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Protein Kinase Activity Changes in the Aging Brain

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Biomedical and Environmental Sciences 1991年第Z1期 173-181页

作者： MICHAE LR.PISANO,HOAU-YAN WANG,EITAN FRIEDMAN departments of psychiatry and pharmacology Medical College of Pennsylvania departments of psychiatry and pharmacology Medical College of Pennsylvania departments of psychiatry and pharmacology Medical College of Pennsylvania Philadelphia Pennsylvania 19129 Philadelphia Pennsylvania 19129 Philadelphia Pennsylvania 19129 To whom correspondence should be addressed

The aging process in mammals is correlated with changes in psychomotor performance, cognitive function, and ability to adapt to stress (Montgomery et al., 1982; Lorens et al., 1990). These changes may be related to alterations in neuronal tissue that occur during the aging process. The normal aging process may be conceived of as the neuronal cell's increasing inability to maintain normal cellular function which ultimately results in a number of morphological and biochemical changes. Morphologically, there is a loss of neuronal cells with increasing age (Brizzee and

关键词： Protein Kinase Activity Changes in the Aging Brain

Molecular mechanism of noradrenaline during the stress-induced major depressive disorder

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Neural Regeneration Research 2018年第7期13卷 1159-1169页

作者： Kenjiro Seki Satomi Yoshida Manoj Kumar Jaiswal Department of pharmacology School of Pharmaceutical ScienceOhu University Department of psychiatry Icahn School of Medicine at Mount Sinai

Chronic stress-induced depression is a common hallmark of many psychiatric disorders with high morbidity ***-induced dysregulation of noradrenergic system has been implicated in the pathogenesis of *** of monoamine in the brain has been believed to be the main causative factor behind pathophysiology of major depressive disorder（MDD） and several antidepressants functions by increasing the monoamine level at the synapses in the ***,it is undetermined whether the noradrenergic receptor stimulation is critical for the therapeutic effect of *** to noradrenergic receptor stimulation,it has been suggested that the desensitization of β-adrenoceptor is involved in the therapeutic effect of *** addition,enhanced noradrenaline（NA） release is central response to stress and thought to be a risk factor for the development of ***,fast acting antidepressant suppresses the hyperactivation of noradrenergic neurons in locus coeruleus（LC）.However,it is unclear how they alter the firing activity of LC *** inconsistent reports about antidepressant effect of NA-reuptake inhibitors（NRIs） and enhanced release of NA as a stress response complicate our understanding about the pathophysiology of *** this review,we will discuss the role of NA in pathophysiology of stress and the mechanism of therapeutic effect of NA in *** will also discuss the possible contributions of each subtype of noradrenergic receptors on LC neurons,hypothalamic-pituitary-adrenal axis（HPA-axis） and brain derived neurotrophic factor-induced hippocampal neurogenesis during stress and therapeutic effect of NRIs in MDD.

关键词： major depression stress noradrenaline noradrenaline-reuptake inhibitors serotonin receptors hypothalamic-pituitary-adrenal axis locus coeruleus selective serotonin reuptake inhibitors serotonin noradrenaline-reuptake inhibitors

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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

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

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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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Brain GABA and glutamate levels in workers of two ant species （Hymenoptera： Formicidae）： Interspecific differences and effects of queen presence/absence

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Insect Science 2014年第5期21卷 647-658页

作者： Andrzej Wnuk Wojciech Kostowski Julita Korczynska Anna Szczuka Beata Symonowicz Przemyslaw Bienkowski Pawel Mierzejewski Ewa Joanna Godzinska Laboratory of Ethology Department of Neurophysiology Nencki Institute of Experimental Biology PAS Warsaw Department of pharmacology and Physiology of the Nervous System Institute of Psychiatry and Neurology Warsaw Poland

Presence of amino acid neurotransmitters gamma-aminobutyric acid （GABA） and glutamate （Glu） in ant brains was reported in very few studies. To learn more about factors influencing GABA and Glu levels in ant brains, we applied high-performance liquid chromatography to measure levels of these compounds in single brains of workers of 2 ant species, Myrmica ruginodis （subfamily Myrmicinae） and Formica polyctena （subfamily Formicinae） taken from queenright/queenless colony fragments and tested in dyadic aggression tests consisting of an encounter with a nestrnate, an alien conspecific or a small cricket. Brain glutamate levels were higher than those of GABA in both tested species. Brain GABA levels （in μmol/brain） and GABA ： Glu ratio were higher in M. ruginodis （a submissive species） than in E polyctena （a dominant, aggressive species） in spite of smaller brain weight of M. ruginodis. Brain glutamate levels （in μmol/brain） did not differ between the tested species, which implies that glutamate concentration （in μmol/mg of brain tissue） was higher in M. ruginodis. Queen absence was associated with increased worker brain GABA levels in E polyctena, but not in M. ruginodis. No significant effects of opponent type were discovered. As GABA agonists enhance friendly social behavior in rodents, we hypothesize that elevated brain GABA levels of orphaned workers of *** facilitate the adoption of a new queen. This is the first report providing information on GABA and glutamate levels in single ant brains and documenting the effects of queen presence/absence on brain levels of amino acid neurotransmitters in workers of social Hymenoptera.

关键词： Formica polyctena GABA glutamate interspecific differences Myrmica ruginodis queen

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

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

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

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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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

Icariin decreases neuro-pathogenesis and improves learning and memory functions in Tg2576 mice

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中国药理学与毒理学杂志 2012年第3期 436-437页

作者：李菲 Department of pharmacology Zunyi Medical College Department of psychiatry and Behavioral Sciences Northwestern University Feinberg School of MedicineChicago IL 60611USA

Alzheimer′s disease(AD) is one of the most common neurodegenerative diseases,showing progressive memory and cognitive *** predominant neuropathological features of AD are extracellular senile plaques(SP) composed by over expression of amyloid beta protein(Aβ),hyperphosphorylation of Tau protein forming the neurofibrillary tangles(NFTs) and neuronal loss in the specific brain ***,the cause of dementia of AD are still not known,the neurotoxicity of over expressed Aβ coming from the proteolysis of amyloid precursor protein(APP) may play a important role.Aβ neurotoxicity has been widely reported in vitro and in vivo,including the impairment of long term potentiation(LTP),disruption of synaptic plasticity.Aβ also triggered neuron inflammation,and disturbed *** neuronal oxidative damage and apoptosis,eventually resulted in memory loss At this moment,there are no effective pharmacologic interventions that could halt the progression of *** pharmacotherapies,such as acetylcholinesterase inhibitors including donepezil,rivastigmine and galantamine,and a NMDA antagonist,memantine,improve symptoms but do not block the disease *** strategies to slow and/or reverse the pathogenesis of patients with AD are greatly *** Chinese Medicine such as icariin may provide an unique opportunity for seeking more safe and effective therapies for *** this study we were examine the protective effect of icariin on Tg2576 mice,a well established animal model of *** results demonstrated that chronic treatment of Tg2576 mice with icariin from age of 8 to 11 months,could improve the memory function of Tg2576 *** addition,icariin decreased the APP,Aβ levels,and amyloid plaque number in Tg2576 mouse ***,icariin promoted cell proliferation and differentiation into neuron in the dentate gyrus(DG) of hippocampus in aged Tg2576 *** following icariin administration may due to the decrease of Aβ levels

关键词： Icariin Alzheimer′s disease β-amyloid protein neurogenesis Tg2576 mice

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