Journal of pharmacological sciences
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Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. Mexiletine, an orally available Na(+)-channel blocker, has widely been used in patients with chronic painful diabetic neuropathy. ⋯ Lidocaine (30, but not 3 and 10, mg/kg, i.p.) also significantly relieved both pain behaviors. These results suggest that mexiletine may be effective in relieving the oxaliplatin-induced neuropathic pain clinically.
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The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1alpha subunit by PDH kinase contributes to the suppression of PDH activity. PDH requires thiamine as a coenzyme. ⋯ The O-glycosylated protein was markedly increased in RCFs exposed to high glucose, which was inhibited by thiamine. These results suggest that thiamine ameliorates diabetes-induced PDH inhibition by suppressing the increased expression of the O-glycosylated protein. The O-glycosylation of PDH E1alpha may be involved in the regulation of the PDH activity.
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This study examines the influence of receptor expression level on signaling pathways activated via endothelin type A receptor (ET(A)R) expressed in Chinese hamster ovary cells at 32,100 (ET(A)R-high-CHO) and 893 (ET(A)R-low-CHO) fmolmg protein(-1). Endothelin-1 (ET-1) elicited a sustained increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), which was dependent on G(q/11) protein, phospholipase C (PLC), Na(+)/H(+) exchanger (NHE), and p38 mitogen-activated protein kinase (p38MAPK) in ET(A)R-high-CHO, whereas the sustained [Ca(2+)](i) increase was negligible in ET(A)R-low-CHO. Functional study with Cytosensor(TM) microphysiometer showed that ET-1 evoked an NHE1-mediated increase in extracellular acidification rate (ECAR) in ET(A)R-high-CHO and ET(A)R-low-CHO. ⋯ Western blot analysis demonstrated that ET-1-induced p38MAPK phosphorylation in ET(A)R-low-CHO but not in ET(A)R-high-CHO was mediated via G(q/11) and PLC. The G(q/11)/PLC-independent p38MAPK phosphorylation in ET(A)R-high-CHO was suppressed by expression of the C terminus of G(alpha12) protein to disrupt receptor-G(12) protein coupling. These results provide evidence for multiple signaling pathways of ET(A)R that were activated via at least the G(q/11)/PLC/NHE, G(12)/p38MAPK/NHE, and G(q/11)/PLC/p38MAPK/NHE cascades in an expression level-dependent manner.
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In the present study, we assessed the effects of gluco-obtusifolin, isolated from the seeds of Cassia obtusifolia L., and its aglycone, obtusifolin, on the learning and memory impairments induced by scopolamine using the passive avoidance and the Morris water maze tasks in mice. Gluco-obtusifolin (1, 2, and 4 mg/kg, p.o.) and obtusifolin (0.25, 0.5, 1, and 2 mg/kg, p.o.) significantly reversed scopolamine-induced cognitive impairments in the passive avoidance test (P<0.05). ⋯ In the acetylcholinesterase assay, gluco-obtusifolin and obtusifolin were found to inhibit acetylcholinesterase activity in vitro (IC(50) = 37.2 and 18.5 microM, respectively) and ex vivo. These results suggest that gluco-obtusifolin and its aglycone may be useful for the treatment of cognitive impairment, and that its beneficial effects are mediated, in part, by the enhancement of cholinergic signaling.
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Morphine, oxycodone, and fentanyl are clinically prescribed drugs for the management of severe pain. We investigated whether these opioids possess different efficacy profiles on several types of pain in mouse pain models. When the three opioids were tested in the femur bone cancer model, all of them significantly reversed guarding behavior, whereas the effects on limb-use abnormality and allodynia-like behavior differed among the opioids. ⋯ When the effects of these opioids were examined in a sciatic nerve ligation (SNL) model of neuropathic pain, oxycodone was the most effective, producing an antinociceptive effect without affecting the withdrawal threshold of sham-treated animals. When the effects of these opioids were examined with the tail-flick test using naive animals, oxycodone, morphine, and fentanyl exhibited antinociceptive effects on thermal nociception. These results show that the three opioids exhibit different efficacy outcomes in multiple pain models and that the efficacy profile of oxycodone does not overlap those of morphine and fentanyl.