The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 2011
Improved cerebrovascular function and reduced histological damage with darbepoietin alfa administration after cortical impact injury in rats.
Darbepoetin alfa (darbEpo) is an erythropoietic glycoprotein that activates the erythropoietin receptor. The aim of our study was to determine whether darbEpo is neuroprotective in a cortical impact injury (CII) model and to determine the characteristics of dose response and time window. To better understand the vascular mechanism of darbEpo neuroprotection, the reactivity of cerebral blood flow (CBF) to l-arginine administration was also studied. ⋯ In the time window study, darbEpo reduced contusion volume when given in a dose of 25 μg/kg at 5 min to 6 h after the impact injury. In animals pretreated with darbEpo, the CBF response to l-arginine was significantly greater than in the animals pretreated with saline. These data demonstrate that darbEpo has neuroprotective effects in traumatic brain injury in a dose- and time-dependent manner and that vascular effects of darbEpo may have a role in neuroprotection.
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J. Pharmacol. Exp. Ther. · Apr 2011
Comparative StudyIncreased presynaptic and postsynaptic α2-adrenoceptor activity in the spinal dorsal horn in painful diabetic neuropathy.
Diabetic neuropathy is a common cause of chronic pain that is not adequately relieved by conventional analgesics. The α(2)-adrenoceptors are involved in the regulation of glutamatergic input and nociceptive transmission in the spinal dorsal horn, but their functional changes in diabetic neuropathy are not clear. The purpose of the present study was to determine the plasticity of presynaptic and postsynaptic α(2)-adrenoceptors in the control of spinal glutamatergic synaptic transmission in painful diabetic neuropathy. ⋯ Furthermore, the amplitude of postsynaptic G protein-coupled inwardly rectifying K(+) channel (GIRK) currents elicited by UK-14304 was significantly larger in the diabetic group than in the control group. In addition, intrathecal administration of UK-14304 increased the nociceptive threshold more in diabetic than vehicle-control rats. Our findings suggest that diabetic neuropathy increases the activity of presynaptic and postsynaptic α(2)-adrenoceptors to attenuate glutamatergic transmission in the spinal dorsal horn, which accounts for the potentiated antinociceptive effect of α(2)-adrenoceptor activation in diabetic neuropathic pain.
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J. Pharmacol. Exp. Ther. · Apr 2011
Comparative StudySynergistic interaction between the two mechanisms of action of tapentadol in analgesia.
The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, μ-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. ⋯ Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action.
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J. Pharmacol. Exp. Ther. · Apr 2011
Comparative StudyGenistein, resveratrol, and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside induce cytochrome P450 4F2 expression through an AMP-activated protein kinase-dependent pathway.
Activators of AMP-activated protein kinase (AMPK) increase the expression of the human microsomal fatty acid ω-hydroxylase CYP4F2. A 24-h treatment of either primary human hepatocytes or the human hepatoma cell line HepG2 with 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), which is converted to 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5'-monophosphate, an activator of AMPK, caused an average 2.5- or 7-fold increase, respectively, of CYP4F2 mRNA expression but not of CYP4A11 or CYP4F3, CYP4F11, and CYP4F12 mRNA. Activation of CYP4F2 expression by AICAR was significantly reduced in HepG2 cells by an AMPK inhibitor, 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyrrazolo[1,5-a]-pyrimidine (compound C) or by transfection with small interfering RNAs for AMPKα isoforms α1 and α2. ⋯ Compound C greatly diminished genistein activation of CYP4F2 expression. 7H-benz[de]benzimidazo[2,1-a]isoquinoline-7-one-3-carboxylic acid acetate (STO-609), a calmodulin kinase kinase (CaMKK) inhibitor, reduced the level of expression of CYP4F2 elicited by genistein, suggesting that CaMKK activation contributed to AMPK activation by genistein. Transient transfection studies in HepG2 cells with reporter constructs containing the CYP4F2 proximal promoter demonstrated that AICAR, genistein, and resveratrol stimulated transcription of the reporter gene. These results suggest that activation of AMPK by cellular stress and endocrine or pharmacologic stimulation is likely to activate CYP4F2 gene expression.
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J. Pharmacol. Exp. Ther. · Apr 2011
Comparative StudyInvolvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin.
The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. ⋯ In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.