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pde4 inhibitor

Amanda Santiago, Lígia Mendes Soares, Melissa Schepers, Humberto Milani, Tim Vanmierlo, Jos Prickaerts, Rúbia M Weffort de Oliveira
Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH...
June 19, 2018: Neuropharmacology
Stephan Weidinger, Lisa A Beck, Thomas Bieber, Kenji Kabashima, Alan D Irvine
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration...
June 21, 2018: Nature Reviews. Disease Primers
Walter Gulisano, Maria Rosaria Tropea, Ottavio Arancio, Agostino Palmeri, Daniela Puzzo
Cyclic nucleotides cAMP and cGMP cooperate to ensure memory acquisition and consolidation. Increasing their levels by phosphodiesterase inhibitors (PDE-Is) enhanced cognitive functions and rescued memory loss in different models of aging and Alzheimer's disease (AD). However, side effects due to the high doses used limited their application in humans. Based on previous studies suggesting that combinations of sub-efficacious doses of cAMP- and cGMP-specific PDE-Is improved synaptic plasticity and memory in physiological conditions, here we aimed to study whether this treatment was effective to counteract the AD phenotype in APPswe mice...
June 6, 2018: Neuropharmacology
Weiwei Li, Lingling Yu, Xiaodi Yan, Linlin Cai, Li Wan, Qinyu Teng, Yonghua Li, Yun Wang, Haitao Xu
Propofol inhibits long-term potentiation (LTP) in the hippocampal CA1 region and impedes episodic memory formation. However, the molecular mechanisms involved in the effect of propofol are still poorly understood. It had been reported that propofol inhibited cAMP response element binding protein signaling, which was proposed to contribute to memory retention impairment in rats. Here, we first demonstrated that propofol perfusion could inhibit forskolin induced LTP in the rat hippocampal CA1 slices. Propofol also reduced the level of cAMP, which could be reversed by non-selective PDE inhibitor IBMX...
2018: Frontiers in Neuroscience
Amy Huang, Christine Cho, Donald Y M Leung, Kanwaljit Brar
Therapeutic regimens for the treatment and long-term management of AD traditionally had a two-fold objective of decreasing skin inflammation and repairing the defective skin barrier. Essential treatments for AD in children should include topical moisturizers for skin hydration and prevention of flares, topical anti-inflammatory medications (e.g. corticosteroids, calcineurin inhibitors, PDE4 inhibitor), allergen/irritant avoidance, and treatment of skin infections. Treatment regimens should be severity-based, and implemented in a stepwise approach tailored to the individual patient...
September 2017: Current Treatment Options in Allergy
Baskaran Purushothaman, Parthasarathy Arumugam, Joon Myong Song
Degradation of cyclic adenosine mono phosphate (cAMP) by phosphodiesterase-4B (PDE-4B) in the inflammatory cells leads to elevated expression of inflammatory cytokines in inflammatory cells. Suppression of cytokines has proved to be beneficial in the treatment of atopic dermatitis (AD). Henceforth, application of PDE4B specific inhibitor to minimize the degradation of cAMP can yield better results in the treatment of AD. PDE4B specific inhibitor with a limited side effect is highly warranted. Herein, we synthesized a novel PDE4 inhibitor, compound 2 comprising catecholopyrimidine core functionalized with trifluoromethyl (-CF3 ) group...
2018: Frontiers in Pharmacology
Wei Xie, Yangliang Ye, Ying Feng, Tifei Xu, Suling Huang, Jianhua Shen, Ying Leng
The role of phosphodiesterase 3 (PDE3), a cyclic AMP (cAMP)-degrading enzyme, in modulating gluconeogenesis remains unknown. Here, linderane, a natural compound, was found to inhibit gluconeogenesis by activating hepatic PDE3 in rat primary hepatocytes. The underlying molecular mechanism and its effects on whole-body glucose and lipid metabolism were investigated. The effect of linderane on gluconeogenesis, cAMP content, phosphorylation of cAMP-response element-binding protein (CREB) and PDE activity were examined in cultured primary hepatocytes and C57BL/6J mice...
2018: Frontiers in Pharmacology
Xuemei Liu, Rui Chen, Guanghuai Zeng, Ying Gao, Xiuping Liu, Donglei Zhang, Pei Hu, Hongyun Wang, Ji Jiang
AIM: Hemay005 is a novel small-molecule inhibitor of phosphodiesterase-4 developed for the treatment of psoriasis. Measurement of Hemay005 in biological samples is critical for evaluation of its pharmacokinetics in clinical studies. Methodology & results: Plasma and urine samples were extracted and then chromatographed on an Acquity UPLC HSS T3 column with a gradient elution. Detection was performed on a Xevo TQ-S tandem mass spectrometer using negative ESI. CONCLUSION: For the first time, a sensitive and robust ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the quantitative determination of Hemay005 in human plasma and urine, and it was successfully applied to evaluate the pharmacokinetics of Hemay005 in healthy subjects in a first-in-human study...
June 4, 2018: Bioanalysis
Ofir Elalouf, Vinod Chandran
PURPOSE OF REVIEW: To highlight the recently approved therapeutic agents in psoriatic arthritis (PsA), drugs in the pipeline, as well as to discuss efficacy with regard to different clinical domains of PsA. RECENT FINDINGS: More than 15 years ago, tumor necrosis factor inhibitors (TNFi) were the first biologic disease modifying anti-rheumatic drugs (bDMARDs) that were approved for the treatment of PsA. Since then, multiple new therapeutic agents inhibiting other targets have emerged including biologics targeting interleukin (IL) 12/23, and IL 17 and oral agents targeting phosphodiesterase 4 (PDE4) and Janus kinases (JAKs)...
May 30, 2018: Current Rheumatology Reports
Erica B Lee, Mark G Lebwohl, Jashin J Wu
Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor, is effective in patients with atopic dermatitis. As systemic PDE4 inhibition has also been used with success in psoriasis, clinical trials are underway to determine the utility of topical PDE4 inhibitors in these patients. However, there is no current literature documenting use of crisaborole for psoriasis. Here, we present two cases in which patients with psoriasis were treated successfully with crisaborole.
May 29, 2018: Journal of Dermatological Treatment
P R A Heckman, A Blokland, N P Van Goethem, B T J Van Hagen, J Prickaerts
The current study investigated the mediating role of phosphodiesterase type 4 (PDE4) regulated cAMP in the dopaminergic modulation of premature responding (action restraint) in rats. Response inhibition, which includes action restraint, finds its neurobiological origin in cortico-striatal-thalamic circuitry and can be modulated by dopamine. Intracellularly, the effect of dopamine is largely mediated through the cAMP/PKA signaling cascade. Areas in the prefrontal cortex are very sensitive to their neurochemical environment, including catecholamine levels...
May 17, 2018: Behavioural Brain Research
Carlos Duarte Correia, Juliana Oliveira, Ricardo Almir Angnes, Ismat Ullah Khan, Ellen Christine Polo, Gabriel Heerdt, Bruno Servilha, Vitor Silva, Ataualpa Braga
Highly diastereo and enantioselective non-covalent substrate directable Heck desymmetrizations of cyclopentenyl olefins bearing hydroxymethyl and carboxylate functional groups are presented. These conformationally unbiased cyclic olefins underwent effective arylations in yields of up to 97%, diastereoselectivity up to >20:1, and enantiomeric excesses of up to 99%. Non-covalent directing effects were shown to be present in Heck-Matsuda and oxidative Heck reactions allowing the preferential formation of cis-substituted aryl cyclopentenes containing two stereocenters, including quaternary stereocenters...
May 3, 2018: Chemistry: a European Journal
Qun Li, Yucong Peng, Linfeng Fan, Hangzhe Xu, Pingyou He, Shenglong Cao, Jianru Li, Ting Chen, Wu Ruan, Gao Chen
Phosphodiesterase-4 (PDE4) plays a fundamental role in a range of central nervous system (CNS) insults, however, the role of PDE4 in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The current study was designed to investigate the role of PDE4 in EBI after SAH and explore the potential mechanism. The SAH model in Sprague-Dawley rat was established by endovascular perforation process. Rats were randomly divided into: sham group, SAH?+?vehicle group, SAH?+?rolipram (PDE4 inhibitor) group, SAH?+?rolipram?+?sirtinol (SIRT1 inhibitor) group and SAH?+?rolipram+MK2206 (Akt inhibitor) group...
March 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Lou Ann Friend, J Howard James
PDE4-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by 6-fold, but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B KO-rats. As reported by us previously, burn injury significantly increased EDL muscle total and myofibrillar proteolysis in WT-rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO-rat with burn injury...
April 25, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Xiaonan Liang, Zheng Yong, Ruibin Su
Opioid-induced respiratory depression is a major obstacle to improving the clinical management of moderate to severe chronic pain. Opioids inhibit neuronal activity via various pathways, including calcium channels, adenylyl cyclase, and potassium channels. Currently, the underlying molecular pathway of opioid-induced respiratory depression is only partially understood. This study aimed to investigate the mechanisms of opioid-induced respiratory depression in vivo by examining the effects of different pharmacological agents on fentanyl-induced respiratory depression...
June 11, 2018: Neuroscience Letters
Lamei Yu, Kuichang Yuan, Byung Mun Park, Suhn Hee Kim
This study aimed to determine the effects of levosimendan, a calcium sensitizer, on atrial contractility and atrial natriuretic peptide (ANP) secretion and its modification in hypertrophied atria. Isolated perfused beating rat atria were used from control and isoproterenol-treated rats. Levosimendan and its metabolite OR-1896 caused a positive inotropic effect and suppressed ANP secretion in rat atria. Similar to levosimendan, the selective phosphodiesterase 3 (PDE3) or PDE4 inhibitor also suppressed ANP secretion...
June 15, 2018: European Journal of Pharmacology
Tommaso Prosdocimi, Luca Mollica, Stefano Donini, Marta S Semrau, Anna Paola Lucarelli, Egidio Aiolfi, Andrea Cavalli, Paola Storici, Silvana Alfei, Chiara Brullo, Olga Bruno, Emilio Parisini
Selected members of the large rolipram-related GEBR family of type 4 phosphodiesterase (PDE4) inhibitors have been shown to facilitate long-term potentiation and to improve memory functions without causing emetic-like behavior in rodents. Despite their micromolar-range binding affinities and their promising pharmacological and toxicological profiles, few if any structure-activity relationship studies have been performed to elucidate the molecular bases of their action. Here, we report the crystal structure of a number of GEBR library compounds in complex with the catalytic domain of PDE4D as well as their inhibitory profiles for both the long PDE4D3 isoform and the catalytic domain alone...
May 15, 2018: Biochemistry
Esther Barreiro, Ester Puig-Vilanova, Anna Salazar-Degracia, Sergi Pascual-Guardia, Carme Casadevall, Joaquim Gea
Peripheral muscle weakness and mass loss are characteristic features in severe COPD. We hypothesized that the phosphodiesterase-4 inhibitor roflumilast-induced cAMP may ameliorate proteolysis and metabolism in skeletal muscles of COPD patients with severe muscle wasting. In myogenic precursor cells (isolated from muscle biopsies and cultured up to obtain differentiated myotubes) from 10 severe COPD patients and 10 healthy controls, which were treated with 1 microM roflumilast N-oxide (RNO) for three time-cohorts (1h, 6h, and 24h), genes of antioxidant defense and oxidative stress marker, myogenesis and muscle metabolism, proteolysis (tyrosine release assay) and ubiquitin-proteasome system markers, autophagy, and myosin isoforms were analyzed using RT-PCR and immunoblotting...
April 12, 2018: Journal of Applied Physiology
René Blöcher, Karen M Wagner, Raghavender R Gopireddy, Todd R Harris, Hao Wu, Bogdan Barnych, Sung Hee Hwang, Yang K Xiang, Ewgenij Proschak, Christophe Morisseau, Bruce D Hammock
Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1-propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h...
April 26, 2018: Journal of Medicinal Chemistry
Giulia Vigone, Leia C Shuhaibar, Jeremy R Egbert, Tracy F Uliasz, Matthew A Movsesian, Laurinda A Jaffe
Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cyclic adenosine monophosphate (cAMP) in the granulosa cells, and the activity of cAMP phosphodiesterases (PDEs), including PDE4, contributes to preventing premature responses. However, two other cAMP-specific PDEs, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these PDEs also contribute to preventing uncontrolled activation of meiotic resumption and ovulation...
May 1, 2018: Endocrinology
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