Search Results (4)

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline, neuroinflammation and neuronal damage. This study aimed to investigate the neuroprotective effects of cilomilast (CILO), a phosphodiesterase-4 (PDE4) inhibitor, alone and in combination with chlorogenic acid (CGA), a natural polyphenol, against scopolamine (SCOP)-induced cognitive impairment in mice. Forty male albino mice were divided into five groups: normal control, SCOP control, CGA + SCOP, CILO + SCOP and CILO + CGA + SCOP. Behavioral assessments, including the Y-maze and pole climbing tests, demonstrated that SCOP significantly impaired cognition, while treatment with CILO and CGA reversed these deficits, with the combination group showing the greatest improvement. Histopathological analyses revealed that CILO and CGA reduced neuronal damage and amyloid beta (Aβ) accumulation. Immunohistochemical and biochemical assessments confirmed a decrease in neuroinflammatory markers, including tumor necrosis factor-alpha (TNF-α) and nuclear factor kappa B (NF-κB). Molecular analyses showed that CILO restored cyclic adenosine monophosphate (cAMP) levels, leading to activation of protein kinase A (PKA), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF), key regulators of neuronal plasticity and survival. CGA enhanced these effects by further inhibiting PDE4, amplifying the neuroprotective response. These findings suggest that PDE4 inhibitors, particularly in combination with CGA, may represent promising therapeutic strategies for AD-related cognitive impairment. Full article

Phosphodiesterase 4 (PDE4) catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing a crucial role in the cAMP signaling pathway. cAMP is a secondary messenger involved in numerous physiological functions, such as inflammatory responses, immune responses, neural activity, learning, and memory. PDE4 inhibition is important for controlling anti-inflammatory and neuroprotective effects. In this review, we provide a comprehensive overview of the molecular functions and properties of human PDE4s. The study presents detailed sequence information for the PDE4 isoforms and the structural properties of the catalytic domain in members of the PDE4 family. We also review the inhibitory effects of the PDE4 inhibitors roflumilast and cilomilast related to respiratory diseases in PDE4. The crystal structures of PDE4 in complex with roflumilast and cilomilast are also analyzed. This review provides useful information for the future design of novel PDE4 inhibitors. Full article

Background: Cilomilast, a phosphodiesterase-4 (PDE4) selective inhibitor, has anti-inflammatory effects in vitro and in vivo and reduces COPD exacerbations. We tested the hypothesis that cilomilast inhibits virus-induced airway epithelial intercellular adhesion molecule-1 (ICAM-1) expression and inflammatory cytokine/chemoattractants, IL-6, CXCL8, and CCL5 production in vitro. Methods: BEAS-2B bronchial epithelial cells were incubated with 0.5–2 MOI (multiplicity of infection–infectious units/cell) of rhinovirus 16 (RV16). Then, 0.1–10 μM cilomilast or 10 nM dexamethasone, as inhibition control, were added pre- or post-1 h RV16 infection. Supernatant and cells were sampled at 8, 24, 48, and 72 h after infection. Cell surface ICAM-1 expression was detected by immunogold labelling and visualised by high-resolution scanning electron microscopy (HR-SEM), while IL-6, CXCL8, and CCL5 protein release and mRNA expression were measured using an ELISA and RT-PCR. Results: Cilomilast significantly decreased RV16-induced ICAM-1 expression to approximately 45% (p < 0.01). CXCL8 protein/mRNA production was reduced by about 41% (p < 0.05), whereas IL-6 protein/mRNA production was increased to between 41–81% (p < 0.001). There was a trend to reduction by cilomilast of RV16-induced CCL5. Conclusions: Cilomilast has differential effects on RV16-induced ICAM-1 and interleukins, inhibiting virus-induced ICAM-1 expression and CXCL8 while increasing IL-6 production. These in vitro effects may help to explain the beneficial actions of this PDE4 inhibitor in vivo. Full article

Hyperphosphatemia can occur as a result of reduced phosphate (P_i) excretion in cases of kidney dysfunction, which can induce muscle wasting and suppress myogenic differentiation. Higher P_i suppresses myogenic differentiation and promotes muscle atrophy through canonical (oxidative stress-mediated) and noncanonical (p62-mediated) activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. However, the crosstalk between myogenin and Nrf2/p62 and potential drug(s) for the regulation of myogenin expression needed to be addressed. In this study, we further identified that myogenin may negatively regulate Nrf2 and p62 protein levels in the mouse C2C12 muscle cell line. In the drug screening analysis, we identified N-acetylcysteine, metformin, phenformin, berberine, 4-chloro-3-ethylphenol, cilostazol, and cilomilast as ameliorating the induction of Nrf2 and p62 expression and reduction in myogenin expression that occur due to high P_i. We further elucidated that doxorubicin and hydrogen peroxide reduced the amount of myogenin protein mediated through the Kelch-like ECH-associated protein 1/Nrf2 pathway, differently from the mechanism of high Pi. The dual functional roles of L-ascorbic acid (L-AA) were found to be dependent on the working concentration, where concentrations below 1 mM L-AA reversed the effect of high P_i on myogenin and those above 1 mM L-AA had a similar effect of high P_i on myogenin when used alone. L-AA exacerbated the effect of hydrogen peroxide on myogenin protein and had no further effect of doxorubicin on myogenin protein. In summary, our results further our understanding of the crosstalk between myogenin and Nrf2, with the identification and verification of several potential drugs that can be applied in rescuing the decline of myogenin due to high P_i in muscle cells. Full article