Regulation of M1-receptor mRNA stability by smilagenin and its significance in improving memory of aged rats.
The purpose of this work is to study the effect of smilagenin on the mRNA stability of muscarinic receptor subtype 1 (M(1); m1 mRNA) in aged rat brains and its significance in improving memory. The Y-maze avoidance task showed that oral administration of smilagenin significantly improved spatial memory performance in aged rats. Mechanistic studies showed that smilagenin was neither a ligand of the M receptors nor a cholinesterase inhibitor, while radioligand binding assays revealed that smilagenin significantly increased the M(1)-receptor density. The increase of M(1)-receptor density correlated with memory improvement. Real-time polymerase chain reaction (RT-PCR) revealed that the m1 mRNA in m1 gene-transfected CHO cells increased significantly, and the average half-life of m1 mRNA was approximately doubled by smilagenin treatment. These results suggest that smilagenin improves memory of aged rats at least partially by increasing the stability of m1 mRNA. However since the ChAT activity in the cortex of aged rats was also elevated by smilagenin, it cannot be excluded that the increase of intrinsic acetylcholine excretion also plays a role in the memory-improvement effect of smilagenin.
Hu
Yaer
Y
Research Laboratory of Cell Regulation, Shanghai Jiaotong University Medical School, Shanghai, China.
Wang
Zimei
Z
Zhang
Rui
R
Wu
Pingping
P
Xia
Zongqin
Z
Orsi
Antonia
A
Rees
Daryl
D
D015100:3,3'-Diaminobenzidine / Q000493:pharmacokinetics; D000375:Aging; D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy* / Q000473:pathology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000235:genetics* / Q000378:metabolism; D013150:Spirostans / Q000627:therapeutic use*; D013619:Tacrine / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000493:pharmacokinetics
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D013150:Spirostans; D014316:Tritium; D015100:3,3'-Diaminobenzidine; D013619:Tacrine; D001285:Atropine; C046297:sarsasapogenin; D002802:Cholinesterases