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Study on the Effect of Phosphodiesterase 2A Inhibition in Cognitive Impairment

中島, 政人 筑波大学 DOI:10.15068/00160451

2020.07.22

概要

Cognitive impairment in the elderly, and in psychiatric and neurodegenerative diseases is a serious health problem worldwide, resulting in reduced quality of life, and a social and economic burden on the patients families and caregivers. There is an unmet medical need for novel therapeutic drugs that can slow down or restore cognitive impairment. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) have been suggested to regulate synaptic neurotransmission and plasticity, which are associated with multiple cognitive functions. Phosphodiesterase 2A (PDE2A), highly expressed in the forebrain, is one of the key phosphodiesterase enzymes that hydrolyses both cAMP and cGMP. Therefore, PDE2A inhibition has the potential to ameliorate cognitive impairment in diseases by modulating the neural circuit via the up-regulation of cAMP and cGMP levels in the brain. In the first chapter, to probe the potential of PDE2A inhibition as a treatment for schizophrenia, I investigated the effect of a brain penetrant and selective PDE2A inhibitor, TAK-915, in rat models of schizophrenia based on N-methyl-D-aspartate (NMDA) receptor hypofunction. Oral administration of TAK-915 ameliorated cognitive impairment and social withdrawal induced by NMDA receptor antagonists in rats. This selective PDE2A inhibitor has therapeutic potential in cognitive impairment and the negative symptoms in schizophrenia. In the second chapter, the effect of PDE2A inhibition on the cognitive functions associated with aging were evaluated. The selective PDE2A inhibitor TAK-915 ameliorated age-related cognitive deficits in rats. Based on these findings, PDE2A inhibition demonstrated a beneficial effect on multiple cognitive domains, such as spatial learning, episodic memory, and attention, and may provide a new therapeutic option in patients with cognitive impairment.

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