids tested had a bell-shaped curve. Preadministration of L-NAME (10 and 20 mg/kg, i.p.), at doses that did not disrupt cognition alone in either young or aged mice, significantly blocked the beneficial and antiamnesic effects of neurosteroids PS (5 mg/kg) and DHEAS (10 mg/kg). A selective action of L-NAME on the effects of neurosteroids was indicated, since the effects of L-NAME were completely reversed by L-arginine (300 mg/kg, i.p.), a competitive substrate for NO synthase. Neither L-NAME nor L-arginine alone affected the antinociception, locomotor activity or rota-rod performance of young or aged mice. These observations suggest that a NO-dependent mechanism may be involved in the beneficial and antiamnesic effects of neurosteroids PS and DHEAS on the aging- and dizocilpine-induced impairment of learning and memory processes.
使用两种不同的长期记忆行为模型，在小鼠中测试了一氧化氮（NO）合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）调节神经甾体对衰老和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂地佐环平诱导的学习障碍的减轻作用的能力。与年轻小鼠（3个月大）相比，老年小鼠（16个月大）在阶梯式被动回避和高架十字迷宫范式中的表现明显受损。神经甾体硫酸孕烯醇酮（PS）和硫酸脱氢表雄酮（DHEAS），皮下注射剂量为1-20mg/kg，可显著改善老年小鼠的被动回避和十字迷宫表现。神经甾体PS和DHEAS，皮下注射剂量为1-20mg/kg，可显著减轻地佐环平（0.1mg/kg，腹腔注射）诱导的失忆，在成年小鼠中单独使用时不会产生任何促记忆作用。在这两种认知任务中，所测试的神经甾体的作用呈现钟形曲线。预先给予L-NAME（10和20mg/kg，腹腔注射），该剂量在年轻或老年小鼠中单独使用时均不会破坏认知，可显著阻断神经甾体PS（5mg/kg）和DHEAS（10mg/kg）的有益和抗失忆作用。表明L-NAME对神经甾体的作用具有选择性，因为L-NAME的作用可被L-精氨酸（300mg/kg，腹腔注射）完全逆转，L-精氨酸是NO合酶的竞争性底物。单独使用L-NAME或L-精氨酸均不影响年轻或老年小鼠的抗伤害感受、运动活动或转棒性能。这些观察结果表明，NO依赖性机制可能参与了神经甾体PS和DHEAS对衰老和地佐环平诱导的学习和记忆过程损伤的有益和抗失忆作用。
