Diabetes-associated cognitive impairment is improved by a calcium channel blocker, nifedipine.
Nifedipine, a calcium channel blocker, has been reported to exert pleiotropic effects on atherosclerosis, mainly through its antioxidative properties. However, the effect of the calcium channel blocker on cognitive impairment associated with type 2 diabetes mellitus is not well known. Here, we examined the possibility that a calcium channel blocker could improve cognitive function in a type 2 diabetic mouse model, KK-A(y). KK-A(y) mice subjected to 20 trials of a passive avoidance task every week from 7 weeks of age exhibited impairment of the increase in avoidance rate and, moreover, exaggeration of its age-dependent decline, especially after 12 weeks of age. Oral administration of nifedipine at a nonhypotensive dose (0.001% in laboratory chow) to KK-A(y) mice from 10 weeks of age improved cognitive function. Nifedipine treatment decreased serum insulin level to one fifth of that in KK-A(y) mice without nifedipine. Moreover, nifedipine treatment significantly reduced superoxide anion production in the brain. Furthermore, treatment with nifedipine markedly reduced the mRNA level of Id-1, inhibitor of neural differentiation, in the brain hippocampus. We also observed the increase in blood flow in the brain in KK-A(y) mice with nifedipine treatment compared with nontreated mice. Taken together, our findings suggest that nifedipine ameliorates impaired cognitive function in type 2 diabetic mice, at least because of attenuation of hyperinsulinemia and superoxide production in the brain and possible upregulation of the neural differentiation-controlling gene, Id-1.
Tsukuda
Kana
K
Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan.
Mogi
Masaki
M
Li
Jian-Mei
JM
Iwanami
Jun
J
Min
Li-Juan
LJ
Sakata
Akiko
A
Fujita
Teppei
T
Iwai
Masaru
M
Horiuchi
Masatsugu
M
D000818:Animals; D001921:Brain / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology* / Q000523:psychology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000523:psychology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D051379:Mice; D008817:Mice, Mutant Strains; D009543:Nifedipine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013481:Superoxides / Q000037:antagonists & inhibitors; D015854:Up-Regulation
D002121:Calcium Channel Blockers; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D007328:Insulin; D012333:RNA, Messenger; D013481:Superoxides; D009543:Nifedipine