The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 2010
Nitro-oleic acid inhibits firing and activates TRPV1- and TRPA1-mediated inward currents in dorsal root ganglion neurons from adult male rats.
Nitro-oleic acid (OA-NO(2)), an electrophilic fatty acid by-product of nitric oxide and nitrite reactions, is present in normal and inflamed mammalian tissues at up to micromolar concentrations and exhibits anti-inflammatory signaling actions. The effects of OA-NO(2) on cultured dorsal root ganglion (DRG) neurons were examined using fura-2 Ca(2+) imaging and patch clamping. OA-NO(2) (3.5-35 microM) elicited Ca(2+) transients in 20 to 40% of DRG neurons, the majority (60-80%) of which also responded to allyl isothiocyanate (AITC; 1-50 microM), a TRPA1 agonist, and to capsaicin (CAPS; 0.5 microM), a TRPV1 agonist. ⋯ A large percentage (46-57%) of OA-NO(2)-responsive neurons also responded to CAPS (0.5 microM) or AITC (0.5 microM). OA-NO(2) currents were reduced by TRPV1 (diarylpiperazine; 5 microM) or TRPA1 (HC-030031; 5 microM) antagonists. These data reveal that endogenous OA-NO(2) generated at sites of inflammation may initially activate transient receptor potential channels on nociceptive afferent nerves, contributing to the initiation of afferent nerve activity, and later suppresses afferent firing.
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J. Pharmacol. Exp. Ther. · Jun 2010
A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation.
Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. ⋯ PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFalpha model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFalpha production in the acute model and inhibition of paw swelling in the chronic model is observed with ED(50) values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C(min) higher than the EC(50) measured in the rat LPS-induced TNFalpha model.
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J. Pharmacol. Exp. Ther. · Jun 2010
Protection against acute kidney injury via A(1) adenosine receptor-mediated Akt activation reduces liver injury after liver ischemia and reperfusion in mice.
Hepatic ischemia reperfusion (IR) injury causes acute kidney injury (AKI). However, the contribution of AKI to the pathogenesis of liver IR injury is unclear. Furthermore, controversy still exists regarding the role of A(1) adenosine receptors (A(1)ARs) in AKI. ⋯ Renal A(1)AR-mediated kidney protection plays a crucial role in protecting the liver after IR because: 1) selective unilateral renal lentiviral overexpression of human A(1)ARs [enhanced green fluorescent protein (EGFP)-huA(1)AR] in A(1)KO mice protected against both kidney and liver injury sustained after liver IR, 2) removal of the EGFP-huA(1)AR lentivirus-injected kidney from A(1)KO mice abolished both renal and hepatic protection after liver IR, and 3) bilateral nephrectomy before hepatic ischemia abolished the protective effects of A(1)AR activation in A(1)WT mice. Finally, inhibition of Akt, but not extracellular signal-regulated kinase mitogen-activated protein kinase, prevented the kidney and liver protection afforded by A(1)AR agonist treatment. Taken together, we show that endogenous and exogenous activation of renal A(1)ARs protect against liver and kidney injury after liver IR in vivo via pathways involving Akt activation.
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J. Pharmacol. Exp. Ther. · Jun 2010
Cisplatin and oxaliplatin inhibit gap junctional communication by direct action and by reduction of connexin expression, thereby counteracting cytotoxic efficacy.
Cisplatin [cis-diamminedichloroplatinum(II)]/oxaliplatin [1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)] toxicity is enhanced by functional gap junctions between treated cells, implying that inhibition of gap junctions may decrease cytotoxic activity of these platinum-based agents. This study investigates the effect of gap junction modulation by cisplatin/oxaliplatin on cytotoxicity in a transformed cell line. The effects were explored using junctional channels expressed in transfected HeLa cells and purified hemichannels. ⋯ However, higher concentrations strongly inhibited GJIC, and this counteracted the enhancing effect of greater cell density on toxicity. The present results indicate that inhibition of GJIC by cisplatin/oxaliplatin decreases their cytotoxicity. Direct inhibition of GJIC and reduction of connexin expression by cisplatin/oxaliplatin may thereby compromise the effectiveness of these compounds and be a factor in the development of resistance to this class of chemotherapeutic agents.