Advances in clinical and safety studies of phosphodiesterase 4 inhibitors / 药学学报

Phosphodiesterase 4 (PDE4) is an important member of the phosphodiesterase enzyme family that specifically catalyzes the hydrolysis of cyclic adenosine monophosphate (cAMP), activates the downstream phosphorylation cascade pathway by altering cAMP concentration, and is strongly associated with multiple diseases. Inhibition of PDE4 is clinically investigated as a therapeutic strategy in a broad range of disease areas, including respiratory system diseases, autoimmune disorders, central nervous system diseases, and dermatological conditions. However, the incidence of adverse reactions such as nausea and vomiting is relatively high in the marketed PDE4 inhibitors, which has stalled their clinical development. In this review, we provide an overview of the clinical progression and safety issues of the marketed PDE4 inhibitors. We also review the main causes underlying PDE4-mediated adverse effects by combining the structural analysis of the PDE4 protein, the mechanism of action of PDE4 inhibitors, and the related side effect mechanism research, aiming to provide a reference for the development of safe and effective PDE4 inhibitors.

PDE4 inhibition protects against rotenone-induced neurotoxicity through activation of the AMPK/Sirt1 pathway / 中国药理学与毒理学杂志

OBJECTIVE We have previously shown that inhibition of phosphodiesterase-4(PDE4)protects against neuronal damage in models of Parkinson's dis-ease(PD).However,the mechanisms have not yet been completely revealed.Here we aimed to elucidate the pharmacological effects and mechanisms of action of rof-lupram(ROF),an novel PDE4 inhibitor,in experimen-tal models of PD.METHODS The survival rate,apopto-sis rate and toxicity level of SH-SY5Y cells were deter-mined by MTT,flow cytometry and lactate dehydroge-nase detection kit.At the same time,LYT staining was used to detect the changes of lysosome fluorescence intensity:Western blotting was used to detect the changes of lysosome associated proteins,Sirtuin1 and α-Syn;NAD/NADH assay kit was used to determine the change of NAD content.To explore whether SIRT1 inhibitor(EX527)and lysosomal inhibitor could block the effect of ROF.In addition,ROT was used to stimulate C57BL/6J mice to construct a mouse model of PD to verify the effect and mechanism of ROF.The changes of motor function were evaluated by behavioral experiments(pole climb-ing,bar rotating and balance beam experiments).Super-oxide dismutase kit and Western blotting were used to detect the changes of SOD activity and expression of related proteins in substantia nigra.RESULTS We showed that pretreatment with ROF significantly attenu-ated cell apoptosis in ROT-treated SH-SY5Y cells.Fur-thermore,ROF significantly enhanced the lysosomal function,as evidenced by the increased levels of mature cathepsin D(CTSD)and lysosomal-associated mem-brane protein 1(LAMP1)through increasing NAD+/NADH and the expression of sirtuin 1(SIRT1).Pretreatment with an SIRT1 inhibitor selisistat(SELI,10 μ mol·L-1)attenuated the neuroprotection of ROF,and ROF-increased expression levels of LAMP1 and mature CTSD.Moreover,inhibition of CTSD by pepstatin A(20 μmol·L-1)attenuated the protective effects of ROF.In vivo study was conducted in mice exposed to ROT(10 mg·kg-1·d-1,ig)for six weeks;then,ROT-treated mice received ROF(0.5,1 and 2 mg·kg-1·d-1,ig)for four weeks.ROF significantly ameliorated motor deficits,which was accompanied by increased expression levels of tyro-sine hydroxylase,SIRT1,mature CTSD,and LAMP1 in the substantia nigra pars compacta.CONCLUSION Taken together,these results demonstrate that ROF exerts a neuroprotective action in PD models.The mech-anisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

Roflumilast therapy in COPD − Update and Trials

Chronic Obstructive Pulmonary Disease (COPD) represents an important public health challenge that is both preventable and treatable. Pharmacological treatment regimen for COPD needs to be patient specific. Hence  management of  COPD    should  be  based  on  strategy  considering  both  disease  impact  and  future  risk  of  disease  progression ( especially of  exacerbation ). Risk of exacerbations significantly increases in GOLD 3 and GOLD 4 COPD. Exacerbations  increase  the   decline in  lung function , deteorriation  in  health  status  and  risk   of  death. Roflumilast   is   a   phosphodiesterase-4 (PDE4) inhibitor. It reduces   risk of moderate to severe   exacerbations in patients   of   GOLD 3   & GOLD 4   COPD. It  has  no  direct  bronchodilator  activity, although it  has  been  shown  to  improve  FEV1  in  patients treated  with   inhaled  long-acting  bronchodilator. Adverse  effects  may occur  early during the  treatment  but  these  are  reversible  and  diminish  overtime  with  continued  treatment .

Novel phosphodiesterase 4 inhibitor chlorbipram enhanced memory deficits in AD rats and its mechanisms involved / 中国药学杂志

OBJECTIVE: To investigate the effect and mechanism of novel phosphodiesterase 4 inhibitor chlorbipram on learning and memory disorders in Alzheimer's disease animal model. METHODS: The rat model of learning and memory deficits with AD was used by bilateral microinjection of Aβ25-35 into the CA1 region of the hippocampus. Then the rats were randomly divided into six groups; sham-operated group, Aβ25-35 microinjected (model group), chlorbipram treatment(0.05 and 0.15 mg · kg-1) group, rolipram-treated (0.05 mg · kg-1) and donepezil (1.0 mg · kg-1) group. The effect of chlorbipram on memory behavioral performance were evaluated with Morris water maze and step-through passive avoidance test, and the open field test was performed to determine the animal locomotor activity. After the last behavioral performance test, the hippocampus were dissected for further molecular analysis. The protein level of BDNF and the phosphorylation of PKA and CREB were analyzed by Western blotting; the mRNA level of BDNF in the hippocampus was detected by real-time PCR. RESULTS: Microinfusion with Aβ25-35 produced impairment of spatial memory in behavioral tests, which was reversed by either PDE4 inhibitor or donepezil administration. Chlorbipram, rolipram and donepezil increased the number of crossing and percent of time in the target quadrant in the Morris water maze probe trial. In the step-through passive avoidance test, the 24 h latency was significantly decreased in rats treated with either chlorbipram or positive control drugs, while no significant difference were shown in total locomotor activity among the groups. Western blot analyses showed that Aβ25-35-microinjection decreased the phosphorylation of PKA and CREB and inhibited the protein expression of BDNF in the hippocampus. Chlorbipram, rolipram and donepezil reversed the reduction of the phosphorylated PKA and CREB induced by Aβ25-35. Moreover, these drugs also enhanced both the mRNA and protein levels of BDNF. CONCLUSION: Chlorbipram produces a significant improvement of learning and memory in AD animal, and this effect is due to the mediation of cAMP/PKA/CREB/BDNF signal pathway.

Electrophysiological and Behavioral Changes by Phosphodiesterase 4 Inhibitor in a Rat Model of Alcoholic Neuropathy

OBJECTIVE: Alcoholic neuropathy is characterized by allodynia (a discomfort evoked by normally innocuous stimuli), hyperalgesia (an exaggerated pain in response to painful stimuli) and spontaneous burning pain. The aim of the present study is to investigate the effect of rolipram, a phosphodiesterase 4 inhibitor, against alcohol-induced neuropathy in rats. METHODS: Allodynia was induced by administering 35% v/v ethanol (10 g/kg; oral gavage) to Spraue-Dawley rats for 8 weeks. Rolipram and saline (vehicle) were administered intraperitoneally. Mechanical allodynia was measured by using von Frey filaments. Somatosensory evoked potential (SEP) was proposed as complementary measure to assess the integrity of nerve pathway. RESULTS: The ethanol-induced mechanical allodynia began to manifest from 3 week, and then peaked within 1 week. Beginning from 3 week, latency significantly started to increased in control group. In rolipram treated rats, the shorter latency was sustained until 8 weeks (p<0.05). The mechanical allodynia, which began to manifest on the 3 weeks, intraperitoneal injections of rolipram sustained statistical difference until 8 weeks, the final week of the study (p<0.05). CONCLUSION: This study suggests that rolipram might alleviate mechanical allodynia induced by alcohol in rats, which clearly has clinical implication.