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Role of Steroids in the Onset of Labor
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Guy Germain, Leroy Marie Josèphe, Michelle Breuiller-Fouche
So far, the presence of a single or of two isoform(s) of PDE according to species and/or techniques of purification were reported. Recently, four soluble PDE isozymes have been isolated and characterized from pregnant and nonpregnant human myometrium.69 On the basis of the potencies of classical selective modulators of PDEs, a calcium-calmodulin-sensitive PDE (CaM-PDE), a cGMP-stimulated PDE (cGS-PDE), a cGMP-inhibited PDE (cGi-PDE), and a cAMP-specific PDE (rolipram sensitive or ROI-PDE) were identified. CaM-PDE, an integrating agent between both second messengers—calcium and cyclic nucleotides—is the major form present in the nonpregnant myometrium. During the second half of human pregnancy, the ROI-PDE isoform is the most abundant myometrial PDE. The abundance near term of this isoform, which exhibits a high affinity for cAMP, could help the myometrium to get ready to develop important contractile activity during the parturition process. Rolipram, the selective inhibitor of the ROI-PDE isoform, is a potent relaxant of the isolated pregnant human and guinea pig myometrium.70 It may thus be surmised that the cyclic nucleotide phosphodiesterase activity could be regulated by steroid changes during pregnancy, but decisive proofs are still lacking.
Receptors and Signal Transduction Pathways Involved in Autonomic Responses
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Selective inhibitors include rolipram, Ro 20–1724 (Table 13.4) and denbufylline (Table 13.3). Rolipram has undergone clinical evaluation of its antidepressant activity and has been found to be effective in the treatment of major depression. Mood elevation and neuroexcitability associated with enhanced transmitter release in the brain provide a basis for possible application in conditions associated with cerebral ischaemia. Denbufylline and other selective PDE IV inhibitors may have possible applications in senile dementia by elevating mood and improving cognitive function (Nicholson et al. 1991, Thompson 1991). Gastrointestinal side-effects occur, including an increase in gastric acid secretion. Also of major concern with selective PDE IV inhibitors is emesis arising from a central site of action (Murray & England 1992).
Hypogonadism, erectile dysfunction, and infertility in men
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Pierre-Marc G. Bouloux, Shalender Bhasin
A number of novel selective phosphodiesterase inhibitors are under development. Milrinone is a selective type 3 phosphodiesterase inhibitor in human corpus cavernosum. Rolipram is a selective type 4 phosphodiesterase inhibitor.
Second messengers and their importance for novel drug treatments of patients with bipolar disorder
Published in International Review of Psychiatry, 2022
Gabriele Sani, Georgios D. Kotzalidis, Federica Fiaschè, Giovanni Manfredi, S. Nassir Ghaemi
As often happens in biological research, the trigger to investigate the role of biological mechanisms in disease stemmed from pharmacological discovery. The lithium story started in the late forties (Cade, 1949), when nothing was known about second messengers in bipolar disorder (BD). Lithium was later discovered to impinge upon such systems, with its involvement in neurotransmission and in phosphoinositide, calcium, and AKT/GSK-3β pathway activity (reviewed in Won & Kim, 2017; Kalcev et al., 2021). In the early eighties, the phosphodiesterase (PDE, a protein of the cAMP cascade that hydrolyzes cAMP, thus reducing its intracellular concentration) inhibitor, rolipram, was found to possess anti-depressant-like effects (Wachtel, 1983). Human trials at first were promising (Zeller et al., 1984), showing better tolerance and clinical equivalence with desipramine (Bobon et al., 1988; Guiot-Goffioul et al., 1987) and imipramine (Bertolino et al., 1988), but later trials showed rolipram to perform less well than imipramine in the longer term (Hebenstreit et al., 1989) and amitriptyline (Scott et al., 1991), thus cooling all enthusiasm about this molecule (and its mechanism of action). It was only later that it was discovered that rolipram selectively inhibited phosphodiesterase-4 (Torphy et al., 1993), thus leaving unaffected the other members of the PDE superfamily (PDE1-3,5-10).
Phosphodiesterase‑4 inhibitors: a review of current developments (2013–2021)
Published in Expert Opinion on Therapeutic Patents, 2022
Zhihao Liu, Mingjian Liu, Zhenqing Cao, Pengsen Qiu, Gaopeng Song
To our knowledge, only four small-molecule PDE4 inhibitors 2–5 have been marketed while other novel PDE4 inhibitors 6–12 (Figure 1 and Table 1) have entered the phase Ι/II/III clinical trials for treatment of asthma, COPD, Alzheimer’s diseases, and other human diseases. When compared with rolipram, these marked small molecules showed significant reduced gastrointestinal effects such as nausea and vomiting [34]. Specifically, roflumilast (2), the first approved PDE4 inhibitor, was approved in the EU and the US in 2010 and 2011 for the oral treatment of severe COPD and asthma symptoms, respectively [9], which was found to reduce lung inflammation and enhance mucosal clearance [35]. Clinical studies suggest that the most commonly side effects caused by roflumilast include emesis, diarrhea, weight loss, nausea, anxiety, depression, vomit and insomnia [36,37].
MicroRNA-30d-5p ameliorates lipopolysaccharide-induced acute lung injury via activating AMPKα
Published in Immunopharmacology and Immunotoxicology, 2021
Weixin Li, Guoqiang Hou, Jianfa Lv, Feng Lin, Gan Song, Ruiyun Li
Lipopolysaccharide (LPS, from Escherichia coli O111: B4, #L2360), lactate dehydrogenase activity assay kit and compound C (CpC, #171260) were purchased from Sigma-Aldrich (St. Louis, MO). Mouse IL-1β (#MLB00C), IL-6 (#M6000B), tumor necrosis factor-α (TNF-α, #MTA00B) and IL-10 (#M1000B) ELISA kits were obtained from R&D Systems (Minneapolis, MN). Lactate dehydrogenase activity (LDH, #ab102526), myeloperoxidase (MPO, #ab155458) activity, malondialdehyde (MDA, #ab118970) content, total superoxide dismutase (SOD, #ab65354) activity, reduced glutathione (GSH, #ab235670) level, cyclic AMP (cAMP, #ab65355) level and protein kinase A (PKA) activity (#ab139435) detecting kits were purchased from Abcam (Cambridge, MA). Amplex™ Red Hydrogen Peroxide/Peroxidase Assay Kit (#A22188) and 2′,7′-dichlorofluorescin diacetate (DCFH-DA, #C2938) were purchased from ThermoFisher Scientific (Waltham, MA). Rolipram (#S1430), a specific inhibitor of phosphodiesterase 4 D (PDE4D), was purchased from Selleck Chemicals (Houston, TX). The agomir, agomir control, antagomir and scramble antagomir were synthesized by RiboBio Co., LTD (Guangzhou, China). Anti-nuclear factor-erythroid 2 related factor 2 (NRF2; #ab137550), anti-PDE4D (#ab171750) and anti-β-actin (#ab8226) were purchased from Abcam (Cambridge, MA), while the primary antibodies for phosphorylated (#2535) and total (#2603 P) AMPKα were obtained from Cell Signaling Technology (Danvers, MA).