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 α_2A-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 α_2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α_2A-AR agonists that can cross the blood–brain barrier.

摘要

去甲肾上腺素 (NE) 抗癫痫作用的潜在机制尚不清楚，结果相互矛盾。我们的目标是最终描述参与减弱海马 CA3 癫痫样活动的特定肾上腺素能受体 (AR)，并评估先导药物开发的化合物。我们利用电生理记录在大鼠脑切片中产生癫痫发作的印防己毒素模型。肾上腺素 (EPI) 以浓度依赖性方式降低癫痫样爆发频率。为了确定参与该反应的特定受体，确定了一组配体的平衡解离常数，并与 α ₁、α ₂和其他受体亚型的既定结合值进行了比较。发现了 α 的相关性和单位斜率_2A -AR，但不是其他受体。确定了不同化学类别的 α-AR 激动剂通过效力 (pEC ₅₀ ) 和相对功效 (RE) 抑制癫痫样活动的影响。与 NE（pEC 50，6.20 _； RE，100%）相比，右美托咪定，一种咪唑啉（pEC 50，8.59 _； RE，67.1%）和胍那苯，一种胍（pEC 50，7.94 _； RE，37.9%），表现出最高效力 (pEC ₅₀ )。相比之下，儿茶酚胺、EPI（pEC 50，6.95 _； RE，120%）和 α-甲基-NE（pEC 50，6.38 _； RE，116%）是最有效的。这些发现证实 CA3 癫痫样活动仅由 α _2A介导-ARs 没有激活其他受体系统。这些发现表明了治疗癫痫的药物治疗靶点，并强调了对可以穿过血脑屏障的选择性和有效的 α _{2A -AR 激动剂的需求。}