Effect of a novel phosphodiesterase 4 inhibitor ZL-n-91 on proliferation, cell cycle and apoptosis of human glioma U87 cells / 中国药理学通报

Aim: To investigate the effect of ZL-n-91, a novel phosphodiesterase 4 (PDE4) inhibitor, on proliferation, cell cycle and apoptosis of human glioma U87 cells. Methods In vitro the different concentrations of ZL-n-91 were set up to evaluate the proliferation of U87 cells by CCK-8 assay. The cell apoptosis and cell cycle distribution were examined by flow cytometry. The expression of CDK2, CDK4, cyclin Dl and apoptosis-related protein Bax and Bcl-2 proteins were detected by Western blot. A subcutaneous transplanted tumor model of U87 in nude mice was established for the in vivo experiment using a dosage of 5 mg · kg

Research progress of PDE4 in the central nervous system / 中国药理学通报

Phosphodiesterase-4 ( PDE4 ) has been one of the most popular drug targets during recent years due to its critical role in the control of intracellular cyclic adenosine monophos-phate ( cAMP ) concentration and downstream signal transduc-tion. PDE4 is widely distributed in the central nervous system ( CNS) with different expression levels of its four subtypes. Re-cent data indicate that altered PDE4 expression and/or activity is relevant to multiple CNS disorders, such as depression, memory deficiency, drug dependence, and neural lesion. Selective PDE4 inhibitors exhibit therapeutic effects on these disorders and might be a promising pharmacotherapy. The paper highlights recent re-search progress in the roles of PDE4 in CNS function, and dis-cusses the prospects of PDE4 as a novel therapeutic target for CNS disorders.

Rolipram, a Phosphodiesterase 4 Inhibitor, Stimulates Inducible cAMP Early Repressor Expression in Osteoblasts

Phosphodiesterase (PDE) 4 inhibitors have been shown to induce the cAMP-mediated signaling pathway by inhibiting cAMP hydrolysis. This study investigated the effect of a PDE4 inhibitor on the expression of the inducible cAMP early repressor (ICER), which is an endogenous inhibitor of CRE- mediated transcription, in osteoblastic cells. RT-PCR analysis revealed that rolipram, a PDE4 inhibitor, stimulates the ICER mRNA in a dose dependent manner. The induction of ICER mRNA expression by rolipram was suppressed by the inhibitors of protein kinase A (PKA) and p38 MAPK, suggesting the involvement of PKA and p38 MAPK activation in ICER expression by rolipram. It was previously shown that rolipram induced the expression of TNF-related activation-induced cytokine (TRANCE, also known as RANKL, ODF, or OPGL) in osteoblasts. This paper provides evidences that a transcriptional repressor like ICER might modulate TRANCE mRNA expression by rolipram in osteoblasts.

The Effect of PDE 4 Inhibitor on Urinary Bladder Function in Normal Rats

PURPOSE: PDE 4 inhibitor is known to be a bladder relaxant. In this study, the effects of PDE 4 inhibitor on the urinary bladder function were evaluated in vivo experiment. We postulated that PDE 4 inhibitor of appropriate concentration might be helpful in the treatment of overactive bladder. MATERIALS AND METHODS: Fifteen Spraque-dawley female rats, weighing approximately 250~300 mg, were used for this study and divided into three groups. PDE 4 inhibitor 486,051 was administrated to each rat by different drug concentrations(0.5 mg/kg, 1 mg/kg, 5 mg/kg). Cystometrogram(CMG) was performed before and 20~60 minutes afterV), bladder capacity(BC), maximal bladder voiding contraction pressure(MVP), intercontrac drug application considering first voiding. Cystometric parameters investigated were voided volume(VV), residual volume (RV), bladder capacity(BC), maximal bladder voiding contraction pressure(MVP), intercontraction interval(ICI). Mean blood pressure was monitored in all rats. RESULTS: PDE 4 inhibitor of 0.5 mg/kg increased the intercontraction interval but not the bladder capacity significantly. PDE 4 inhibitor of 5 mg/kg increased the bladder capacity significantly, but did not show the increased intercontraction interval compared to other groups, and showed the greatest increased residual volume among three groups. PDE 4 inhibitor of 1 mg/kg showed the most increased intercontraction interval and the bladder capacity, and the least decreased voided volume and maximal bladder voiding contraction pressure change. CONCLUSION: PDE 4 inhibitor of different concentrations affects cystometric parameters variably by bladder smooth muscle relaxant. PDE 4 inhibitor of appropriate concentration may be helpful in the treatment of overactive bladder. PDE 4 inhibitor, at the concentration of 1 mg/kg, increased the bladder capacity and intercontraction interval most significantly. This study may provide an important basic data in the future when drug effects were assessed in variable animal models of overactive bladder, etc. However, main limitations of drug use are the increase of residual urine and the decrease of blood pressure. Therefore more bladder specific drug is needed.