Batuecas A, Pereira R, Centeno C, Pulido J A, Hernández M, Bollati A, Bogónez E, Satrústegui J
Departmento de Biología, Universidad Autónoma de Madrid, Spain.
Eur J Pharmacol. 1998 Jun 5;350(2-3):141-50. doi: 10.1016/s0014-2999(98)00250-7.
The present study was designed to investigate whether chronic (from 12 to 23 months of age) dietary treatment with the L-type Ca2+ channel blocker nimodipine (30 mg/kg body weight) enhances the cognitive behavior of aged animals and whether such a treatment would have long-term effects on the mechanisms of Ca2+ regulation in synaptic terminals from the aged rat brain. Cognitive behavior was evaluated in an 8-arm radial maze in 6 test series comprising a total of 105 test sessions, with intervals of no training between series. Nimodipine-treated rats performed better than vehicle-treated, aged-matched controls in all the test series, making more correct choices every time a new series was initiated. However, differences between nimodipine- and vehicle-treated rats were most remarkable in the last three test series, when the rats were 19 to 22 months. In these series 74% of the nimodipine-treated rats were able to perform the task in 4 to 9 test sessions whereas only 12%, 14% or none of the control rats learned the task. To study Ca2+ regulation in synaptosomes derived from cerebral cortex and hippocampus, we analyzed 45Ca2+ accumulation as well as the levels of the Ca2+-binding proteins calbindin-D28K and calreticulin by Western blotting. Nimodipine administration had no effect on hippocampal synaptosomes but increased the levels of calbindin-D28K and calreticulin in cerebral cortex preparations. These results indicate that chronic nimodipine treatment from 12 to 23 months of age prevents age-induced learning deficits without showing any signs of toxicity, and that these effects are associated with a small increase in the levels of synaptosomal Ca2+-binding proteins from cerebral cortex. The up-regulation of these proteins might provide a link between the long-term effects of nimodipine on gene expression and learning ability in old rats.
本研究旨在调查，从12至23月龄开始长期使用L型钙通道阻滞剂尼莫地平（30毫克/千克体重）进行饮食治疗，是否能增强老龄动物的认知行为，以及这种治疗是否会对老龄大鼠大脑突触终末的钙调节机制产生长期影响。在8臂放射状迷宫中对认知行为进行评估，共进行6个测试系列，总计105次测试，各系列之间无训练间隔。在所有测试系列中，尼莫地平治疗组大鼠的表现均优于给予赋形剂处理的、年龄匹配的对照组，每次开始新系列测试时做出的正确选择更多。然而，尼莫地平治疗组和赋形剂处理组大鼠之间的差异在最后三个测试系列中最为显著，此时大鼠为19至22月龄。在这些系列中，74%的尼莫地平治疗组大鼠能够在4至9次测试中完成任务，而对照组大鼠中只有12%、14%或无一学会该任务。为了研究源自大脑皮层和海马体的突触体中的钙调节，我们通过蛋白质免疫印迹法分析了45Ca2+积累以及钙结合蛋白钙结合蛋白-D28K和钙网蛋白的水平。给予尼莫地平对海马突触体没有影响，但增加了大脑皮层制剂中钙结合蛋白-D28K和钙网蛋白的水平。这些结果表明，从12至23月龄开始长期使用尼莫地平治疗可预防年龄引起的学习缺陷，且未显示出任何毒性迹象，并且这些作用与大脑皮层突触体钙结合蛋白水平的小幅升高有关。这些蛋白质的上调可能为尼莫地平对老年大鼠基因表达和学习能力的长期影响之间提供了联系。
