Abstract
Objective
To characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated.
Methods
To examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice.
Results
EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 μmol/L EUK1001 directly induced long-term potentiation in the hippocampus slices.
Conclusion
We conclude that EUK1001 can improve the agerelated cognitive deficits.
摘要
目的
为了分析EUK1001-新的呫诺美林衍生物的功能性质, 本实验以老年小鼠为实验材料, 研究了该化合物的急性毒理以及对突触可塑性和识别记忆的影响。
方法
通过口服及腹腔注射途径, 对小鼠进行梯度剂量的毒理学实验, 测定EUK1001的半致死剂量(median lethal dose, LD50); 采用新奇物体识别任务和离体脑片电生理学技术研究EUK1001对老年小鼠识别记忆和海马突触可塑性的影响。
结果
EUK1001比呫诺美林呈现出更小的毒副作用。 在新奇事物识别实验中, EUK1001能够显著改善老年小鼠在识别记忆任务中的表现。 此外, 海马脑片灌流1 μmol/L的EUK1001, 能直接诱导产生长时程突触增强(long-term potentiation)。
结论
EUK1001能够改善正常老龄化过程中学习记忆能力的衰退。
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References
Tanzi RE, Bertram L. Twenty years of the Alzheimer’s disease amyloid hypothesis: a genetic perspective. Cell 2005, 120: 545–555.
Bartus RT. On neurodegenerative diseases, models, and treatment strategies: lessons learned and lessons forgotten a generation following the cholinergic hypothesis. Exp Neurol 2000, 163: 495–529.
Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS, Gracon SI. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. The tacrine study group. JAMA 1994, 271: 985–991.
Schwarz RD, Callahan MJ, Davis RE, Jaen JC, Tecle H. Development of M1 subtype selective muscarinic agonists for Alzheimer’s disease: translation of in vitro selectivity to in vivo efficacy. Drug Dev Res 1997, 40: 133–143.
Svensson AL, Warpman U, Hellström-Lindahl E, Bogdanovic N, Lannfelt L, Nordberg A. Nicotinic receptors, muscarinic receptors and choline acetyltransferase activity in the temporal cortex of Alzheimer patients with differing apolipoprotein E genotypes. Neurosci Lett 1997, 232: 37–40.
Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, et al. M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 2006, 49: 671–682.
Eglen RM, Choppin A, Watson N. Therapeutic opportunities from muscarinic receptor research. Trends Pharmacol Sci 2001, 22: 409–414.
Christopoulos A, Pierce TL, Sorman JL, El-Fakahany EE. On the unique binding and activating properties of xanomeline at the M1 muscarinic acetylcholine receptor. Mol Pharmacol 1998, 53: 1120–1130.
Christopoulos A, Parsons AM, El-Fakahany EE. Pharmacological analysis of the novel mode of interaction between xanomeline and the M1 muscarinic acetylcholine receptor. J Pharmacol Exp Ther 1999, 289: 1220–1228.
DeLapp N, Wu S, Belagaje R, Johnstone E, Little S, Shannon H, et al. Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein(FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells. Biochem Biophys Res Commun 1998, 244: 156–160.
Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, et al. Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer’s disease. Arch Neurol 1997, 54: 465–473.
William SM, Kenneth AB, Colleen D, Afif AE, Ezdihar H, Nicola H, et al. Development of CDD-0102 as a selective M1 agonist for the treatment of Alzheimer’s disease. Drug develop Res 2002, 57: 200–213.
Cao X, Cui Z, Feng R, Tang YP, Qin Z, Mei B, et al. Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 2007, 25: 1815–1822.
Bartolomeo AC, Morris H, Buccafusco JJ, Kille N, Rosenzweig-Lipson S, Husbands MG, et al. The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist. J Pharmacol Exp Ther 2000, 292: 584–596.
Sramek JJ, Sedman AJ, Reece PA, Hourani J, Bockbrader H, Cutler NR. Safety and tolerability of CI-979 in patients with Alzheimer’s disease. Life Sci 1995, 57: 503–510.
Adamus WS, Leonard JP, Tröger W. Phase I clinical trials with WAL 2014, a new muscarinic agonist for the treatment of Alzheimer’s disease. Life Sci 1995, 56: 883–890.
Cui YH, Wang D, Si W, Lv W, Niu Y, Lei XP, et al. Enhancement of memory function in aged mice by a novel derivative of xanomeline. Cell Res 2008, in press.
Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, et al. Genetic enhancement of learning and memory in mice. Nature 1999, 401: 63–69.
Burgard EC, Sarvey JM. Muscarinic receptor activation facilitates the induction of long-term potentiation (LTP) in the rat dentate gyrus. Neurosci Lett 1990, 116: 34–39.
Boddeke EW, Enz A, Shapiro G. SDZ ENS 163, a selective muscarinic M1 receptor agonist, facilitates the induction of long-term potentiation in rat hippocampal slices. Eur J Pharmacol 1992, 222: 21–25.
Sokolov MV, Kleschevnikov AM. Atropine suppresses associative potentiation in the hippocampus. Brain Res 1995, 672: 281–284.
Avery EE, Baker LD, Asthana S. Potential role of muscarinic agonists in Alzheimer’s disease. Drug Aging 1997, 11: 450–459.
Dikinson AH, Winkler J, Fisher JL, Song HJ, Poo M, Gage FH. Acetylcholine-secreting cells improve age-induced memory deficits. Mol Ther 2003, 8: 51–61.
Burke SN, Barnes CA. Neural plasticity in the ageing brain. Nat Rev Neurosci 2006, 7: 30–40.
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Cui, YH., Si, W., Yin, L. et al. A novel derivative of xanomeline improved memory function in aged mice. Neurosci. Bull. 24, 251–257 (2008). https://doi.org/10.1007/s12264-008-0204-5
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DOI: https://doi.org/10.1007/s12264-008-0204-5