Kurosaki Rumiko, Akasaka Megumi, Michimata Mari, Matsubara Mitsunobu, Imai Yutaka, Araki Tsutomu
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Aoba-ku, Sendai 980-8578, Japan.
Neurobiol Aging. 2003 Mar-Apr;24(2):315-9. doi: 10.1016/s0197-4580(02)00085-4.
We investigated the effects of the Ca(2+) antagonist nilvadipine on the dopaminergic system and motor activity in aged mice, in comparison with an other Ca(2+) antagonist, amlodipine. Furthermore, we examined the close correlation between the dopaminergic system and motor activity during the aging process. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) contents were measured in 2-, 4-, 8-, 18- and 36-week-old mice. Behavioral tests (pole and catalepsy test) were performed with 4- and 36-week-old mice. Nilvadipine or amlodipine was administered intraperitoneally twice a day for 3 consecutive days to 30-36-week-old mice. The striatal dopamine, DOPAC and HVA contents were examined and behavioral tests were performed 1h after the last injection of each Ca(2+) antagonist. The dopamine, DOPAC and HVA contents in 2-week-old mice were significantly decreased in the striatum, as compared with 4-week-old animals. Thereafter, age-related increases in the dopamine, DOPAC and HVA contents were observed from 4 to 18 weeks old. However, in 36-week-old mice, the dopamine and DOPAC contents were reduced in the striatum, as compared with 18-week-old animals. Age-related decreases in motor function between 5- and 36-week-old mice were observed in both pole test and catalepsy tests. On the other hand, nilvalipine treatment produced a significant and dose-dependent increase in the striatal dopamine and DOPAC contents in 30-36-week-old mice. In contrast, no significant changes were observed in the striatal dopamine content in amlodipine-treated mice, although this drug showed a significant and dose-dependent increase in the striatal DOPAC and HVA content. In our behavioral study, nilvadipine also showed a significant and dose-dependent inhibition against motor deficits in 30-36-week-old mice. In contrast, amlodipine showed no significant effect on motor deficits in 30-36-week-old mice. The present study demonstrated that nilvadipine has a protective effect against the deficits in both the striatal dopaminergic system and motor activity in aged mice. Our study also suggested that the beneficial effect of nilvadipine against motor abnormalities may be mediated by a protective effect against the reduced activity of the dopaminergic system in aged mice. These results suggested that nilvadipine may offer a new approach for the treatment of hypobulia in aged humans.
我们研究了钙通道拮抗剂尼伐地平对老年小鼠多巴胺能系统和运动活性的影响，并与另一种钙通道拮抗剂氨氯地平进行比较。此外，我们还研究了衰老过程中多巴胺能系统与运动活性之间的密切关系。我们测定了2周龄、4周龄、8周龄、18周龄和36周龄小鼠纹状体中的多巴胺、3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）含量。对4周龄和36周龄小鼠进行了行为测试（爬杆试验和僵住试验）。对30 - 36周龄小鼠连续3天每天腹腔注射尼伐地平或氨氯地平两次。在最后一次注射每种钙通道拮抗剂1小时后，检测纹状体中的多巴胺、DOPAC和HVA含量，并进行行为测试。与4周龄动物相比，2周龄小鼠纹状体中的多巴胺、DOPAC和HVA含量显著降低。此后，在4至18周龄时观察到多巴胺、DOPAC和HVA含量随年龄增长而增加。然而，与18周龄动物相比，36周龄小鼠纹状体中的多巴胺和DOPAC含量降低。在爬杆试验和僵住试验中均观察到5至36周龄小鼠的运动功能随年龄增长而下降。另一方面，尼伐地平治疗使30 - 36周龄小鼠纹状体中的多巴胺和DOPAC含量显著且呈剂量依赖性增加。相比之下，氨氯地平治疗的小鼠纹状体多巴胺含量未观察到显著变化，尽管该药物使纹状体DOPAC和HVA含量显著且呈剂量依赖性增加。在我们的行为学研究中，尼伐地平对30 - 36周龄小鼠的运动缺陷也表现出显著且呈剂量依赖性的抑制作用。相比之下，氨氯地平对30 - 36周龄小鼠的运动缺陷无显著影响。本研究表明，尼伐地平对老年小鼠纹状体多巴胺能系统和运动活性的缺陷具有保护作用。我们的研究还表明，尼伐地平对运动异常的有益作用可能是通过对老年小鼠多巴胺能系统活性降低的保护作用介导的。这些结果表明，尼伐地平可能为治疗老年人的意志减退提供一种新方法。
