Phosphodiesterase-2 Inhibitor Bay 60-7550 Ameliorates Aβ-Induced Cognitive and Memory Impairment via Regulation of the HPA Axis

Abstract

The dysfunction of the hypothalamus–pituitary–adrenal (HPA) axis is often seen in Alzheimer’s disease (AD) patients with cognitive deficits. Selective inhibition of phosphodiesterase (PDE) 4 and 5 has already proven to be effective in reducing beta-amyloid 1–42 (Aβ1–42)-mediated pathology by regulating corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR) expression, suggesting that PDE-dependent signaling is involved in Aβ1–42-induced HPA axis dysfunction. However, nausea and vomiting are the side effects of some PDE4 inhibitors, which turn our attention to other PDEs. PDE2 are highly expressed in the hippocampus and cortex, which associate with learning and memory, but not in the area postrema that would cause vomiting. The present study suggested that microinjection of Aβ1–42 to the intracerebroventricle induced learning and memory impairments and dysregulation of the HPA axis by increased expression of CRF and GR. However, the PDE2 inhibitor Bay 60-7550 significantly ameliorated the learning and memory impairment in the Morris water maze (MWM) and step-down passive avoidance tests. The Aβ1–42-induced increased CRF and GR levels were also reversed by the treatment with Bay 60-7550. These Bay 60-7550’s effects were prevented by pretreatment with the PKG inhibitor KT5823. Moreover, the Bay 60-7550-induced downstream phosphorylation of cyclic AMP response element binding (pCREB) and brain-derived neurotrophic factor (BDNF) expression was also prevented (or partially prevented) by KT5823 or the PKA inhibitor H89. These results may lead to the discovery of novel strategies for the treatment of age-related cognitive disorders, such as AD, which affects approximately 44 million people worldwide.

Baicalein Ameliorates Aβ-Induced Memory Deficits and Neuronal Atrophy via Inhibition of PDE2 and PDE4

“…Our studies along with others demonstrate that the high levels of PDE2, PDE4 and its subtypes were found in Aβ-treated mice hippocampi ( Xu et al, 2015 ; Wang et al, 2017 ; Cui et al, 2019 ). Previous studies suggested that chronic treatment with PDE2 or PDE4 inhibitors may enhance memory via amelioration of neuronal remodeling in the frontal cortex and hippocampus, regions vulnerable to Aβ insults ( Zhang et al, 2018 ; Ruan et al, 2019 ). The improvement of neuroplasticity in the Aβ-treated mouse brain after baicalein treatment was significant in our present study, which may be related to inhibition of PDE2A, PDE4A, 4B and PDE4D expression in the hippocampus.…”

Roles for H+/K+‐ATPase and zinc transporter 3 in cAMP‐mediated lysosomal acidification in bafilomycin A1‐treated astrocytes

“…Hence, cAMP‐induced activation of H + /K + ‐ATPase in astrocytes may help ameliorate the accumulation and propagation of these proteins in neurodegenerative conditions. This mechanism may underlie the amyloid beta‐reducing effects of phosphodiesterase inhibitors such as cilostazol, rolipram, and BAY 60‐7550 in animal models of Alzheimer's disease (Hiramatsu, Takiguchi, Nishiyama, & Mori, 2010; Ruan et al, 2019; Xu et al, 2018). Conversely, the dysfunction of this pathway may underlie the symptom‐aggravating effects of H + /K + ‐ATPase inhibitors such as OPZ in patients with Alzheimer's disease (Ortiz‐Guerrero, Amador‐Munoz, Calderon‐Ospina, Lopez‐Fuentes, & Nava Mesa, 2018).…”

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…Bay 60-7550 is likely the most studied PDE2A inhibitor, probably due to its commercial availability. It has been reported to have anxiolytic properties and to ameliorate learning, memory, and synaptic plasticity in normal animals [64][65][66] and in neurodegeneration models [67,68]. This drug could also be used for treatment of alcoholism since it was reported to decrease ethanol intake and preference in mice [69].…”