E2027 (irsenontrine), a phosphodiesterase 9 inhibitor, enhances cholinergic function when combined with donepezil hydrochloride

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.