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

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.

trans-Resveratrol ameliorates anxiety-like behaviors and neuropathic pain in mouse model of post-traumatic stress disorder.

BACKGROUND: trans-Resveratrol has been extensively investigated for its anti-inflammatory, antioxidant, and anti-psychiatric properties. However, whether it could rescue posttraumatic stress disorder-like stress-induced pain abnormality is unknown. AIM: The present study examined the effects of trans-resveratrol on anxiety-like behavior and neuropathic pain induced by single-prolonged stress, which is a classical animal model for mimicking posttraumatic stress disorder. METHODS: The single-prolonged stress-induced anxiety-like behavior and pain response were detected by the novelty suppressed feeding, marble burying, locomotor activity, von Frey, and acetone-induced cold allodynia tests in mice. The serum corticosterone levels and glucocorticoid receptor, protein kinase A, phosphorylated cAMP response element binding protein, and brain-derived neurotrophic factor expression were detected by enzyme-linked immunosorbent assay and immunoblot analyses. RESULTS: trans-Resveratrol reversed single-prolonged stress-induced increased latency to feed and the number of marbles buried in the novelty suppressed feeding and marble burying tests, but did not significantly influence locomotion distance in the locomotor activity test. trans-Resveratrol also reversed single-prolonged stress-induced cold and mechanical allodynia. Moreover, single-prolonged stress induced abnormality in the limbic hypothalamus-pituitary-adrenal axis was reversed by trans-resveratrol, as evidenced by the fact that trans-resveratrol reversed the differential expression of glucocorticoid receptor in the anxiety- and pain-related regions. In addition, trans-resveratrol increased protein kinase A, phosphorylated cAMP response element binding protein, and brain-derived neurotrophic factor levels, which were decreased in mice subjected to single-prolonged stress. CONCLUSIONS: These results provide compelling evidence that trans-resveratrol protects neurons against posttraumatic stress disorder-like stress insults through regulation of limbic hypothalamus-pituitary-adrenal axis function and activation of downstream neuroprotective molecules such as protein kinase A, phosphorylated cAMP response element binding protein, and brain-derived neurotrophic factor expression.

Protection from Amyloid ß Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor.

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.

The antidepressant- and anxiolytic-like effects of resveratrol: Involvement of phosphodiesterase-4D inhibition.

Resveratrol is a natural non-flavonoid polyphenol found in red wine, which has numerous pharmacological properties including anti-stress and antidepressant-like abilities. However, whether the antidepressant- and anxiolytic-like effects of resveratrol are related to the inhibition of phosphodiesterase 4 (PDE4) and its subtypes remains unknown. The same holds true for the subsequent cAMP-dependent pathway. The first set of studies investigated whether resveratrol exhibited neuroprotective effects against corticosterone-induced cell lesion as well as its underlying mechanism. We found that 100 µM corticosterone induced PDE2A, PDE3B, PDE4A, PDE4D, PDE10 and PDE11 expression in HT-22 cells, which results in significant cell lesion. However, treatment with resveratrol increased cell viability in a dose- and time-dependent manner. These effects seem related to the inhibition of PDE4D, as evidenced by resveratrol dose-dependently decreasing PDE4D expression. In addition, the PKA inhibitor H89 reversed resveratrol's effects on cell viability. Resveratrol prevented corticosterone-induced reduction in cAMP, pVASP(s157), pCREB, and BDNF levels, indicating that cAMP signaling is involved in resveratrol-induced neuroprotective effects. Not to mention, PDE4D knockdown by PDE4D siRNA potentiated the effect of low dose of resveratrol on cAMP, pVASP, pCREB, and BDNF expression, while PDE4D overexpression reversed the effect of high dose of resveratrol on the expression of the above proteins. Finally, the subsequent in vivo data supports the in vitro findings, suggesting that resveratrol-induced antidepressant- and anxiolytic-like effects are mediated by PDE4D. Overall, these findings support the hypothesis that PDE4D-mediated cAMP signaling plays an important role in resveratrol's protective effects on stress-induced depression- and anxiety-like behavior.

Evaluating the economic impact of casino liberalization in Macao.

This paper aims to evaluate the economic impact after Macao decided to liberalize its gaming industry. By analysing both objective data of official statistics and subjective data of the perceptions of quality of life, we painted a picture of mixed blessings. Although objective indicators showed strong economic growth in terms of a rise in per capita GDP and public revenue as well as a decline in unemployment rate, subjective indicators revealed that local residents were less than optimistic about their own employment outlook and did not perceive any improvement in their overall economic situation. While casino liberalization brought forth tremendous economic gain, the general population did not subjectively feel the benefits. An integrative analysis of both objective and subjective indicators would therefore allow us to look closer how residents' lives in the micro-level could have been adversely affected by the prosperous economic outlook at the macro-level.