Phosphodiesterase 2A Inhibitor TAK-915 Ameliorates Cognitive Impairments and Social Withdrawal in N-Methyl-d-Aspartate Receptor Antagonist–Induced Rat Models of Schizophrenia

Abstract

The pathophysiology of schizophrenia has been associated with glutamatergic dysfunction. Modulation of the glutamatergic signaling pathway, including -methyl-d-aspartate (NMDA) receptors, can provide a new therapeutic target for schizophrenia. Phosphodiesterase 2A (PDE2A) is highly expressed in the forebrain, and is a dual substrate enzyme that hydrolyzes both cAMP and cGMP, which play pivotal roles as intracellular second messengers downstream of NMDA receptors. Here we characterize the in vivo pharmacological profile of a selective and brain-penetrant PDE2A inhibitor, (-{(1)-1-[3-fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-]pyrazine-4(1)-carboxamide) (TAK-915) as a novel treatment of schizophrenia. Oral administration of TAK-915 at 3 and 10 mg/kg significantly increased cGMP levels in the frontal cortex, hippocampus, and striatum of rats. TAK-915 at 10 mg/kg significantly upregulated the phosphorylation of -amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor subunit GluR1 in the rat hippocampus. TAK-915 at 3 and 10 mg/kg significantly attenuated episodic memory deficits induced by the NMDA receptor antagonist (+)-MK-801 hydrogen maleate (MK-801) in the rat passive avoidance test. TAK-915 at 10 mg/kg significantly attenuated working memory deficits induced by MK-801 in the rat radial arm maze test. Additionally, TAK-915 at 10 mg/kg prevented subchronic phencyclidine-induced social withdrawal in social interaction in rats. In contrast, TAK-915 did not produce antipsychotic-like activity; TAK-915 had little effect on MK-801- or methamphetamine-induced hyperlocomotion in rats. These results suggest that TAK-915 has a potential to ameliorate cognitive impairments and social withdrawal in schizophrenia.

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…Hcyb1 produces neuroprotective and antidepressant‐like effects in mice [ 60 ]. TAK-915 shows efficacy in ameliorating cognitive and social impairment in induced rat models of SCZ [ 61 ] and it improves cognitive impairment associated with aging in mice [ 62 ]. To date, one phase I clinical trial has been reported for this compound (Supplementary Table V ).…”

Target Engagement of a Phosphodiesterase 2A Inhibitor Affecting Long-Term Memory in the Rat

“…PDE2A is highly expressed in brain regions that are important for cognitive functions, including the cerebral cortex, hippocampus, and striatum (Stephenson et al, 2012;Kelly et al, 2014). In in vitro and in vivo animal studies, PDE2A-selective inhibitors enhanced long-term potentiation and improved the performance of multiple memory tasks (Boess et al, 2004;Domek-Łopaci nska and Strosznajder, 2008;Helal et al, 2018;Nakashima et al, 2018).…”

Role of Prefrontal Cortex Anti- and Pro-inflammatory Cytokines in the Development of Abnormal Behaviors Induced by Disconnection of the Ventral Hippocampus in Neonate Rats

“…In vitro and in vivo studies provide evidence towards the role of TGF-β1 regulating synaptogenesis in cortical and thalamic neurons (Diniz et al, 2012 ; Bialas and Stevens, 2013 ). TGF-β signaling pathway plays a critical role in neuron specification and its disruption has been identified as one of the factors contributing to neurodevelopmental disorders such as schizophrenia (Yi et al, 2010 ; Nakashima et al, 2018 ). Apart from its role in synaptic growth, TGF-β signaling has been suggested to maintain synaptic homeostasis.…”