The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · May 2009
Altered responses to propofol, but not ketamine, in mice deficient in the 65-kilodalton isoform of glutamate decarboxylase.
GABA is synthesized by two isoforms of glutamate decarboxylase (GAD), GAD65, and GAD67. However, the relative contributions of GAD65-mediated GABA synthesis to the in vivo actions of anesthetics remain unknown. To address this issue, we used mice deficient in the 65-kDa isoform of GAD and tested the hypothesis that partial reduction of GABA content in GAD65-deficient mice [GAD65(-/-)] would contribute to hypnotic and immobilizing actions of the anesthetics. ⋯ HCl) (0.75 mg/kg i.p.), reinstated diminished actions of propofol in GAD65(-/-) mice. Cortical pyramidal neurons in GAD65(-/-) mice had smaller tonic conductances, and propofol-induced enhancement of tonic inhibition was smaller than in WT mice, suggesting that genotype differences in GAD65-mediated GABAergic inhibitory tone may be, at least in part, a cellular basis underlying behavioral differences. In conclusion, GAD65(-/-) mice show a diminished response to propofol, but not ketamine, indicating that GAD65-mediated GABA synthesis plays an important role in hypnotic and immobilizing actions of propofol.
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J. Pharmacol. Exp. Ther. · May 2009
Camostat attenuates airway epithelial sodium channel function in vivo through the inhibition of a channel-activating protease.
Inhibition of airway epithelial sodium channel (ENaC) function enhances mucociliary clearance (MCC). ENaC is positively regulated by channel-activating proteases (CAPs), and CAP inhibitors are therefore predicted to be beneficial in diseases associated with impaired MCC. The aims of the present study were to 1) identify low-molecular-weight inhibitors of airway CAPs and 2) to establish whether such CAP inhibitors would translate into a negative regulation of ENaC function in vivo, with a consequent enhancement of MCC. ⋯ In vivo, topical airway administration of camostat induced a potent and prolonged attenuation of ENaC activity in the guinea pig trachea (ED(50) = 3 microg/kg). When administered by aerosol inhalation in conscious sheep, camostat enhanced MCC out to at least 5 h after inhaled dosing. In summary, camostat attenuates ENaC function and enhances MCC, providing an opportunity for this approach toward the negative regulation of ENaC function to be tested therapeutically.
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J. Pharmacol. Exp. Ther. · May 2009
Helium-induced early preconditioning and postconditioning are abolished in obese Zucker rats in vivo.
Preconditioning is abolished in the prediabetic Zucker obese rat. It has been shown that prevention of mitochondrial permeability transition pore (mPTP) opening is involved in preconditioning by the noble gas helium. Here, we investigated: 1) whether helium induces pre- and postconditioning in Zucker rats and 2) whether possible regulators of the mPTP [i.e., mitochondrial respiration or the extracellular signal-regulated kinase (Erk) 1/2, Akt/glycogen synthase kinase (GSK)-3beta signaling pathway] are influenced. ⋯ Helium had no effect on Erk1/2 and Akt phosphorylation. GSK-3beta phosphorylation during ischemia was reduced after helium application in ZL but not in ZO rats. Helium-induced preconditioning is abolished in obese Zucker rats in vivo, probably caused by a diminished effect of helium on mitochondrial respiration.
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J. Pharmacol. Exp. Ther. · May 2009
Carbon monoxide rescues mice from lethal sepsis by supporting mitochondrial energetic metabolism and activating mitochondrial biogenesis.
Use of metal carbonyl-based compounds capable of releasing carbon monoxide (CO) in biological systems have emerged as a potential adjunctive therapy for sepsis via their antioxidant, anti-inflammatory, and antiapoptotic effects. The role of CO in regulation of mitochondrial dysfunction and biogenesis associated with sepsis has not been investigated. In the present study, we employed a ruthenium-based water-soluble CO carrier, tricarbonylchoro(glycinato)ruthenium (II) (CORM-3), one of the novel CO-releasing molecules (CO-RMs), to test whether CO can improve cardiac mitochondrial dysfunction and survival in peritonitis-induced sepsis. ⋯ CORM-3 treatment in septic mice restored the deleterious effects of sepsis on mitochondrial membrane potential, respiratory control ratio, and energetics. It is interesting that administration of CORM-3 during sepsis elicited a mild oxidative stress response that stimulated mitochondrial biogenesis with PGC-1alpha protein expression and mtDNA copy number increases. Our results reveal that delivery of controlled amounts of CO dramatically reduced mortality in septic mice, indicating that CO-RMs could be used therapeutically to prevent organ dysfunction and death in sepsis.
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J. Pharmacol. Exp. Ther. · May 2009
Edaravone, a free radical scavenger, protects against retinal damage in vitro and in vivo.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, is used for the treatment of acute cerebral infarction. In this study, we investigated whether edaravone is neuroprotective against retinal damage. In vitro, we used a radical-scavenging capacity assay using reactive oxygen species-sensitive probes to investigate the effects of edaravone on H(2)O(2), superoxide anion (O(2)*), and hydroxyl radical (*OH) production in a rat retinal ganglion cell line (RGC-5). ⋯ Edaravone at 5 and 50 nmol intravitreous injection or at 1 and 3 mg/kg i.v. significantly protected against NMDA-induced retinal cell death. At 50 nmol intravitreous injection, it 1) decreased the retinal expressions of TUNEL-positive cells, 4-HNE, and 8-OHdG and 2) reduced the retinal expressions of NMDA-induced phosphorylated JNK and phosphorylated p38 but not that of phosphorylated ERK. These findings suggest that oxidative stress plays a pivotal role in retinal damage and that edaravone may be a candidate for the effective treatment of retinal diseases.