E-2027

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.

The umbrella term "neurodegenerative disorders" (NDDs) refers to several conditions characterized by a progressive loss of structure and function of cells belonging to the nervous system.Such diseases affect more than 50 million people worldwide.Neurodegenerative disorders are characterized by sundry factors and pathophysiol. mechanisms that are challenging to be fully profiled.Many of these rely on cell signaling pathways to preserve homeostasis, involving second messengers such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine 3′, 5′-monophosphate (cGMP).Their ability to control the duration and amplitude of the signaling cascade is given by the presence of several common and uncommon effectors.Protein kinases A and G (PKA and PKG), phosphodiesterases (PDEs), and scaffold proteins are among them.