1 We characterized the regulation of cyclooxygenase-2 (COX-2) at the mRNA, protein and mediator level in two rat models of acute in¯ammation, carrageenan-induced paw údema and mechanical hyperalgesia. 2 Carrageenan was injected in the hind paw of rat at low (paw údema) and high doses (hyperalgesia). COX-2 and prostaglandin E 2 (PGE 2 ) levels were measured by RT ± PCR and immunological assays. We also determined the distribution of COX-2 by immunohistochemistry. 3 The injection of carrageenan produced a signi®cant and parallel induction of both COX-2 and PGE 2 . This induction was signi®cantly higher in hyperalgesia than in paw údema. This was probably due to the 9 fold higher concentration of carrageenan used to provoke hyperalgesia. 4 Immunohistochemical examination showed COX-2 immunoreactivity in the epidermis, skeletal muscle and in¯ammatory cells of rats experiencing hyperalgesia. In paw údema however, only the epidermis showed positive COX-2 immunoreactivity. 5 Pretreatment with indomethacin completely abolished the induction of COX-2 in paw údema but not in hyperalgesia. 6 These results suggest that multiple mechanisms regulate COX-2 induction especially in the more severe model. In carrageenan-induced paw údema, prostanoid production have been linked through the expression of the COX-2 gene which suggest the presence of a positive feedback loop mechanism.
The preferential release of the neurohypophyseal hormones vasopressin and oxytocin by appropriate stimuli implies that neurons secreting each hormone receive different afferent connections and may therefore contain membrane receptors for different neurotransmitters. Since electrophysiological studies on rat supraoptic nucleus (SON) neurosecretory neurons suggest that the activated vasopressin-secreting neuron may be selectively identified by a phasic activity pattern, extracellular recordings were performed in pentobarbital anesthetized male Sprague-Dawley rats to compare the responses of 59 phasically-active SON neurosecretory cells to several neurotransmitter candidates endogenous to SON and applied by microiontophoresis. Among excitatory agents, most SON cells demonstrated a brisk depolarization to aspartate and glutamate; quiescent cells could also be induced into phasic activity by continuous application of either amino acid with low currents. During applications of acetylcholine and nicotine, phasically active neurons demonstrated elongated periods of continued activity, but without an increase in overall firing frequency, suggesting a possible mechanism for cholinergic enhancement of vasopressin release. In contrast, norepinephrine (NE) exerted an opposite action by either terminating a burst of activity prematurely or decreasing the number of action potentials per burst; some cells displayed a prolonged arrest of phasic activity for several minutes following NE applications. This mechanism of action could explain any inhibitory effect of NE on vasopressin secretion. We observed no apparent tachyphylaxis to repeated NE applications. GABA applications also terminated phasic activity prematurely, but cell firing resumed within seconds of removal of the application currents. Leucine enkephalin exerted a weak depressant action on the excitability of a small percentage of phasically-active SON neurons. For further comparison, we tested these agents on 18 continuously-active (possible oxytocin-secreting) SON neurosecretory neurons. Most of these neurons demonstrated changes in excitability similar to that noted on phasically-active cells; however, the duration of drug action seldom outlasted the period of its application. One exception was the observation that acetylcholine, but not nicotine, depressed the firing of a portion of the continuously-active SON neurosecretory cell population. These extracellular observations provide preliminary evidence of differences in the neuropharmacological properties of SON putative vasopressin- and oxytocin-secreting neurons that may be better clarified with detailed intracellular measurements.
Renal effects of a selective cyclooxygenase-2 (COX-2) inhibitor [MF-Tricyclic; 3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone] were studied in control and volume-depleted conscious dogs. MF-Tricyclic was compared with the nonselective COX-1/COX-2 inhibitor indomethacin. Six instrumented male dogs were randomly selected to receive MF-Tricyclic or indomethacin at 10 mg/kg. Volume depletion was effected by a sodium-restricted diet (14 days) with administration of furosemide (7.5 mg/kg, i.v.) the day before the experiment. Indomethacin ablated systemic COX-1 activity (p < 0.05), whereas MF-Tricyclic did not affect this activity. Each compound achieved plasma concentrations in excess of their respective median inhibitory concentrations (IC50 values) against canine COX-2. In controls, neither compound affected mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), fractional excretion (FE) Na+, or FE K+. In volume-depleted dogs, indomethacin reduced RBF (p < 0.05), whereas MF-Tricyclic did not affect this parameter. Indices of renal function in volume-depleted dogs were not affected. These data are consistent with the view that the effects of indomethacin on RBF are a consequence of inhibition of COX-1 activity. Furthermore, in these studies, short-term administration of a selective COX-2 inhibitor was without deleterious effects on renal function.
Praziquantel is currently the only drug available to treat schistosomiasis, a disease of enormous public health significance caused by a blood fluke of the genus Schistosoma. Diminazene, a drug approved by the FDA, has been successfully used to treat diseases caused by blood protozoan parasites. In this study, we evaluated the antiparasitic properties of diminazene against S. mansoni ex vivo and in mice harboring either chronic or early S. mansoni infection. In vitro, we monitored phenotypic and tegumental changes as well as the effects of the drug on pairing and egg production. In a mouse infected with either adult (chronic infection) or immature (early infection) worms, diminazene was administered intraperitoneally (10-100 mg/kg) or by oral gavage (100-400 mg/kg), and we studied the influence of drug on worm burden and egg production. Liver and spleen pathologies and serum aminotransferase levels were also analyzed. In vitro, EC50 and EC90 values revealed that diminazene is able to kill both immature and adult parasites, and its effect was time- and concentration-dependent. In addition, confocal laser scanning microscopy showed morphological alterations in the tegument of schistosomes. In an animal model, the influence of the drug on worm burden, egg production, hepatomegaly, and splenomegaly depended on the dosing regimen applied and route of administration. Diminazene also caused a significant reduction in aminotransferase levels. Comparatively, diminazene treatment was more effective in chronic infection than early infection. In tandem, our study revealed that diminazene possesses anthelmintic properties and it improves liver injury caused by Schistosoma eggs.
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