Effects Of Chronic Amlodipine Ingestion On Learning And Memory

Amlodipine is a long-acting dihydropydidine calcium channel blocker that is widely used for the treatment of hypertensive patients, especially for the elderly. Amlodipine has long half-life and can keep blood drug level steady all day, which results in a long duration of action. Amlodipine has less adverse reaction. In addition, amlodipine is also used for children with diseases such as pulmonary hypertension and HRPD and so on. There's a high incidence of hypertension in China. It has been showed that there are nearly 160 million patients with hypertension in China Nutrition Survey in 2002.Accordingly amlodipine is extensively used in clinic.Learning and memory is one of the advanced functions of the brain. Learning and memory impairment, one of the early symptoms of vascular dementia, will produce a bad effect on patients's life. Amlodipine is widely used for patients of all ages, however, the effect of chronic amlodipine administration on learning and memory has not been reported. This study contains three experiments investigating the effect of chronic amlodipine treatment on learning and memory in underage mice, adult mice and VD rats from behavioral tests, pathology, cholinergic system and free radical. The results will provide a theoretical basis for the security of drug treatment in clinic.In the first experiment, underage mice were randomly divided into normal control group and AM group by weight. Groups of mice were treated with either amlodipine(0.5～0.8mg·kg^-1·d^-1) or drinking water for one and a half months. The learning and memory function were determined with Morris water maze test, step through test, step-down test and pathology. Compared with control group, latency, distance, starting angle, average speed of mice treated with amlodipine did not significantly change from the 1st day to the 4th day; in two minutes times of passing platform, time in platform, time in platform quadrant, the percentage of distance in platform/total distance, starting angle and average speed also did not significantly change on the 5th day;the strategy of searching platform did not significantly change in Morris water maze test; error times and latency of AM group did not significantly change on the 2nd day in step through test; error times of AM group did not significantly change on the 1st and 2nd day, latency did not prolong on the 2nd day in step-down test. It is showed that the cortex and hippocampus cells of AM group have no significant pathological changes compared with control group. In conclusion, chronic administration of amlodipine has no effect on learning and memory in normal underage mice.In the second experiment, adult mice were randomly divided into normal control group and AM group by weight. Groups of mice were treated with either amlodipine(0.7～1.2mg·kg^-1·d^-1) or drinking water for three months. We explored the effects of chronic amlodipine administration of adult mice by behavioral tests and detecting cholinergic system and free radical. Compared with control group, latency, distance, starting angle, average speed of AM group did not significantly change from the 1st day to the 4th day; in two minutes times of passing platform, time in platform, time in platform quadrant, the percentage of distance in platform/total distance, starting angle and average speed also did not significantly change on the 5th day; the strategy of searching platform did not significantly change in Morris water maze test; error times and latency of AM group did not significantly change on the 2nd day in step through test; error times of AM group did not significantly change on the 1st and 2nd day, latency did not prolong on the 2nd day in step-down test. Compared with control group, the content of ACh was increased(P<0.01) and the activity of AChE was also increased(P<0.05) in AM group; the content of MDA was decreased(P<0.05), but the activity of SOD, GSH-Px, Na+-K+-ATPase and Ca²⁺-Mg²⁺-ATPase did not change. We came to the conclusion that chronic amlodipine administration may has effect on learning and memory in normal adult mice.In the third experiment, blocking the bilateral common carotid arteries to establish vascular dementia rat model, and they were randomly divided into model group and AM group by weight. AM group was treated with amlodipine(0.3～0.6 mg·kg^-1·d^-1) while sham operated group and model group were treated with drinking water for 2 months. We explored the effects of chronic amlodipine administration in VD rats by ethology, pathology and detecting cholinergic system and free radical. Compared with model group, distance of AM group decreased on the 1st day(P<0.05), starting angle diminished on the 5th day(P<0.05), latency, average speed of AM group did not significantly change; in two minutes times of passing platform, time in platform, time in platform quadrant, the percentage of distance in platform/total distance, starting angle and average speed also did not significantly change on the 7th day; It speeded up that the searching strategy turned to linear type and trend type on the 3rd and 5th day(P<0.05及P<0.01) in Morris water maze test; error times and latency of AM group did not significantly change on the 2nd day in step through test. Pathology results shows that the number of cortex cells in AM group did not obviously diminish, compared with model group, pyknosis, necrosis cells deeply stained and phagocytic cells diminished; the number of hippocampal cells did not obviously diminish, regular-arranged, necrosis cells were less than the model group. Compared with model group, the content of ACh had no change and the activity of AChE goes obviously up(P<0.01) in AM group; the content of MDA did not change, the activity of SOD was increased(P<0.01), GSH-Px, Na⁺-K⁺-ATPase and Ca²⁺ -Mg²⁺ -ATPase did not change. The experiment shows that chronic amlodipine administration can improve learning and memory in VD rats. It is may be related to cholinergic system improving and the reduction of free radical damagement.