ah-23848 and Inflammation

ah-23848 has been researched along with Inflammation* in 5 studies

Other Studies

5 other study(ies) available for ah-23848 and Inflammation

ArticleYear
Molecular and preclinical basis to inhibit PGE2 receptors EP2 and EP4 as a novel nonsteroidal therapy for endometriosis.
    Proceedings of the National Academy of Sciences of the United States of America, 2015, Aug-04, Volume: 112, Issue:31

    Endometriosis is a debilitating, estrogen-dependent, progesterone-resistant, inflammatory gynecological disease of reproductive age women. Two major clinical symptoms of endometriosis are chronic intolerable pelvic pain and subfertility or infertility, which profoundly affect the quality of life in women. Current hormonal therapies to induce a hypoestrogenic state are unsuccessful because of undesirable side effects, reproductive health concerns, and failure to prevent recurrence of disease. There is a fundamental need to identify nonestrogen or nonsteroidal targets for the treatment of endometriosis. Peritoneal fluid concentrations of prostaglandin E2 (PGE2) are higher in women with endometriosis, and this increased PGE2 plays important role in survival and growth of endometriosis lesions. The objective of the present study was to determine the effects of pharmacological inhibition of PGE2 receptors, EP2 and EP4, on molecular and cellular aspects of the pathogenesis of endometriosis and associated clinical symptoms. Using human fluorescent endometriotic cell lines and chimeric mouse model as preclinical testing platform, our results, to our knowledge for the first time, indicate that selective inhibition of EP2/EP4: (i) decreases growth and survival of endometriosis lesions; (ii) decreases angiogenesis and innervation of endometriosis lesions; (iii) suppresses proinflammatory state of dorsal root ganglia neurons to decrease pelvic pain; (iv) decreases proinflammatory, estrogen-dominant, and progesterone-resistant molecular environment of the endometrium and endometriosis lesions; and (v) restores endometrial functional receptivity through multiple mechanisms. Our novel findings provide a molecular and preclinical basis to formulate long-term nonestrogen or nonsteroidal therapy for endometriosis.

    Topics: Animals; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Line; Cell Movement; Cell Survival; Disease Models, Animal; Endometriosis; Endometrium; Estrogens; Female; Humans; Inflammation; Mice; Neovascularization, Pathologic; Pelvic Pain; Poly(ADP-ribose) Polymerases; Progesterone; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Signal Transduction; Steroids; Xanthones

2015
The long-lasting sensitization of primary afferent nociceptors induced by inflammation involves prostanoid and dopaminergic systems in mice.
    Pharmacology, biochemistry, and behavior, 2013, Volume: 103, Issue:3

    In recent years, evidence that sensitization of primary afferent nociceptors is an important event associated with chronic pain has been accumulating. The present study aimed to evaluate the participation of the prostaglandin and sympathetic components in the long-lasting sensitization of nociceptors induced by acute inflammation in mice. The intraplantar administration of carrageenan (100 μg) enhanced the nociceptive response to a small dose of PGE(2) (9 ng/paw) or dopamine (3 μg/paw) up to 30 days later. This long-lasting sensitization is dependent on dopaminergic and prostanoid systems, since the pre-treatment with chlorpromazine (3 μg/paw) or indomethacin (100 μg/paw), but not local (6 μg/paw) or systemic (6 mg/kg) treatment with morphine, prevented its development. In agreement with this idea, the previous intraplantar administration of hyperalgesic doses of PGE(2) or dopamine also induced long-lasting sensitization, which was fully prevented by pretreatment with EP(4) and D(1) antagonists, respectively. In summary, the present work described in mice a long-lasting sensitization of nociceptors, initiated by an acute inflammatory stimulation and dependent on dopaminergic and prostanoid systems. The present data represent new insights on the mechanisms of peripheral sensitization that could contribute to establish the basis of new therapeutic strategies for acute and chronic inflammatory pain.

    Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Carrageenan; Central Nervous System Sensitization; Chlorpromazine; Dinoprostone; Disease Models, Animal; Dopamine; Dopamine Antagonists; Hyperalgesia; Indomethacin; Inflammation; Male; Mice; Morphine; Nociceptors; Pain; Pain Measurement; Prostaglandin Antagonists; Prostaglandins

2013
Influence of influenza A infection on capsaicin-induced responses in murine airways.
    The Journal of pharmacology and experimental therapeutics, 2012, Volume: 340, Issue:2

    The principal aim of the study was to determine the influence of influenza A virus infection on capsaicin-induced relaxation responses in mouse isolated tracheal segments and clarify the underlying mechanisms. Anesthetized mice were intranasally inoculated with influenza A/PR-8/34 virus (VIRUS) or vehicle (SHAM), and 4 days later tracheal segments were harvested for isometric tension recording and biochemical and histologic analyses. Capsaicin induced dose-dependent relaxation responses in carbachol-contracted SHAM trachea (e.g., 10 μM capsaicin produced 66 ± 4% relaxation; n = 11), which were significantly inhibited by capsazepine [transient receptor potential vanilloid type 1 (TRPV1) antagonist], (2S,3S)-3-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-2-phenylpiperidine hydrochloride (L-733,060) [neurokinin 1 (NK₁) receptor antagonist], indomethacin [cyclooxygenase (COX) inhibitor], and the combination of 6-isopropoxy-9-oxoxanthene-2-carboxylic acid (AH6809) and 7-[5α-([1S,1α(Z)-biphenyl]-4-ylmethoxy)-2β-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid, calcium salt, hydrate (AH23848) [E-prostanoid (EP)₂ and EP₄ receptor antagonists, respectively], indicating that capsaicin-induced relaxation involved the TRPV1-mediated release of substance P (SP), activation of epithelial NK₁ receptors, and production of COX products capable of activating relaxant EP₂/EP₄ receptors. Consistent with this postulate, capsaicin-induced relaxation was associated with the significant release of SP and prostaglandin E₂ (PGE₂) from mouse tracheal segments. As expected, influenza A virus infection was associated with widespread disruption of the tracheal epithelium. Tracheal segments from VIRUS mice responded weakly to capsaicin (7 ± 3% relaxation) and were 25-fold less responsive to SP than tracheas from SHAM mice. In contrast, relaxation responses to exogenous PGE₂ and the β-adrenoceptor agonist isoprenaline were not inhibited in VIRUS trachea. Virus infection was associated with impaired capsaicin-induced release of PGE₂, but the release of SP was not affected. In summary, influenza A virus infection profoundly inhibits capsaicin- and SP-induced relaxation responses, most likely by inhibiting the production of PGE₂.

    Topics: Animals; Biphenyl Compounds; Bronchoalveolar Lavage Fluid; Capsaicin; Carbachol; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Indomethacin; Inflammation; Influenza A virus; Isoproterenol; Leukocytes; Male; Mice; Mice, Inbred BALB C; Models, Biological; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Orthomyxoviridae Infections; Piperidines; Prostaglandin Antagonists; Respiratory Mucosa; Specific Pathogen-Free Organisms; Substance P; Trachea; TRPV Cation Channels; Xanthones

2012
MAPK signaling drives inflammation in LPS-stimulated cardiomyocytes: the route of crosstalk to G-protein-coupled receptors.
    PloS one, 2012, Volume: 7, Issue:11

    Profound cardiovascular dysfunction is an important cause of mortality from septic shock. The molecular underpinnings of cardiac dysfunction during the inflammatory surge of early sepsis are not fully understood. MAPKs are important signal transducers mediating inflammation whereas G-protein signaling pathways modulate the cardiac response to stress. Using H9c2 cardiomyocytes, we investigated the interaction of MAPK and G-protein signaling in a sepsis model to test the hypothesis that the cardiomyocyte inflammatory response is controlled by MAPKs via G-protein-mediated events. We found that LPS stimulated proinflammatory cytokine production was markedly exacerbated by siRNA knockdown of the MAPK negative regulator Mkp-1. Cytokine production was blunted when cells were treated with p38 inhibitor. Two important cellular signaling molecules typically regulated by G-protein-coupled receptors, cAMP and PKC activity, were also stimulated by LPS and inflammatory cytokines TNF-α and IL-6, through a process regulated by Mkp-1 and p38. Interestingly, neutralizing antibodies against Gα(s) and Gα(q) blocked the increase in cellular cAMP and PKC activation, respectively, in response to inflammatory stimuli, indicating a critical role of G-protein coupled receptors in this process. LPS stimulation increased COX-2 in H9c2 cells, which also express prostaglandin receptors. Blockade of G-protein-coupled EP4 prostaglandin receptor by AH 23848 prevented LPS-induced cAMP increase. These data implicate MAPKs and G-proteins in the cardiomyocyte inflammatory response to LPS as well as crosstalk via COX-2-generated PGE(2). These data add to our understanding of the pathogenesis of septic shock and have the potential to guide the selection of future therapeutics.

    Topics: Animals; Antibodies, Neutralizing; Biphenyl Compounds; Cell Line; Cyclic AMP; Cyclooxygenase 2; Dual Specificity Phosphatase 1; Gene Expression Regulation; Inflammation; Interleukin-6; Lipopolysaccharides; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Prostaglandins E; Protein Kinase C; Protein Kinase Inhibitors; Rats; Receptors, G-Protein-Coupled; RNA, Small Interfering; Signal Transduction; Tumor Necrosis Factor-alpha

2012
Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity.
    The Journal of pharmacology and experimental therapeutics, 2006, Volume: 319, Issue:3

    Prostaglandin E(2) (PGE(2)) is both an inflammatory mediator released at the site of tissue inflammation and a neuromodulator that alters neuronal excitability and synaptic processing. The effects of PGE(2) are mediated by four G-protein-coupled EP receptors (EP1-EP4). Here we show that the EP4 receptor subtype is expressed by a subset of primary sensory dorsal root ganglion (DRG) neurons, and that its levels, but not that of the other EP1-3 subtypes, increase in the DRG after complete Freund' adjuvant-induced peripheral inflammation. Administration of both an EP4 antagonist [AH23848, (4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid] and EP4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity, without changing basal pain sensitivity. AH23848 also reduces the PGE(2)-mediated sensitization of capsaicin-evoked currents in DRG neurons in vitro. These data suggest that EP4 is a potential target for the pharmacological treatment of inflammatory pain.

    Topics: Animals; Biphenyl Compounds; Blotting, Western; Capsaicin; Cells, Cultured; Dinoprostone; Electrophysiology; Ganglia, Spinal; Hot Temperature; Hyperalgesia; Image Processing, Computer-Assisted; Immunohistochemistry; In Situ Hybridization; Inflammation; Injections, Spinal; Male; Neurons; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP4 Subtype; RNA, Small Interfering

2006