Ando Mai, Yamazaki Kazuto, Takahashi Eri, Kotani Sadaharu, Patel Toshal, Bradford Andrea, Gartlon Jane, Norimine Yoshihiko, Horie Kanta
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.
EMEA Knowledge Centre, Eisai Ltd., Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, United Kingdom.
Eur J Pharmacol. 2025 Nov 5;1006:178126. doi: 10.1016/j.ejphar.2025.178126. Epub 2025 Sep 4.
Phosphodiesterase 9 (PDE9) is an enzyme that hydrolyzes cyclic guanosine monophosphate (cGMP)-a second messenger that regulates neuronal plasticity and memory function. PDE9 inhibition has been shown to enhance cognitive function in rodents, underlining the potential of PDE9 inhibitors (PDE9Is) as novel therapeutics for cognitive dysfunction. Considering the critical role of nitric oxide (NO)-cGMP signaling cascade in acetylcholine (ACh) release, the combination of PDE9Is and acetylcholinesterase inhibitors may synergistically elevate ACh levels in the brain. In this study, we investigated the combined effects of a potent and selective PDE9I-E2027 (irsenontrine)-and donepezil hydrochloride using rat cognition impairment models and human induced pluripotent stem cell (iPSC)-derived cholinergic neurons. In rat models of natural forgetting and scopolamine-induced memory impairment, co-administration of E2027 and donepezil hydrochloride at sub-efficacious doses significantly improved the novel object discrimination index compared to monotherapy with donepezil hydrochloride. Moreover, we detected a significant increase in hippocampal ACh levels in rats treated with the combination. In human iPSC-derived cholinergic neurons, E2027 increased both intracellular cGMP and extracellular ACh levels in a concentration-dependent manner. The combination of E2027 and donepezil hydrochloride synergistically elevated extracellular ACh levels in the human cholinergic neurons model. These findings suggest a potential therapeutic mechanism for E2027 and donepezil hydrochloride combination therapy for dementia.
磷酸二酯酶9（PDE9）是一种能够水解环磷酸鸟苷（cGMP）的酶，cGMP是一种调节神经元可塑性和记忆功能的第二信使。研究表明，抑制PDE9可增强啮齿动物的认知功能，这突出了PDE9抑制剂（PDE9Is）作为认知功能障碍新型治疗药物的潜力。鉴于一氧化氮（NO）-cGMP信号级联在乙酰胆碱（ACh）释放中的关键作用，PDE9Is与乙酰胆碱酯酶抑制剂联合使用可能会协同提高大脑中的ACh水平。在本研究中，我们使用大鼠认知障碍模型和人诱导多能干细胞（iPSC）衍生的胆碱能神经元，研究了强效选择性PDE9I-E2027（异司农曲林）与盐酸多奈哌齐的联合作用。在自然遗忘和东莨菪碱诱导的记忆损伤大鼠模型中，与盐酸多奈哌齐单药治疗相比，亚有效剂量的E2027与盐酸多奈哌齐联合给药显著改善了新物体辨别指数。此外，我们检测到联合治疗的大鼠海马ACh水平显著升高。在人iPSC衍生的胆碱能神经元中，E2027以浓度依赖性方式增加细胞内cGMP和细胞外ACh水平。在人胆碱能神经元模型中，E2027与盐酸多奈哌齐联合使用可协同提高细胞外ACh水平。这些发现提示了E2027与盐酸多奈哌齐联合治疗痴呆的潜在治疗机制。
