A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway

Abstract

A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders.

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

“…SIRT1 is a histone deacetylase that transfers acetyl groups from ε-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription [14,15,55,86,87,144,[180][181][182][183][184][185]. SIRT1 is involved in neurodegenerative disorders [162,184,186,187] that require the modulation of autophagy [120,[188][189][190][191][192].…”

“…It is interesting to note that SIRT1 also has an inverse relationship with mTOR [14, 189,[210][211][212][213]. As previously mentioned, SIRT1 also can significantly affect pathways of autophagy [58,69,161,[189][190][191]206,[214][215][216]. SIRT1 activity can result in neurite outgrowth and increased neuronal survival during nutrient limiting conditions with the inhibition of mTOR [217].…”

Phosphodiesterase-4D Knockdown in the Prefrontal Cortex Alleviates Memory Deficits and Synaptic Failure in Mouse Model of Alzheimer’s Disease

“…Retention tests were conducted 3 h and 24 h after the training session, respectively. During the retention session, the electric shock of the grid was removed, a mouse was individually placed on the platform and the time when it first jumped off the platform was recorded as step-down latency, with an upper cutoff time of 300 s (Wang et al, 2020).…”

Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm

“…SIRT1 maintains an inverse relationship with mTOR [19,[176][177][178][179][180]. SIRT1 can also affect pathways of autophagy [49,65,163,178,[181][182][183][184][185][186]. SIRT1 activity can lead to the expansion of neurites and promote the survival of neurons during conditions that limit nutrients that involves mTOR inhibition [187].…”

“…SIRT1 is a histone deacetylase that can transfer acetyl groups from ϵ-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription [19,45,48,84,85,152,[195][196][197][198][199][200]. As noted above, SIRT1 plays a critical role in nervous system diseases [164,199,201,202] that also are dependent upon autophagy regulation [113,178,185,186,190,203]. Other work focuses on SIRT1 to control the expression of clock genes through PER2 deacetylation [204].…”