Pharmacological characterization of the α2A-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Joseph P Biggane, Ke Xu, Brianna L Goldenstein, Kylie L Davis, Elizabeth J Luger, Bethany A Davis, Chris W D Jurgens, Dianne M Perez, James E Porter, Van A Doze
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引用次数: 1

Abstract

The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α1, α2, and other receptor subtypes. Correlation and slope of unity were found for the α2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50) and relative efficacy (RE) were determined. Compared with NE (pEC50, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50, 7.94; RE, 37.9%), exhibited the highest potency (pEC50). In contrast, the catecholamines, EPI (pEC50, 6.95; RE, 120%) and α-methyl-NE (pEC50, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A-AR agonists that can cross the blood-brain barrier.

抑制大鼠海马 CA3 癫痫样活动的 α2A-肾上腺素能受体的药理学特征:配体功效和效力的比较。
去甲肾上腺素(NE)抗癫痫作用的机制尚不清楚,结果也相互矛盾。我们的目标是最终确定参与减弱海马 CA3 癫痫样活动的特定肾上腺素能受体 (AR),并评估用于先导药物开发的化合物。我们利用电生理记录在大鼠脑片上建立了癫痫发作的微毒素模型。肾上腺素(EPI)以浓度依赖的方式降低了癫痫样爆发频率。为了确定参与这种反应的特定受体,测定了一组配体的平衡解离常数,并与α1、α2和其他受体亚型的既定结合值进行了比较。结果发现,α2A-AR 与其他受体的相关性和斜率相同。测定了不同化学类别的α-AR激动剂抑制癫痫样活动的效力(pEC50)和相对效力(RE)。与 NE(pEC50,6.20;RE,100%)相比,咪唑啉类右美托咪定(pEC50,8.59;RE,67.1%)和胍类胍(pEC50,7.94;RE,37.9%)表现出最高的效力(pEC50)。相比之下,儿茶酚胺、EPI(pEC50,6.95;RE,120%)和α-甲基-NE(pEC50,6.38;RE,116%)的效力最高。这些研究结果证实,CA3 癫痫样活动仅由α2A-ARs 介导,而没有激活其他受体系统。这些发现提出了治疗癫痫的药物治疗靶点,并强调了对可穿过血脑屏障的选择性和高效α2A-AR激动剂的需求。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Receptors and Signal Transduction
Journal of Receptors and Signal Transduction 生物-生化与分子生物学
CiteScore
6.60
自引率
0.00%
发文量
19
审稿时长
>12 weeks
期刊介绍: Journal of Receptors and Signal Tranduction is included in the following abstracting and indexing services: BIOBASE; Biochemistry and Biophysics Citation Index; Biological Abstracts; BIOSIS Full Coverage Shared; BIOSIS Previews; Biotechnology Abstracts; Current Contents/Life Sciences; Derwent Chimera; Derwent Drug File; EMBASE; EMBIOLOGY; Journal Citation Reports/ Science Edition; PubMed/MedLine; Science Citation Index; SciSearch; SCOPUS; SIIC.
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