European journal of pharmacology
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Neutrophils are innate immune cells in chronic inflammatory diseases including chronic obstructive pulmonary disease (COPD) and can be attracted to the site of inflammation via the collagen breakdown product N-acetyl Proline-Glycine-Proline (N-Ac-PGP). To elucidate whether CXCR2 is involved in N-Ac-PGP-induced neutrophil migration and activation, studies using specific antagonists were performed in vivo. N-Ac-PGP and keratinocyte cell-derived chemokine (KC; CXCL1) were administered in C57Bl/6 mice via oropharyngeal aspiration. ⋯ In conclusion, neutrophil migration induced by N-Ac-PGP is mediated via direct CXCR2 interaction. The N-Ac-PGP-induced release of CXCL1 is independent of CXCR2. Related to the maximal effect of CXCL1, N-Ac-PGP is more potent at inducing neutrophil migration in the pulmonary tissue than into the bronchoalveolar lavage fluid, or N-ac-PGP may be more potent at inducing MPO levels in the lung tissue.
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Luteolin occurs in a variety of plants and possesses antioxidant and anti-inflammatory properties. However, its role in protection against ischemia-reperfusion injury in Sprague-Dawley rats has not been elucidated. In the present study, we tested the contractile function of left ventricular cardiomyocytes with different concentrations of luteolin: 0.5, 1.5, 2.5 and 5.0 μg/ml after simulated. ⋯ Luteolin inhibited the activation of Caspase3 after ischemia-reperfusion in cardiomyocytes. Furthermore, luteolin at 10.0 μg/ml improved ischemia-reperfusion induced myocardial function, by improving heart rate, +dp/dt(max) and -dp/dt(max), and also limiting the decline of left ventricular systolic pressure (LVSP) and elevation of left ventricular end-diastolic pressure (LVEDP) to some extent. Our results demonstrated that luteolin prevents ischemia-reperfusion injury by reducing necrosis and apoptosis in rat cardiomyocytes.
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There is increased understanding that distinct GABA(A) receptor subtypes mediate different effects of classical benzodiazepines. Here, we aimed to define the contributions of α(1)-containing subtypes of the subtype-selective GABA(A) receptor positive allosteric modulators TPA023, ocinaplon, and NG2-73 using drug discrimination. We characterized these compounds with defined subunit preferences in rats that were trained to discriminate either the non-selective benzodiazepine chlordiazepoxide (CDP, 5.0 mg/kg) or the α(1)-selective drug zolpidem (1.5 mg/kg). ⋯ Overall, our data confirm and extend the previous findings in rats that compounds that lack efficacy at α(1)-containing GABA(A) receptors generalize to CDP, whereas the opposite holds true for α(1)-preferential compounds, which generalize to the α(1)-selective positive allosteric modulator zolpidem. Also, our data support the hypothesis that subtle in vitro differences in α subunit efficacy and/or affinity may eventually have large consequences in vivo. Together, our data demonstrate a reliable in vivo method to determine the contribution of the subtype-selective mechanism(s) of action for novel and subtype-selective GABA(A) receptor positive allosteric modulators, suggesting that a complex activation of multiple α subunits accounts for drug discrimination between non-selective and selective GABA(A) receptor ligands.
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Persistent pain associated with inflammatory arthritis is an aggravating factor that decreases patients' quality of life. Current therapies for joint pain have limited effectiveness and produce unwanted negative side effects. Although the involvement of substance P and its cognate tachykinin receptor, NK(1), in joint inflammation has been extensively documented through animal experiments, the development of oral tachykinin NK(1) receptor antagonists against arthritis-induced pain has been unsuccessful in humans to date. ⋯ Administration of the tachykinin NK(1) receptor antagonist WIN 51708 or GR 82334 into the affected ankle joint at day 3 following intra-articular CFA injection reduced the mechanical hyperalgesia 12 h after the tachykinin NK(1) receptor antagonist injection and their analgesic effects persisted for at least 2 days. Histological examinations revealed that intra-articular WIN 51708 reduced the CFA-induced destructive changes in the cartilage. These findings suggest that intra-articular injection of tachykinin NK(1) receptor antagonists is a promising strategy for relieving the hyperalgesia that occurs in inflammatory arthritis.
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In this study, the antinociceptive, anti-hypernociceptive and toxic effects of orally administered (R)-Se-phenyl thiazolidine-4-carboselenoate (Se-PTC, 1-50 mg/kg) were evaluated in mice. Se-PTC did not change plasma aspartate (AST) and alanine aminotransferase (ALT) activities or urea and creatinine levels. Furthermore, in an open field test, Se-PTC did not alter the number of crossings and rearing. ⋯ Se-PTC (25 mg/kg) significantly inhibited nociceptive behavior induced by intrathecal (i.t.) injection of glutamate, N-methyl-D-aspartate (NMDA) and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD), but failed to affect nociception induced by kainate and α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA). Mechanical hypernociception induced by carrageenan and Complete Freund's Adjuvant was attenuated by Se-PTC administration. These results indicate that Se-PTC produces antinociception in several models of nociception.