کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8516246 | 1556574 | 2018 | 16 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo
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کلمات کلیدی
NMDATTXHEK293THACTZAMPACAS2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acidFJBPPIIC50N-methyl-d-aspartateFDAFBSNMDARsDCKAFluoro-Jade B5,7-dichlorokynurenic acid - 5،7-dichlorokynurenic اسیدD(−)-2-amino-5-phosphonopentanoic acid - D (-) - 2-amino-5-phosphonopentanoic acidd-AP5 - D-AP5EPSC - EPSCoRCGC - GTCUS Food and Drug Administration - اداره غذا و داروی ایالات متحدهElectrophysiology - الکتروفیزیولوژیAlzheimer's disease - بیماری آلزایمرtetrodotoxin - تترو دوتوکسین analysis of variance - تحلیل واریانسANOVA - تحلیل واریانس Analysis of varianceexcitatory postsynaptic current - جریان پستیینپتیک تحریک کنندهstandard error of the mean - خطای استاندارد میانگینMembrane domain - دامنه غشاءCNS - دستگاه عصبی مرکزیfoetal bovine serum - سرم جنین گاوCerebellar granule cell - سلول گرانول Cerebellarcentral nervous system - سیستم عصبی مرکزیcyclothiazide - سیکلوتیازیدPharmacology - فارماکولوژی یا داروشناسیdgl - مانندSEM - مدل معادلات ساختاری / میکروسکوپ الکترونی روبشیpre-pulse inhibition - مهار پیش از پالسthe half maximal inhibitory concentration - نیمه حداکثر غلظت مهاریPostnatal - پس از زایمانIon channel - کانال یونیN-Methyl-d-aspartate receptors - گیرنده های N-methyl-d-aspartateGlutamate receptor - گیرنده گلومات
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب رفتاری
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چکیده انگلیسی
N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors that mediate excitatory neurotransmission in the mammalian central nervous system (CNS), and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials (including memantine) and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine (tacrine; THA) was the first approved drug for Alzheimer's disease (AD) treatment. 7-methoxyderivative of THA (7-MEOTA) is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293â¯cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are “foot-in-the-door” open-channel blockers of GluN1/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GluN2Aâ¯<â¯GluN1/GluN2Bâ¯<â¯GluN1/GluN2Câ¯=â¯GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluN1/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a “foot-in-the-door” open-channel blocker of GluN1/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDARs was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuropharmacology - Volume 140, 15 September 2018, Pages 217-232
Journal: Neuropharmacology - Volume 140, 15 September 2018, Pages 217-232
نویسندگان
Martina Kaniakova, Lenka Kleteckova, Katarina Lichnerova, Kristina Holubova, Kristyna Skrenkova, Miloslav Korinek, Jan Krusek, Tereza Smejkalova, Jan Korabecny, Karel Vales, Ondrej Soukup, Martin Horak,