TAK-915, a phosphodiesterase 2A inhibitor, ameliorates the cognitive impairment associated with aging in rodent models

Abstract

Changes in the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) signaling are implicated in older people with dementia. Drugs that modulate the cAMP/cGMP levels in the brain might therefore provide new therapeutic options for the treatment of cognitive impairment in aging and elderly with dementia. Phosphodiesterase 2A (PDE2A), which is highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyze cAMP and cGMP. In this study, we investigated the effects of PDE2A inhibition on the cognitive functions associated with aging, such as spatial learning, episodic memory, and attention, in rats with a selective, brain penetrant PDE2A inhibitor, N-{(1S)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915). Repeated treatment with TAK-915 (3\u2009mg/kg/day, p.o. for 4 days) significantly reduced escape latency in aged rats in the Morris Water Maze Task compared to the vehicle treatment. In the novel object recognition task, TAK-915 (1, 3, and 10\u2009mg/kg, p.o.) dose-dependently attenuated the non-selective muscarinic antagonist scopolamine-induced memory deficits in rats. In addition, oral administration of TAK-915 at 10\u2009mg/kg significantly improved the attentional performance in middle-aged, poorly performing rats in the 5-choice Serial Reaction Time Task. These findings suggest that PDE2A inhibition in the brain has the potential to ameliorate the age-related cognitive decline.