The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 2006
Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling.
The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. ⋯ GalR2 is antiepileptogenic through the Gi mechanism independent of GIRK. A secondary proconvulsant pathway coupled to GalR2 involves G(q/11) and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.
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J. Pharmacol. Exp. Ther. · Aug 2006
Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) induces apoptosis and cell cycle arrest in A549 cells through p53 accumulation via c-Jun NH2-terminal kinase-mediated phosphorylation at serine 15 in vitro and in vivo.
This study first investigates the anticancer effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) in human nonsmall cell lung cancer cells, A549. Plumbagin has exhibited effective cell growth inhibition by inducing cancer cells to undergo G2/M phase arrest and apoptosis. Blockade of cell cycle was associated with increased levels of p21 and reduced amounts of cyclinB1, Cdc2, and Cdc25C. ⋯ SP6000125 also inhibited the phosphorylation of Bcl-2 (Ser70) induced by plumbagin. Further investigation revealed that plumbagin's inhibition of cell growth effect was also evident in a nude mice model. Taken together, these results suggest a critical role for JNK and p53 in plumbagin-induced G2/M arrest and apoptosis of human nonsmall cell lung cancer cells.
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J. Pharmacol. Exp. Ther. · Aug 2006
Inhibition of paclitaxel-induced A-fiber hypersensitization by gabapentin.
Paclitaxel (Taxol) is a widely used chemotherapeutic agent in the treatment of several tumors. However, its use is often associated with the generation of peripheral neuropathic pain expressed as mechanical allodynia and thermal hyperalgesia. The molecular mechanism behind this debilitating side effect is obscure, and efficient drugs for its prevention are required. ⋯ The paclitaxel-induced neuropathic pain was completely abrogated by gabapentin (30 mg/kg i.p.) treatment. Furthermore, we found that mRNA and protein levels of the voltage-gated calcium channel (alpha 2)delta-1 subunit (Ca(alpha 2)delta-1), one of the putative targets for gabapentin, was up-regulated in dorsal root ganglions (DRGs), as well as increased expression of Ca(alpha 2)delta-1 protein in medium/large-sized DRG neurons by immunohistochemistry, following paclitaxel treatment. This suggests that paclitaxel induces A-fiber-specific hypersensitization, which may contribute to the functional mechanical allodynia and hyperalgesia, and that gabapentin could be a potential therapeutic agent for paclitaxel-induced neuropathic pain.
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J. Pharmacol. Exp. Ther. · Jul 2006
Comparative StudyVolatile anesthetic preconditioning attenuates myocardial apoptosis in rabbits after regional ischemia and reperfusion via Akt signaling and modulation of Bcl-2 family proteins.
We tested whether isoflurane preconditioning inhibits cardiomyocyte apoptosis and evaluated the role of the phosphatidylinositol-3-kinase (PI3K)/Akt pathway in anesthetic preconditioning and determined whether PI3K/Akt signaling modulates the expression of pro- and antiapoptotic proteins in anesthetic preconditioning. Six-month-old New Zealand rabbits subjected to 40 min of myocardial ischemia followed by 180 min of reperfusion were assigned to the following groups: ischemia-reperfusion (I/R), isoflurane preconditioning and isoflurane plus PI3K inhibitors, wortmannin and 2-(4-morpholinyl)-8-phenyl-4H-l-benzopyran-4-one (LY294002) (0.6 and 0.3 mg/kg i.v., respectively). Sham-operated, wortmannin+I/R, wortmannin+sham, LY294002+I/R, and LY294002+sham groups were also included. ⋯ These effects were inhibited by wortmannin and LY294002. The data indicate that isoflurane preconditioning reduces infarct size and myocardial apoptosis after I/R. Activation of PI3K and modulation of the expression of pro- and antiapoptotic proteins may play a role in isoflurane-induced myocardial protection.
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J. Pharmacol. Exp. Ther. · Jul 2006
Comparative StudyEffects of anesthetics on mutant N-methyl-D-aspartate receptors expressed in Xenopus oocytes.
Alcohols, inhaled anesthetics, and some injectable anesthetics inhibit the function of N-methyl-d-aspartate (NMDA) receptors, but the mechanisms responsible for this inhibition are not fully understood. Recently, it was shown that ethanol inhibition of NMDA receptors was reduced by mutation of residues in the transmembrane (TM) segment 3 of the NR1 subunit (F639A) or in TM4 of the NR2A subunit (A825W), suggesting putative ethanol binding sites. ⋯ Rapid applications of glutamate and glycine by a T-tube device provided activation time constants, which suggested different properties of ketamine and isoflurane inhibition. Thus, amino acids in TM3 and TM4 are important for the actions of many anesthetics, but nitrous oxide, benzene, and ketamine seem to have distinct mechanisms for inhibition of the NMDA receptors.