The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 2007
Neuroprotection with erythropoietin administration following controlled cortical impact injury in rats.
This study was designed to determine the effect of erythropoietin (Epo) on cerebral blood flow (CBF), nitric oxide (NO) concentration, and neurological outcome after traumatic brain injury. In one experiment, the hemodynamic effects of Epo were determined after controlled cortical impact injury (CCII) by measuring mean arterial pressure, intracranial pressure, CBF using laser Doppler flowmetry, and brain tissue NO concentrations using an NO electrode. In total, 41 rats were given either Epo (5000 U/kg) or saline s.c. 3 days before injury. ⋯ The contusion volume was significantly reduced at 5 min, 1 h, 3 h, and 6 h postinjury Epo administration. The neuron density in the CA1 and CA3 region of the hippocampus was increased at 1, 3, and 6 h after injury. These data demonstrate the neuroprotective effects of Epo in traumatic injury, and the effects are optimal when Epo is given within 6 h of injury.
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J. Pharmacol. Exp. Ther. · Aug 2007
Distinct Ca2+ requirement for NO production between proteinase-activated receptor 1 and 4 (PAR1 and PAR4) in vascular endothelial cells.
Proteinase-activated receptors 1 and 4 (PAR(1) and PAR(4)) are the major receptors mediating thrombin-induced NO production in endothelial cells. The intracellular signaling following their activation still remains to be elucidated. The present study provides the first evidence for the distinct Ca(2+) requirement for the NO production between PAR(1) and PAR(4). ⋯ An immunoblot analysis revealed a transient increase in the phosphorylation of Akt and endothelial NO synthase following the PAR(4) stimulation. In conclusion, PAR(1) and PAR(4) engage distinct signal transduction mechanisms to activate NO production in vascular endothelial cells. PAR(4) preferably activates Galpha(i/o) and induced NO production in a manner mostly independent of Ca(2+) but dependent on the PI3K/Akt pathway, whereas PAR(1) activates both the Ca(2+)-dependent and -independent mechanisms.
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J. Pharmacol. Exp. Ther. · Aug 2007
CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties.
The prostaglandin (PG) EP(4) receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP(4) receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP(4) or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP(4) receptor antagonist, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridin-1-yl) phenyl]ethyl}amino) carbonyl]-4-methylbenzenesulfonamide (CJ-023,423). ⋯ Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.
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J. Pharmacol. Exp. Ther. · Aug 2007
Iptakalim, a vascular ATP-sensitive potassium (KATP) channel opener, closes rat pancreatic beta-cell KATP channels and increases insulin release.
Sulfonylureas have been the leading oral antihyperglycemic agents, and they presently continue to be the most popular antidiabetic drugs prescribed for treatment of type 2 diabetes. However, concern has arisen over the side effects of sulfonylureas on the cardiovascular system. Here, we tested the hypothesis that iptakalim, a novel vascular ATP-sensitive potassium (K(ATP)) channel opener, closes rat pancreatic beta-cell K(ATP) channels and increases insulin release. ⋯ In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) K(ATP) channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of beta-cell K(ATP) channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), K(ATP) channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type K(ATP) channels, and this unique pharmacological property suggests the potential use of iptakalim as a new therapeutic strategy for treating type 2 diabetes with the additional benefit of alleviating vascular disorders.
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J. Pharmacol. Exp. Ther. · Jul 2007
Antibodies to nerve growth factor reverse established tactile allodynia in rodent models of neuropathic pain without tolerance.
A considerable body of evidence implicates endogenous nerve growth factor (NGF) in conditions in which pain is a prominent feature, including neuropathic pain. However, previous studies of NGF antagonism in animal models of neuropathic pain have examined only the prevention of hyperalgesia and allodynia after injury, whereas the more relevant issue is whether treatment can provide relief of established pain, particularly without tolerance. In the current work, we studied the effects of potent, neutralizing anti-NGF antibodies on the reversal of tactile allodynia and thermal hyperalgesia in established models of neuropathic and inflammatory pain in rats and mice. ⋯ Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal (days 4 to 21) of tactile allodynia that returned 5 days after the end of dosing. In conclusion, NGF seems to play a critical role in models of established neuropathic and inflammatory pain in both rats and mice, with no development of tolerance to antagonism. Antagonists of NGF, such as fully human monoclonal anti-NGF antibodies, may have therapeutic utility in analogous human pain conditions.