A novel selective phosphodiesterase 9 inhibitor, irsenontrine (E2027), enhances GluA1 phosphorylation in neurons and improves learning and memory via cyclic GMP elevation

Phosphodiesterase 9 (PDE9) plays a critical role in synaptic plasticity and cognitive function by modulating cyclic GMP (cGMP). Many reports have shown that PDE9 inhibition improves cognitive function and synaptic plasticity in rodents. Several studies have found that the NO/cGMP/PKG pathway is downregulated in patients with Alzheimer's disease (AD) or dementia with Lewy bodies (DLB) and in older individuals. A PDE9 inhibitor could therefore be a potential therapeutic approach for improving cognitive dysfunction in dementia, including in AD and DLB. We previously discovered a novel PDE9 inhibitor, irsenontrine (E2027). In the current study, irsenontrine showed highly selective affinity for PDE9 with more than 1800-fold selectivity over other PDEs. Irsenontrine maleate significantly increased intracellular cGMP levels in rat cortical primary neurons, and phosphorylation of AMPA receptor subunit GluA1 was induced following cGMP elevation. Oral administration of irsenontrine significantly upregulated cGMP levels in the hippocampus and cerebrospinal fluid (CSF) of naïve rats, and a novel object recognition test showed that irsenontrine administration also significantly improved learning and memory. The effects of irsenontrine were confirmed in rats treated with Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME), a model of learning and memory impairment due to downregulation of the cGMP pathway. l-NAME downregulated cGMP in the CSF and hippocampus and impaired novel object recognition, but oral administration of irsenontrine clearly attenuated these phenotypes. These results indicate that irsenontrine improves learning and memory via the elevation of cGMP levels, and they strongly suggest that irsenontrine could be a novel therapeutic approach against cognitive dysfunction.