The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Dec 2007
Randomized Controlled TrialPharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics.
3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is increasingly used by young people for its euphoric and empathic effects. MDMA can be used in combination with other drugs such as selective serotonin reuptake inhibitors. A clinical trial was designed where subjects pretreated with paroxetine, one of the most potent inhibitors of both 5-hydroxytryptamine reuptake and CYP2D6 activity, were challenged with a single dose of MDMA. ⋯ These data show that pretreatment with paroxetine significantly attenuates MDMA-related physiological and psychological effects. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.
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J. Pharmacol. Exp. Ther. · Dec 2007
Neuroprotective effects of glyceryl nonivamide against microglia-like cells and 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells.
Glyceryl nonivamide (GLNVA), a vanilloid receptor (VR) agonist, has been reported to have calcitonin gene-related peptide-associated vasodilatation and to prevent subarachnoid hemorrhage-induced cerebral vasospasm. In this study, we investigated the neuroprotective effects of GLNVA on activated microglia-like cell mediated- and proparkinsonian neurotoxin 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in human dopaminergic neuroblastoma SH-SY5Y cells. In coculture conditions, we used lipopolysaccharide (LPS)-stimulated BV-2 cells as a model of activated microglia. ⋯ Furthermore, in 6-OHDA-treated SH-SY5Y cells, GLNVA rescued the changes in condensed nuclear and apoptotic bodies, prevented the decrease in mitochondrial membrane potential, and reduced cells death. GLNVA also suppressed accumulation of iROS and up-regulated heme oxygenase-1 expression. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2, and gp91(phox) was also reduced by GLNVA. In summary, the neuroprotective effects of GLNVA are mediated, at least in part, by decreasing the inflammation- and oxidative stress-associated factors induced by microglia and 6-OHDA.
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J. Pharmacol. Exp. Ther. · Dec 2007
Effects of resveratrol (trans-3,5,4'-trihydroxystilbene) treatment on cardiac remodeling following myocardial infarction.
Resveratrol (RES; trans-3,5,4'-trihydroxystilbene) has been shown to improve health and slow the progression of disease in various models. Several cardioprotective mechanisms have been identified including antioxidant, anti-inflammatory, and antifibrotic actions. Each of these actions is thought to have the ability to attenuate the pathophysiology underlying the deleterious cardiac structural remodeling that results from acute myocardial infarction (MI). ⋯ Resveratrol administration increased beta-adrenoceptor density, so that resveratrol-treated MI rats had beta-adrenoceptor densities similar to normal rats. Real-time reverse transcription-polymerase chain reaction revealed that MI-induced changes in sarcoplasmic reticulum Ca2+-ATPase 2 and transforming growth factor beta-1 expression were unaltered by resveratrol, whereas MI-induced increases in atrial natriuretic factor (ANF) and connective tissue growth factor (CTGF) expression were attenuated. Resveratrol treatment does not improve cardiac remodeling and global hemodynamic function post-MI but does preserve contractile reserve and attenuate ANF and CTGF up-regulation.
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J. Pharmacol. Exp. Ther. · Dec 2007
Deletion of mu-opioid receptor in mice alters the development of acute neuroinflammation.
The realization that the mu-opioid system plays a key role in the control of the process of neuroinflammation is a new concept that may lead to identification of novel therapies for this extremely widespread and intractable syndrome. Fever is the hallmark among the defense mechanisms evoked by the entry into the body of pathogens to initiate the innate immune responses. In an attempt to determine the possible involvement of mu-opioid receptors in the control of brain inflammation, we examined the effect of their deletion on the fever induced by i.c.v. injection of lipopolysaccharide (LPS). ⋯ In the WT, i.c.v. injection of 100 ng of LPS induced fever, but there was no increase in body temperature in the MOP-KO mice. Saline, given i.c.v., did not alter the body temperature, either in WT or MOP-KO. These results show that the mu-opioid system participates in the control of acute neuroinflammation, further reinforcing our earlier finding that the opioid system is involved in the pathogenesis of fever induced by bacterial LPS, and that mu-opioid receptors are the target for morphine-induced hyperthermia.
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J. Pharmacol. Exp. Ther. · Dec 2007
1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a novel gamma-secretase modulator, reduces brain beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease without causing peripheral toxicity.
Some nonsteroidal anti-inflammatory drugs has been shown to allosterically modulate the activity of gamma-secretase, the enzymatic complex responsible for the formation of beta-amyloid (Abeta). 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a new gamma-secretase modulator, devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro. We evaluated the effects of chronic CHF5074 treatment on brain Abeta pathology in Tg2576 transgenic mice. Twenty-eight animals of 9.5 to 10.5 months of age received CHF5074-medicated diet (375 ppm) or standard diet for 17 weeks. ⋯ No abnormal findings were observed upon histopathological examination of the gastrointestinal tract, indicating the absence of COX-related toxicity. Semiquantitative histochemical evaluation of goblet cells in the ileum of vehicle- and CHF5074-treated animals yielded similar results, suggesting no effects on Notch pathway. CHF5074 is therefore a promising therapeutic agent for Alzheimer's disease.