Department of Behavioral Neuroscience and Drug Development, Maj Institute of Pharmacology Polish Academy of Sciences, 12 Smetna Street, 31-343, Krakow, Poland.
Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, USA.
Pharmacol Rep. 2020 Jun;72(3):589-599. doi: 10.1007/s43440-020-00092-4. Epub 2020 Mar 23.
The α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) may represent useful targets for cognitive improvement. It has been recently proposed that a strategy based on positive allosteric modulation of α4β2-nAChRs reveals several advantages over the direct agonist approach. Nevertheless, the procognitive effects of α4β2-nAChR positive allosteric modulators (PAMs) have not been extensively characterized.
The aim of the present study was to evaluate the procognitive efficacy of desformylflustrabromine (dFBr), a selective α4β2-nAChR PAM.
Cognitive effects were investigated in the novel object recognition task (NORT) and the attentional set-shifting task (ASST) in rats.
The results demonstrate that dFBr attenuated the delay-induced impairment in NORT performance and facilitated cognitive flexibility in the ASST. The beneficial effects of dFBr were inhibited by dihydro-β-erythroidine, a relatively selective α4β2-nAChR antagonist, indicating the involvement of α4β2-nAChRs in cognitive processes. The tested α4β2-PAM was also effective against ketamine- and scopolamine-induced deficits of object recognition memory. Moreover, procognitive effects were also observed after combined treatment with inactive doses of dFBr and TC-2403, a selective α4β2-nAChR agonist.
These findings indicate that dFBr presents procognitive activity, supporting the strategy based on α4β2-nAChR potentiation as a plausible therapy for cognitive impairment.
α4β2 烟碱型乙酰胆碱受体（α4β2-nAChRs）可能是改善认知的有价值的靶点。最近有人提出，基于对 α4β2-nAChRs 的正变构调节的策略，与直接激动剂方法相比具有若干优势。然而，α4β2-nAChR 正变构调节剂（PAMs）的促认知作用尚未得到广泛的研究。
本研究旨在评估选择性 α4β2-nAChR PAM 去甲(formyl)氟烷溴（dFBr）的促认知功效。
在大鼠的新物体识别任务（NORT）和注意定势转换任务（ASST）中研究了认知效应。
结果表明，dFBr 可减轻 NORT 表现中的延迟诱导损伤，并促进 ASST 中的认知灵活性。dFBr 的有益作用被二氢-β-erythroidine 抑制，二氢-β-erythroidine 是一种相对选择性的 α4β2-nAChR 拮抗剂，表明 α4β2-nAChRs 参与了认知过程。所测试的 α4β2-PAM 对氯胺酮和东莨菪碱诱导的物体识别记忆缺陷也有效。此外，在与 dFBr 和 TC-2403（一种选择性的 α4β2-nAChR 激动剂）的无效剂量联合治疗后，也观察到了促认知作用。
这些发现表明，dFBr 具有促认知活性，支持基于 α4β2-nAChR 增强的策略作为治疗认知障碍的一种可行方法。
