Molecular pharmacology
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Molecular pharmacology · Mar 2006
Block of peripheral nerve sodium channels selectively inhibits features of neuropathic pain in rats.
Several sodium channel blockers are used clinically to treat neuropathic pain. However, many patients fail to achieve adequate pain relief from these highly brain-penetrant drugs because of dose-limiting central nervous system side effects. Here, we describe the functional properties of trans-N-{[2'-(aminosulfonyl)biphenyl-4-yl]methyl}-N-methyl-N'-[4-(trifluoromethoxy)benzyl]cyclopentane-1,2-dicarboxamide (CDA54), a peripherally acting sodium channel blocker. ⋯ Consistent with the selective inhibition of injury-induced firing, CDA54 (10 mg/kg p.o.) significantly reduced behavioral signs of neuropathic pain in two nerve injury models, whereas the same dose of CDA54 did not affect acute nociception or motor coordination. In anesthetized dogs, CDA54, at plasma concentrations of 6.7 microM, had no effect on cardiac electrophysiological parameters including conduction. Thus, the peripheral nerve sodium channel blocker CDA54 selectively inhibits sensory nerve signaling associated with neuropathic pain.
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Molecular pharmacology · Dec 2005
Involvement of IL-10 in peroxisome proliferator-activated receptor gamma-mediated anti-inflammatory response in asthma.
Peroxisome proliferator-activated receptor gamma (PPARgamma) plays an important role in controlling immune and inflammatory responses. Recent studies have demonstrated that activation of PPARgamma reduces airway hyper-responsiveness and activation of eosinophils that are increased by induction of asthma. We have used a mouse model of asthma to determine the role of PPARgamma in the regulation of the pulmonary immune response, more specifically in the involvement of immunoregulatory cytokine interleukin (IL)-10. ⋯ Levels of IL-4, IL-5, and ovalbumin-specific IgE were also increased after ovalbumin inhalation, and the increased levels were significantly reduced by the administration of the PPARgamma agonists or AdPPARgamma. The results also showed that inhibition of IL-10 activity with anti-IL-10 receptor antibody partially restored the inflammation. These findings suggest that a protective role of PPARgamma in the pathogenesis of the asthma is partly mediated through an IL-10-dependent mechanism.
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Molecular pharmacology · Nov 2005
15-deoxy-Delta12,14 prostaglandin J2 up-regulates Kruppel-like factor 4 expression independently of peroxisome proliferator-activated receptor gamma by activating the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signal transduction pathway in HT-29 colon cancer cells.
15-Deoxy-Delta(12,14) prostaglandin J2 (15d-PGJ2) is a natural ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma) that exhibits antiproliferative activity in colon cancer cells, but its mechanism of action is still poorly understood. In this study, we showed that Krüppel-like factor 4 (KLF4) is one of the downstream effectors of 15d-PGJ2. Treatment of HT-29 cells with 15d-PGJ2 resulted in up-regulation of both KLF4 mRNA and protein expression, and these increases were also observed in other colon cancer cell lines. ⋯ Furthermore, KLF4 induction by 15d-PGJ2 occurred only in signal transducer and activator of transcription 1 (STAT1)-expressing, not in STAT1-knockout cells. Together, these results suggest that 15d-PGJ2-induced growth inhibition of colon cancer cells is mediated, at least in part, through up-regulation of KLF4 expression. This induction is unlikely to be mediated through the PPARgamma receptor but may involve the mitogen-activated protein kinase kinase/ERK pathway and is STAT1-dependent.
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Molecular pharmacology · Aug 2005
Comparative StudyConservation of functional and pharmacological properties in the distantly related temperature sensors TRVP1 and TRPM8.
Members of the transient receptor potential (TRP) superfamily of ion channels have now been defined as molecular transducers capable of reproducing the spectrum of temperature sensation exhibited by mammals. Because of their pivotal role in sensory transduction, many of these channels represent good targets for drug discovery. With a view to gaining further insight into the functional and pharmacological properties of these channels, we have used the whole-cell patch-clamp technique to study the human cold-sensitive menthol receptor transient receptor potential melastatin 8 (TRPM8) and compared its behavior with that of its distant relative, the heat-sensitive capsaicin-gated transient receptor potential vanilloid 1 (TRPV1). ⋯ There is also significant overlap in the antagonist pharmacology of these channels with many TRPV1 antagonists such as capsazepine, N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carboxamide (BCTC), (2R)-4-(3-chloro-2-pyridinyl)-2-methyl-N-[4-(trifluoromethyl)phenyl]-1-piperazinecarboxamide (CTPC), and N-(2-bromophenyl)-N'-{2-[ethyl(3-methylphenyl)amino]ethyl}-urea (SB-452533) exhibiting similar activity at TRPM8. Overall, the degree of pharmacological overlap between TRPV1 and TRPM8 has implications for the interpretation of studies conducted with these ligands to date and highlights a clear challenge for the design of selective TRP channel antagonists. Our finding that N-(3-methoxyphenyl)-4-chlorocinnamide (SB-366791), at least, represents an apparently selective antagonist for TRPV1 suggests that this goal is attainable.
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Molecular pharmacology · Jul 2005
Comparative StudyAlpha 1 subunit-containing GABA type A receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear.
Inhaled anesthetics are believed to produce anesthesia by their actions on ion channels. Because inhaled anesthetics robustly enhance GABA A receptor (GABA(A)-R) responses to GABA, these receptors are considered prime targets of anesthetic action. However, the importance of GABA(A)-Rs and individual GABA(A)-R subunits to specific anesthetic-induced behavioral effects in the intact animal is unknown. ⋯ To test this, we used global knockout mice that completely lack the alpha1 subunit and forebrain-specific, conditional knockout mice that lack the alpha1 subunit only in the hippocampus, cortex, and amygdala. Both knockout mice were 75 to 145% less sensitive to the amnestic effects of the inhaled anesthetic isoflurane. These results indicate that alpha1-containing GABA(A)-Rs in the hippocampus, amygdala, and/or cortex influence the amnestic effects of inhaled anesthetics and may be an important molecular target of the drug isoflurane.