Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Epigen Biosciences, Inc., San Diego, California, USA.
Br J Pharmacol. 2021 Apr;178(7):1684-1704. doi: 10.1111/bph.15392. Epub 2021 Feb 23.
Targeting α7 nicotinic ACh receptors (nAChRs) in neuroinflammatory disorders including acute ischaemic stroke holds significant therapeutic promise. However, therapeutically relevant signalling mechanisms remain unidentified. Activation of neuronal α7 nAChRs triggers ionotropic signalling, but there is limited evidence for it in immunoglial tissues. The α7 ligands which are effective in reducing acute ischaemic stroke damage promote α7 ionotropic activity, suggesting a link between their therapeutic effects for treating acute ischaemic stroke and activation of α7 conductive states.
This hypothesis was tested using a transient middle cerebral artery occlusion (MCAO) model of acute ischaemic stroke, NS6740, a known selective non-ionotropic agonist of α7 nAChRs and 4OH-GTS-21, a partial α7 agonist. NS6740-like ligands exhibiting low efficacy/potency for ionotropic activity will be referred to as non-ionotropic agonists or "metagonists".
4OH-GTS-21, used as a positive control, significantly reduced neurological deficits and brain injury after MCAO as compared to vehicle and NS6740. By contrast, NS6740 was ineffective in identical assays and reversed the effects of 4OH-GTS-21 when these compounds were co-applied. Electrophysiological recordings from acute hippocampal slices obtained from NS6740-injected animals demonstrated its remarkable brain availability and protracted effects on α7 nAChRs as evidenced by sustained (>8 h) alterations in α7 ionotropic responsiveness.
These results suggest that α7 ionotropic activity may be obligatory for therapeutic efficacy of α7 ligands after acute ischaemic stroke yet, highlight the potential for selective application of α7 ligands to disease states based on their mode of receptor activation.
针对神经炎症性疾病（包括急性缺血性中风）中的α7 烟碱型乙酰胆碱受体（nAChR）进行靶向治疗具有重要的治疗前景。然而，相关的治疗信号机制仍未被确定。神经元α7 nAChR 的激活会触发离子型信号，但在免疫胶质组织中，这种信号的证据有限。在减少急性缺血性中风损伤方面有效的α7 配体可促进α7 离子型活性，这表明其治疗急性缺血性中风的疗效与其激活α7 传导状态之间存在联系。
本研究采用短暂性大脑中动脉闭塞（MCAO）急性缺血性中风模型来检验这一假说，使用了 NS6740（一种已知的选择性非离子型α7 nAChR 激动剂）和 4OH-GTS-21（一种部分α7 激动剂）。对离子型活性效力/效能较低的 NS6740 样配体将被称为非离子型激动剂或“变构激动剂”。
4OH-GTS-21 作为阳性对照，与载体和 NS6740 相比，可显著减少 MCAO 后的神经功能缺损和脑损伤。相比之下，NS6740 在相同的检测中无效，并且当这两种化合物共同应用时，会逆转 4OH-GTS-21 的作用。从 NS6740 注射动物的急性海马切片中进行的电生理记录表明，其具有显著的脑可用性和对α7 nAChR 的持久作用，表现为α7 离子型反应性的持续（>8 h）改变。
这些结果表明，α7 离子型活性可能是急性缺血性中风后α7 配体治疗疗效所必需的，但同时也强调了基于受体激活模式，选择性应用α7 配体治疗疾病的潜力。
