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Brucine N-oxide reduces ethanol intake and preference in alcohol-preferring Fawn-Hooded rats

中国药理学与毒理学杂志 2017年第5期31卷 479-480页

作者： LIANG Jian-hui WEI Shou-peng LI Yu-ling GONG Qi WANG Yan-ting LIANG Hui LIU Qing ZHANG Han-ting CHEN Feng Andrew J LOWRENCE Department of Molecular and Cellular pharmacology School of Pharmaceutical Sciences Department of pharmacology School of Basic Medicine SciencesPeking University Institute of Psycopharmacology Central Institute of Mental HealthUniversity of Heidelberg departments of behavioral medicine & psychiatry and physiology& pharmacology West Virginia University Health Sciences Center The Florey Institute of Neuroscience and Mental Health University of Melbourne

OBJECTIVE The alcoholism-related social problems have burdened the public health heavily.A better therapy for alcohol dependence as a chronic brain disease is highly required and interests the scientists worldwide. Our group has focused on screening the right drug with low toxicity and a sound curative effect from traditional Chinese medicine. METHODS Alcohol-preferring Fawn-Hooded(FH/Wjd) rat was used as an animal model of alcoholism to evaluate the effects of brucine N-oxide(BNO),an alkoloid naturally existing in the seeds of Strychnos nux-vomica L,on the alcohol-drinking ***,its adverse action and toxicity were investigated. RESULTS Treatment with BNO at the doses of 30,50 and 70 mg · kg^(-1)reduced the voluntary alcohol consumption and preference dosedependently and selectively without altering their water intake,total fluid intake,food consumption,body weight as well as sucrose preference. Remarkably,70 mg·kg^(-1)of BNO did suppress the deprivationinduced elevation of alcohol ingestion. Moreover,BNO used at the same doses as above had no influence on locomotion in an open field test and could not result in the place preference effect. CONCLUSION Taken together,BNO is of some significant pharmacological profiles to inhibit symptoms of alcohol dependence with high safety,and thence may be a potential pharmacotherapy.

关键词： brucine N-oxide ethanol

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PDE7A expression on alcohol consumption and alcohol withdrawal in striatum of C57BL/6J mice

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中国药理学与毒理学杂志 2019年第10期 851-852页

作者： XU Bing-bing ZHOU Yan-meng ZHANG Han-ting Institute of pharmacology Shandong First Medical University & Shandong Academy of Sciences departments of Neuroscience and behavioral medicine & psychiatry The Rockefeller Neuroscience Institute West Virginia University Health Sciences Center

OBJECTIVE To observe PDE7A expression on alcohol consumption and alcohol withdrawal in the striatum of C57BL/6J mice. METHODS Forty adult female C57BL/6J mice were randomly divided into 3 groups: water intake control, alcohol（10% v/v） drinking(18 h · d;for 7 d), and alcohol withdrawal（for 24 h）.PDE7A expression was analyzed using Western blotting in striatal tissues from mice. RESULTS Compared to the control, alcohol drinking mice displayed increases in the expression of PDE7A in the striatum, which decreased to normal 24 h after withdrawal. CONCLUSION The results suggest that PDE7, in particular PDE7A, may play a unique role in the regulation of ethanol depdendence.

关键词： phosphodiesterase-7A alcohol consumption alcohol withdrawal mice

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MicroRNA-mediated knockdown of the phosphodiesterase-4D(PDE4D) enzyme reversed Aβ42-induced memory deficit in mice

MicroRNA-mediated knockdown of the phosphodiesterase-4D(PDE4...

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第十五届中国神经精神药理学学术会议

作者：张聪 Department of pharmacology School of Pharmaceutical SciencesSouthern Medical University departments of behavioral medicine & psychiatry and physiology & pharmacology West Virginia University College of Medicine

OBJECTIVE Here we examined whether longform PDE4Ds reversed memory impairment produced by Aβ(1-42) (Aβ ).METHODS Morris water - maze and novelty object recognition tests were used for memory *** blotting analysis was used for determination of the expression of CREB,pCREB,BDNF,IL-lβ,TNF-αand NF-kB in order to explore the neurochemical *** Aged Ap (0.5μg/side) infused in bilateral dentate gyri produced memory deficits in the Morris water-maze(P<0.0001) and object recognition tests(P=0.0004 ) in *** of lentiviral vectors containing miRNAs that target long-form PDE4D variants reversed Ap-induced memory deficits and concomitantly increased pCREB(P=0.0001) and BDNF(P<0.0001),and reduced inflammatory cytokines,including IL-lp(P=0.0026), TNF-α(P<0.0001),and NF-kB(P<0.0001) in the hippocampus of Ap-treated *** These results suggest that long-form PDE4D variants maybe potential targets for treatment of memory loss associated with Alzheimer’s disease.

关键词： memory PDE4 long-form PDE4D Alzheimer’s disease pCREB anti-inflammation

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Comparison of PDE4 Expression in Different Brain Regions of C57BL/6J and DBA/2J Mice and the Association with Ethanol Drinking Behavior

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神经药理学报 2019年第4期 54-55页

作者： DU Xian WANG Dong ZHANG Fang-fang ZHOU Yan-meng WANG Hao FU Hua-rong ZHANG Han-ting Institute of pharmacology Shandong First Medical University & Shandong Academy of Sciences departments of behavioral medicine & psychiatry Physiology & Pharmacologyand Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences Center

Background:Alcohol dependence is not only the most common public health problem worldwide,but also the cause of many alcohol-related diseases,yet the mechanisms still remain unclear. Increasing evidence suggests that genetic factors play an important role in alcohol drinking behavior. C57 BL/6 J( B6) mice innately consume larger amounts of alcohol compared to DBA/2 J( DBA) mice,which drink little alcohol. Our recent studies have demonstrated that phosphodiesterase-4( PDE4),an enzyme that catalyzes the hydrolysis of cyclic AMP( cAMP),is an important target for regulating alcohol consumption. However,it is not known which of the four PDE4 subtypes( A-D) is involved. Previous studies demonstrate that lower levels of cAMP signaling are observed in specific brain regions of alcohol-preferring rodents;inhibition of cAMP signaling increases alcohol consumption,while activation of cAMP signaling in the brain decreases alcohol intake,in particularly brain regions such as the striatum and amygdala. Thus,we hypothesized that PDE4 expression in the brain of B6 and DBA mice is different and relevant to alcohol drinking. Objective:To compare the expression of PDE4 subtypes in the ethanol drinking-related brain regions of B6 and DBA mice and their responses to ethanol drinking in the absence or presence of the PDE4 inhibitor. Methods:Adult male and female B6 and DBA mice were tested for ethanol( 7% and 10%,v/v) intake and preference using the twobottle choice. In addition,a separate set of B6 and DBA mice was examined for PDE4 subtype expression levels in the striatum,hippocampus,cerebral cortex,and amygdala of the brain using Western blotting. Further,PDE4 subtype expression in brain regions of B6 mice in response to ethanol drinking was examined. Finally,the PDE4 inhibitor rolipram was administered to B6 mice to detect alcohol drinking behavior changes. Results:1. Differences in ethanol drinking behavior between B6 and DBA mice. Compared to DBA mice,B6 mice did not show signific

关键词： phosphodiesterase-4(PDE4) alcohol drinking C57BL/6J mice DBA/2J mice cAMP

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Effects of phosphodiesterase-4 inhibition on alcohol consumption and withdrawal anxiety in Fawn Hooded rats:Evidence for CREB phosphorylation in accumben nucleus core and central amygdala

Effects of phosphodiesterase-4 inhibition on alcohol consump...

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中国神经科学学会第十届全国学术会议

作者： Rui-Ting Wen Min Zhang Wang-Jun Qin Qing Liu Wei-Ping Wang Hui Liang Han-Ting Zhang Jian-Hui Liang National Institute on Drug Dependence Peking University departments of behavioral medicine & psychiatry and physiology & pharmacology West Virginia University Health Sciences Center

Objective Alcohol dependence is a complex psychiatric disorder demanding development of novel *** the cyclic AMP（cyclic adenosine monophosphate,cAMP） signaling cascade has been implicated in mediating behavioral responses to alcohol,key components in this cascade may serve as potential treatment *** 4（PDE4）,an enzyme that specifically catalyzes the hydrolysis of cAMP,represents as a key point in regulating intracellular cAMP ***,it was of interest to determine whether PDE4was involved in the regulation of alcohol use and *** By using Fawn-Hooded（FH/Wjd） rats as the animal model of alcoholism,we tested the effects of rohpram,the specific PDE4 inhibitor,on ethanol intake in two-bottle choice drinking,ethanol self-administration and anxiety symptoms related to ethanol *** molecular analysis was performed to investigate the possible mechanism of rohpram ***（1） Acute administration of rohpram（0.1,0.2 mg/kg,s.c.） selectively reduced ethanol consumption in continuous- and intermittent-access to ethanol at 5%or 10%,respectively;chronic rohpram treatment time-dependently decreased 5%ethanol consumption and preference during treatment days and after the termination of rohpram *** at the highest doses（0.1 and 0.2 mg/kg） did decrease locomotor activity,but the effect lasted only 10 and 20 min,respectively,which did not likely alter long-term ethanol drinking.（2） Rohpram（0.025 mg/kg,0.05 mg/kg,s.c.） dose-dependently inhibited operant self-administration of 5%ethanol,but had no effect on 10%sucrose *** effective dose of rohpram was lower than that of naloxone（0.1 mg/kg）.（3） Anxiety-like behavior was induced following acute ethanol withdrawal after long-time two-bottle choice ***（0.1,0.2 mg/kg,s.c.） significantly reversed this effect by increasing the entries and time spent in the open arms of elevated plus maze（EPM）.（4） cAMP levels in NAc and Amy were

关键词： alcohol dependence cyclic AMP signaling phosphodiesterase-4 rolipram FH/Wjd rat

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The Phosphodiesterase-4 Inhibitor Roflumilast Reverses Cognition Deficits and Depression-Like Effects via cAMP Signaling-Mediated Neuroprotection in APP/PS1 Transgenic Mice

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神经药理学报 2019年第Z1期 100-101页

作者： FU Hua-rong WANG Hao ZHANG Fang-fang XU Yong WANG Xiao-dan WANG Lei CHEN Wei XU Xiao-yan GAO Yong-feng ZHANG Ji-guo ZHANG Han-ting Institute of pharmacology Shandong First Medical University & Shandong Academy of Medical Sciences departments of behavioral medicine & psychiatry Physiology & Pharmacologyand Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences Center

Background:Depression is highly correlated with Alzheimer’s disease(AD),but treatment for the comorbidity of both is lacking. Phosphodiesterase-4(PDE4),an enzyme that catalyzes the hydrolysis of cyclic AMP(cAMP),has been considered as a promising target for treatment of both memory loss in AD and depression. Roflumilast,the second generation of PDE4 inhibitors,has been approved for treatment of chronic obstructive pulmonary disease(COPD) in humans. Recent studies have shown that roflumilast improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 inhibitors. However,the effect of roflumilast on memory loss and depression in AD remains largely unknown. Objective:To examine the effects of roflumilast on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model of AD. Methods:APP/PS1 mice and the wild type(WT) controls at 10 months of age were examined for memory using novel object recognition(NOR) and Morris water-maze(WMW) tests and depression using tail-suspension and forced-swimming tests(TST and FST). The protein contents were detected by Western blotting and Elisa kits. HE staining and Nissl staining were used to observe pathological changes. Results:Mice at 10 months of age were first tested in novel object recognition for memory. The recognition index in APP/PS1 mice was decreased compared to WT controls;this was reversed by roflumilast at 10 mg/kg. Similarly,in the Morris water-maze test,the AD mice displayed significantly longer escape latency during acquisition training and fewer entries into the target quadrant during the probe trial,compared to WT controls;these were also reversed by roflumilast at 5 and 10 mg/kg. In the tail-suspension and forced-swimming tests,which measure depression-like behavior,AD mice showed prolonged immobility time,which was reversed by roflumilast. In addition,the staining of HE and Nissl indicated that roflumilast reduced the loss of neurons and

关键词： roflumilast beta amyloid protein APP/PS1 Alzheimer’s disease memory depression

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咯利普兰对H_2O_2致PC12细胞氧化应激损伤的保护作用

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中国药理学通报 2010年第11期26卷 1429-1435页

作者：卓烨烨林焕冰周恒张汉霆徐江平南方医科大学药学院药理学系广东广州510515 departments of behavioral medicine & psychiatry and physiology & pharmacology West Virginia University Health Sciences Center

目的探讨PDE4抑制剂咯利普兰(rolipram)对H2O2致PC12细胞氧化应激损伤的保护作用及其作用机制。方法以H2O2损伤PC12细胞为氧化应激损伤模型,MTT法检测细胞存活率;碘化丙啶(Propidium iodide,PI)染色流式细胞术检测细胞周期变化;化学比... 详细信息

目的探讨PDE4抑制剂咯利普兰(rolipram)对H2O2致PC12细胞氧化应激损伤的保护作用及其作用机制。方法以H2O2损伤PC12细胞为氧化应激损伤模型,MTT法检测细胞存活率;碘化丙啶(Propidium iodide,PI)染色流式细胞术检测细胞周期变化;化学比色法测定细胞清除羟自由基(·OH)和超氧阴离子自由基(O2·)的能力;以及培养上清液中的丙二醛(MDA)、谷胱甘肽(GSH)和一氧化氮(NO)含量、超氧化物歧化酶(SOD)活性。Western blot和Real-time RT-PCR检测细胞内硫氧还蛋白(Trx)和诱导型一氧化氮合酶(iNOS)的表达。结果咯利普兰能明显提高H2O2损伤的PC12细胞存活率,恢复细胞增殖;提高细胞清除·OH和O2·的能力;降低MDA和NO含量,提高GSH含量和SOD活性;使Trx蛋白和mRNA表达增加,同时下调iNOS蛋白和mRNA表达。结论咯利普兰对H2O2致PC12细胞损伤具有保护作用,其作用机制可能与提高PC12细胞的抗氧化能力相关。

关键词：咯利普兰氧化应激 PC12细胞 cAMP应答元件结合蛋白活性氧簇硫氧还蛋白诱导型一氧化氮合酶

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Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia

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World Journal of Gastroenterology 2015年第6期21卷 1749-1758页

作者： Raymond A Isidro Myrella L Cruz Angel A Isidro Axel Baez Axel Arroyo William A González-Marqués Carmen González-Keelan Esther A Torres Caroline B Appleyard Department of physiology and pharmacology Ponce School of Medicine and Health Sciences Ponce Department of Pathology Ponce School of Medicine and Health Sciences Ponce Department of Anatomy Ponce School of Medicine and Health Sciences Ponce departments of Pathology and Laboratory medicine University of Puerto Rico School of Medicine Department of medicine University of Puerto Rico School of Medicine

AIM:To determine the expression of neurokinin-1receptor(NK-1R),phosphorylated epidermal growth factor receptor(p EGFR),cyclooxygenase-2(Cox-2),and vitamin D receptor(VDR)in normal,inflammatory bowel disease(IBD),and colorectal neoplasia tissues from Puerto ***:Tissues from patients with IBD,colitisassociated colorectal cancer(CAC),sporadic dysplasia,and sporadic colorectal cancer(CRC),as well as normal controls,were identified at several centers in Puerto *** formalin-fixed,paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R,p EGFR,Cox-2,and *** of representative areas of each tissues diagnosis were taken and scored by three observers using a4-point scale that assessed intensity of *** with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia,in addition to the areas of cancer,within each *** in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons *** mean scores for normal tissues and tissues with IBD,dysplasia,CRC,and CAC were calculatedand statistically compared using one-way analysis of variance and Dunnett’s multiple comparisons *** between protein expression patterns were analyzed with the Pearson’s product-moment correlation *** are presented as mean±***:On average,patients with IBD were younger(34.60±5.81)than normal(63.20±6.13,P<0.01),sporadic dysplasia(68.80±4.42,P<0.01),sporadic cancer(74.80±4.91,P<0.001),and CAC(57.50±5.11,P<0.05)***-1R in cancer tissue(sporadic CRC,1.73±0.34;CAC,1.57±0.53)and sporadic dysplasia(2.00±0.45)were higher than in normal tissues(0.73±0.19).p EGFR was significantly increased in sporadic CRC(1.53±0.43)and CAC(2.25±0.47)when compared to normal tissue(0.07±0.25,P<0.05,P<0.001,respectively).Cox-2 was significantly increased in sporadic colorectal cancer(

关键词： Colitis Colon cancer Dysplasia Neurokinin Vitamin

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S1-6 PDE4 Inhibitor Ameliorates Neuropathic Pain by Upregulating Spinal Connexin 43 Expression

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神经药理学报 2018年第4期8卷 8-9页

作者： ZHANG Fang-fang ZHOU Yan-memg WANG Hao GAO Shan WANG Lei TAN Rui DU Xian ZHAO Xiao-min ZHANG Han-ting Institute of pharmacology Taishan Medical UniversityTaian271016China departments of behavioral medicine&psychiatry and physiology Pharmacology&Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownWV 26506USA

Peripheral nerve injury downregulates connexin43(Cx43)expression in spinal ***,restoration of spinal astrocyte Cx43 expression to normal levels could lead to the reduction of nerve injury-induced *** has been shown that inhibitors of phosphodiesterase-4(PDE4),an enzyme catalyzing the hydrolysis of cyclic AMP(cAMP),reverse mechanical pain in mice with neuropathic ***,the antinociceptive mechanism remains *** the present study,we evaluated the antinociceptive effect of PDE4 inhibitors and demonstrated a novel mechanism by which PDE4 mediates nociception via Cx43 in spinal ***:The effects of PDE4 inhibitors on neuropathic pain and Cx43 expression in spinal astrocytes were evaluated in mice with partial sciatic nerve ligation(PSNL).Results:Single or repeated,intraperitoneal treatment with the selective PDE4 inhibitor rolipram or roflumilast of mice with PSNL significantly reduced mechanical *** was mimicked by intrathecal administration of rolipram or *** addition,repeated intrathecal treatment with rolipram or roflumilast of mice with PSNL completely prevented the downregulation of Cx43 expression in the spinal dorsal ***:The results suggest that PDE4 inhibitors ameliorate neuropathic pain,which is mediated by a spinal mechanism through the restoration of spinal Cx43 expression.

关键词： phosphodiesterase-4(PDE4) connexin43 rolipram roflumilast neuropathic pain

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NP-12 The Phosphodiesterase-4 Inhibitor Roflumilast Reverses Cognition Deficits and Depression-Like Effects via cAMP Signaling-Mediated Neuroprotection in APP/PS1 Transgenic Mice

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神经药理学报 2018年第4期8卷 110-111页

作者： WANG Hao ZHANG Fang-fang XU Yong FU Hua-rong WANG Xiao-dan WANG Lei CHEN Wei XU Xiao-yan GAO Yong-feng ZHANG Ji-guo ZHANG Han-ting Institute of pharmacology Taishan Medical UniversityTai’an271016China departments of behavioral medicine&psychiatry and physiology Pharmacology&Neurosciencethe Rockefeller Neurosciences InstituteWest Virginia University Health Sciences CenterMorgantownWV 26506USA

Phosphodiesterase-4(PDE4)has been demonstrated to be a promising target for treatment of Alzheimer’s disease(AD).Roflumilast(Rof),a potent PDE4 inhibitor,has been approved for treatment of chronic obstructive pulmonary disease(COPD)in *** studies have shown that Rof improves cognition at doses that do not cause an emetic response,the major side-effect of PDE4 ***,the effect of Rof on cognition associated with AD remains largely *** we examined the effects of Rof on behavioral dysfunction and the related mechanisms in APP/PS1 double transgenic mice,a widely used model for *** at 10 months of age were first tested in novel object recognition for *** recognition index in APP/PS1 mice was decreased compared to WT mice,which was reversed by Rof at 5 and 10 mg·*** was then verified in the Morris water-maze *** escape latency during acquisition training was significantly longer and the entries into the target quadrant during the probe trial were much less compared to WT controls,these were also reversed by *** the tail-suspension and forced-swimming tests,which measure depression-like behavior,APP/PS1 mice showed prolonged immobility time,which was reversed by *** addition,the staining of HE and Nissl showed that Rof reduced the loss of neurons and neurocyte apoptosis in APP/PS1 *** also reversed the decreased ratio of Bcl-2/BAX and inhibited the increased expression of PDE4D in the cerebral cortex and hippocampus of APP/PS1 ***,Rof reversed the decreased levels of cAMP and expression of phosphorylated cAMP response element-binding protein(CREB)and brain derived neurotrophic factor(BDNF)in APP/PS1 ***,these results suggest that Rof not only improves learning and memory,but attenuates depression-like behavior in AD mice,likely via PDE4D/cAMP/CREB/BDNF signaling-mediated ***,Rof can be a therapeutic agent for AD,in particular the comorbidity of memory deficits and depres

关键词： Alzheimer’s disease roflumilast PDE4 cAMP signaling APP/PS1 mice cognition depression

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