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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Cardiovascular Biology Research Group,Department of Pharmacology,Yong Loo Lin School of Medicine,Singapore,Singapore; and Department of Pharmacy,Faculty of Science,National University of Singapore,Singapore,Singapore
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Cardiovascular Biology Research Group,Department of Pharmacology,Yong Loo Lin School of Medicine,Singapore,Singapore; and Department of Pharmacy,Faculty of Science,National University of Singapore,Singapore,Singapore

机译：新加坡永Lo林医学院药理学系心血管生物学研究组，新加坡;新加坡国立大学理学院药理学系，新加坡

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This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) ga-lantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors,cholinergic proteins,and cognitive function in the aged rat,and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors.Behavioral tests (i.e.,water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day).Forty-eight hours after the last drug injection,cholinergic receptors were measured by [~(125)I]-(+-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([~(125)I]IPH; epibatidine analog),~(125)I-alpha-bungarotoxin (~(125)I-BTX),[~3H]pirenzepine ([~3H]PRZ),and [~3H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([~3H]AFDX-384,or [~3H]AFX) autoradiography.Immunochemical methods were used to measure NGF,high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors,choline acetyltransferase (ChAT),and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions.Depending on dose,both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [~(125)I]IPH,[~3H]PRZ,and [~3H]AFX (but decreased ~(125)I-BTX) binding in some cortical and hippocampal brain regions.Neither AChEI was associated with marked changes in NGF,NGF receptors,or VAChT,although DON did moderately increase ChAT in the basal forebrain and hippocampus.The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.
机译：本研究旨在确定1）反复暴露于乙酰胆碱酯酶抑制剂（AChEI）加兰他敏（GAL）或多奈哌齐（DON）是否对神经生长因子（NGF）及其受体，胆碱能蛋白和认知功能产生积极影响2）由于GAL对烟碱型乙酰胆碱受体具有变构增强配体（APL）活性，因此GAL是否比DON具有任何优势。在衰老的Fisher 344大鼠中进行了行为试验（即水迷宫和明/暗盒）反复（皮下）暴露于GAL（3.0或6.0 mg / kg /天）或DON（0.375或0.75 mg / kg /天）的15天。在最后一次注射药物后48小时，通过[ 〜（125）I]-（+-）-exo-2-（2-碘-5-吡啶基）-7-氮杂双环[2.2.1]庚烷（[〜（125）I] IPH; Epibatidine类似物），〜 （125）I-α-真菌毒素（〜（125）I-BTX），[〜3H]哌仑西平（[〜3H] PRZ）和[〜3H] -5,11-dihydro-11-[（（2- （2-（（（二丙基氨基）甲基）-1-哌啶基）乙基）氨基）羰基] -6H-py rido（2,3-b）（1,4）-benzodiazepin-6-甲磺酸盐（[〜3H] AFDX-384，或[〜3H] AFX）放射自显影。采用免疫化学方法测量NGF，高（TrkA和（-TrkA）和低（p75神经营养因子受体）亲和NGF受体，胆碱乙酰转移酶（ChAT）和水泡乙酰胆碱转运蛋白（VAChT）在与记忆有关的大脑区域。取决于剂量，GAL和DON均可增强空间学习能力（而不影响焦虑程度）并在某些皮质和海马脑区中增加[〜（125）I] IPH，[〜3H] PRZ和[〜3H] AFX的结合（但降低〜（125）I-BTX）的结合。尽管DON确实适度增加了基础前脑和海马区的ChAT，但与NGF，NGF受体或VAChT的显着变化有关。衰老的哺乳动物的大脑，但GAL的APL活性可能无法提供比乙酰胆碱酯酶抑制作用更大的优势独自一人。

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