L-propionyl carnitine, an endogenous ester in fatty acid metabolism, exerts anti-shock and endothelial protective effects in rat splanchnic ischemia-reperfusion injury.

Splanchnic artery occlusion (SAO) results in a severe form of circulatory shock in which oxygen-derived free radicals play an important role. L-Propionyl carnitine (LPC), an endogenous ester that plays a crucial role in cellular fatty acid oxidation and metabolism, has been shown to exert a protective effect in myocardial ischemia/reperfusion injury. Our purpose was to investigate the effects of LPC in an SAO model of ischemia/reperfusion injury. Pentobarbital-anesthetized rats were subjected to 60 min of SAO followed by 120 min of reperfusion. An intravenous bolus of LPC (200 microg/kg) administered 2 min before reperfusion prolonged survival time (116+/-4 vs. 81+/-3 min in 1 mL/kg .9% NaCl vehicle, p < .01), increased survival rate (88 vs. 13.6%, p < .01), and attenuated the percent increase in hematocrits (27+/4% vs. 43+/-3%, p < .05), and the increases in tissue myeloperoxidase activity (1.76+/-.4 U/100 mg vs. 3.79+/-.2 U/100 mg, p < .05). In addition, LPC increased mean arterial blood pressures at 60 min (p < .05), 80 min (p < .05), 100 min (p < .05), and 120 min (p < .05) postreperfusion. Moreover, LPC markedly attenuated splanchnic artery endothelial dysfunction induced by SAO ischemia/reperfusion injury (maximal vasorelaxation to ACh, 74+/-2.7% vs. 57+/-1.9% in vehicle, p < .01). In this murine SAO model of ischemia/reperfusion injury, LPC affords significant protection that may be achieved through inhibiting leukocyte infiltration into intestinal tissue and preserving endothelial function, thereby decreasing microvascular permeability and maintaining tissue perfusion.

Effects of GABAergic drugs on ethanol-induced gastric lesions.

Different classes of GABAergic drugs--baclofen, GABA, muscimol, Na-valproate, Mg-valproate and diazepam--were tested per os on ethanol-induced gastric lesions in rats. The GABAB agonist baclofen failed to affect gastric susceptibility to ethanol damage, while all the other compounds exerted a dose-dependent inhibition on haemorrhagic-necrotic lesions. This effect was not significantly reversed by the specific GABAA antagonist bicuculline, suggesting it to be independent from GABAA receptors. The blockade of prostaglandin synthesis by indomethacin significantly decreased the gastroprotective action of GABA, Na- and Mg-valproate, but did not antagonize the effect of muscimol and diazepam. Gastric juice volume and pH showed remarkable differences between the various treatments.

Hyperalgesic activity of parathyroid hormone and its fragments in male rats.

Results presented in this paper indicate that intracerebroventricular injection of parathyroid hormone reduces pain threshold in male rats. This effect is induced by whole molecule (84 amino acids) or by fragments 1-34 and 44-68 of PTH. The fragment 65-84 of PTH does not induce any change in pain threshold.

Parathyroid hormone fragment 1-34 inhibits drug-induced inflammation in various experimental models.

We investigated the effect of the administration of rat parathyroid hormone-(1-34) on acute or chronic inflammatory processes in different experimental animal models. Fragment 1-34 of parathyroid hormone had an inhibitory effect in all inflammatory acute tests. The dose-response experiments showed that the maximal anti-inflammatory and anti-exudative effects appeared at the dose of 3.30 and 0.33 micrograms/kg, respectively. The anti-inflammatory effect was observed in the first phase of the inflammatory process. In the carrageenin-induced edema test the anti-inflammatory activity began to decline after 180 min. In contrast, this peptide was inactive in the inflammatory chronic test we used.

A role for nitric oxide in the anti-ulcer activity of calcitonin gene-related peptide.

The anti-ulcer activity of calcitonin gene-related peptide (CGRP) was inhibited, in a dose-dependent manner, by pretreatment with NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Our results suggest that endogenous nitric oxide is involved in the anti-ulcer activity of CGRP.

Effect of amylin in various experimental models of gastric ulcer.

Subcutaneous administration of amylin (20-40 micrograms/kg) prevented, in a dose-dependent manner, reserpine- and serotonin-induced gastric damage, but the anti-ulcer effect was not present when lesions were induced by pylorus ligation. The protective effect of amylin was inhibited by pretreatment with capsicin as well as CGRP-(8-37), a calcitonin gene-related peptide (CGRP) and amylin receptor antagonist, and was significantly reduced by domperidone, a dopamine D2 receptor antagonist, or neostigmine, an inhibitor of acetylcholinesterase. Our data suggest that the gastroprotective activity of amylin in some experimental models of gastric ulcers involves capsaicin-sensitive fibers and CGRP receptors. Moreover, the peptide interferes, at least in part, with the dopaminergic and parasympathetic systems.

Protective effects of calcitonin gene-related peptide in different experimental models of gastric ulcers.

Intravenous administration of calcitonin gene-related peptide (CGRP) prevented in a dose-dependent manner reserpine-induced gastric mucosal damage, but failed to affect the lesions produced by ethanol administration. In pylorus-ligated rats, CGRP significantly reduced gastric volume, total acid and peptic activity output as well as ulcer formation. These protective effects of CGRP were not present when rats were pretreated with cysteamine. Our data suggest that CGRP exerts its antisecretory and antiulcer activity, at least in part, by interfering with somatostatin transmission.

The analgesic activity of calcitonin and the central serotonergic system.

The effect of peripherally administered cyproheptadine or reserpine and the administration of 5,7-dihydroxytryptamine (5,7-DHT) in the nucleus raphe dorsalis on the analgesic activity of salmon calcitonin (sCT) injected into the lateral ventricle were investigated in male rats. Cyproheptadine or reserpine, given respectively 30 min or 24 h before the peptide, completely abolished the analgesic activity at all the times studied. However, when reserpine was given before the peptide it increased the effect of sCT at 30 (P less than 0.01), 60 (P less than 0.001), 120 (P less than 0.01) and 180 (P less than 0.01) min. 5,7-DHT injected in the nucleus raphe dorsalis 15 days before the peptide led to complete abolition of the analgesic activity. If neurotoxin was injected 4 days before sCT, the effect of the peptide was significant (P less than 0.05) only at 60 min. The results obtained confirm that the analgesic activity of sCT may involve central serotonergic pathway(s), and that the midbrain raphe nuclei 5-HT content is an important focus for this activity.

Effects of centrally of peripherally injected adrenomedullin on reserpine-induced gastric lesions.

Adrenomedullin intracerebroventricularly administered (0.1 to 20 ng/rat i.c.v.), showed significant gastroprotective activity in a dose-dependent manner. When the peptide was intravenously administered (1 to 1000 ng/kg i.v.) it did not show significant gastroprotective activity in the same test. The gastroprotective effect of the peptide (10 ng/rat) was abolished by bilateral adrenalectomy, by pretreatment with the beta-adrenoceptor antagonist, propranolol (1 mg/kg i.p.), or by a calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8-37) fragment (1 or 10 ng/rat i.c.v.). This study showed that adrenomedullin is protective against reserpine-induced gastric lesions, that the action involves sympathetic nerve activity, and moreover interferes with CGRP receptors.

Effects of salmon calcitonin on plasma renin activity and systolic blood pressure in the rat.

Salmon calcitonin, centrally injected, increased plasma renin activity and blood pressure in rats. It is possible that the peptide through an action on the central serotonergic tone stimulated plasma renin activity with subsequent enhancement of blood pressure. Conversely, peripheral administration of the peptide increased plasma renin activity but did not cause changes in blood pressure. Probably, the enhancement of renin may be a physiological response to the renal activity of calcitonin; however, this activity does not seem to involve urinary prostaglandins.

Protective action of epidermal growth factor and a fraction from Triticum vulgare extract in mouse tail necrosis.

Several peptide growth factors, including EGF, are known to protect endothelium from oxygen-related damage or ischemia-reperfusion, in vitro experiments show that such protective effect involves endogenous endothelium-related factors like nitric oxide and prostanoids. However, in vivo demonstrations of a possible role in related vascular diseases are lacking. In our experiments, human EGF and fraction C, a 3-10 kDa oligosaccharidic fraction from an aqueous extract of Triticum vulgare, known as growth promoters for several cell types including endothelial cells, were found protective against ischemic necrosis of the mouse tail induced by i.v. k-carrageenin plus endothelin-1. After i.p. injection, peak activities were observed at 10 micrograms/kg EGF and 2 mg/kg fraction C. Pretreatment with L-NAME reduced protection in a dose-dependent manner. Addition of indomethacin increased the effect of L-NAME, suggesting that both nitric oxide and eicosanoids are involved in the protective effect of EGF and fraction C.

Antiinflammatory activity of adrenomedullin in the acetic acid peritonitis in rats.

The antiinflammatory effect of ADM was studied in different models of inflammation and compared to the one of CGRP. Peptides were active against acetic acid-induced peritonitis in the rats. ADM and CGRP exerted the antiinflammatory effect at different doses, 400 and 20 ng/kg respectively, but with different efficacy (ADM >CGRP). This effect was blocked by pretreatment with CGRP (8-37) fragment or with L-NAME. No antiinflammatory activity was evidenced against serotonin- or carrageenin-induced rat paw edema. Our data suggest that ADM exerts antiinflammatory activity in the model characterized by a vascular component. This effect involves CGRP receptors and appears to be mediated by nitric oxide system.

Anti-inflammatory activity of amylin and CGRP in different experimental models of inflammation.

The anti-inflammatory activity of amylin was studied in different models of inflammation, and compared to that of CGRP. Both peptides were active against mouse ear oedema induced by croton oil and acetic acid-induced peritonitis in the rat. CGRP was more potent than amylin in both models. Pretreatment with CGRP 8-37 fragment blocked the anti-inflammatory activity of both peptides in croton oil ear oedema. No anti-inflammatory activity was evidenced against serotonin-induced rat paw oedema and plasma protein extravasation induced by dextran in rat skin. Our results suggest that amylin exerts anti-inflammatory activity only in inflammatory models characterized by a vascular component. This effect appears to be mediated by the involvement of CGRP receptors.

Effects of CGRP in different models of mouse ear inflammation.

The anti-inflammatory activity of calcitonin gene-related peptide (CGRP) has been studied in cutaneous inflammation induced by croton oil (CO), arachidonic acid (AA), tetradecanoylphorbol acetate (TPA) or cantharidin (CA). Our results show that mouse ear inflammation induced by CO, AA or TPA is decreased by topical administration of CGRP, whereas that induced by CA is not affected. The dose-response and temporal analysis of CGRP effect show that the maximal activity is present at the dose of 30 pmol/ear and when administered 30 min after the irritating agent. Moreover, pretreatment with capsaicin is able to mimic the anti-inflammatory effect of exogenous CGRP, while simultaneous administration of CGRP and capsaicin produces a reduced response. Our results suggest that CGRP released from sensory.

Grapefruit juice effects on the bioavailability of cyclosporin-A in rats.

Previous studies indicate that blood levels of cyclosporin-A are increased by concomittant administration of grapefruit juice in healthy subjects and patients. It was suggested that grapefruit juice could inhibit the metabolism of cyclosporin-A by CYP3A4, the predominant cytochrome P450 enzyme in the gut wall and liver. However, up to date, the mechanism of action of grapefruit juice has not been conclusively identified and no work has been conducted in animals to quantify its effect on cyclosporin-A metabolism. This study compared the disposition of cyclosporin-A (5 mg/kg) coadministered with grapefruit juice, orange juice or water (10 ml/kg) in male Sprague-Dawley rats. Time to peak concentration was about 5 h for each group. Area under the blood concentration-time curve and peak concentration of cyclosporin-A were increased by 31% and 20%, respectively, with grapefruit juice (P < 0.05). The effects of grapefruit juice were not duplicated by orange juice which did not differ significantly from water for any of the parameters tested. These results confirm that grapefruit juice may act as an inhibitor of drug metabolism altering the disposition of concomittantly administered cyclosporin-A in rats. Nonetheless, it was demonstrated that, under appropriate experimental conditions, rats may be suitable models for in vivo investigation of the interaction mechanism between grapefruit juice and cyclosporin-A.

Pharmacological properties and toxicology of MED-15, a prodrug of tolmetin.

In this study the pharmacological evaluation of MED-15, a non-acidic prodrug of tolmetin, is described. After oral administration the new compound shows a marked anti-inflammatory activity similar to that of tolmetin, but with minor ulcerogenic action and lower acute toxicity.

Anti-inflammatory action of AGF44, a ganglioside ester derivative.

Gangliosides (GA) have been shown to promote axonal sprouting and growth of injured peripheral nerves, and enhance functional biochemical and morphologic recovery after CNS damage. Moreover, it has recently been shown that the natural ganglioside mixture (GM1 + GD1a + GD1b + GT1b) from bovine brain is endowed with powerful anti-inflammatory activity in rodents. Here we report that the novel semisynthetic ganglioside derivative AGF44, the isopropyl ester of monosialoganglioside GM1, displays a potent anti-inflammatory activity when orally or topically administered in various models of acute inflammation. AGF44 was effective (0.5-5 mg/kg p.o. or 0.5% gel topical application) in reducing rat paw oedema induced by either carrageenin, histamine, bradykinin, serotonin, nystatin or kaolin. Moreover, crossed confrontation with the effects elicited by other anti-inflammatory agents revealed that AGE44 seems to act through a different pathway than NSAIDs, steroids or antihistaminic/antiserotoninic agents.

Evidence for the involvement of opioidergic systems in medprotine-induced analgesia in the mouse.

Intramuscular administration of medprotine, a protein fraction of human placenta (30-300 kDa), produced dose-dependent and long lasting analgesia as evaluated by various analgesic tests in mice. Activity was found in a dose range of 0.05-0.6 mg/kg in the phenylbenzoquinone and acetic acid writhing tests and 1.5-5 mg/kg in the hot-plate test. In this latter model, medprotine enhanced morphine-induced analgesia. Pretreatment with naloxone antagonized the effect of medprotine in all assays. The antinociceptive response of medprotine was not modified after a ten day pretreatment and no overt withdrawal symptom could be observed after either interruption of chronic treatment or administration of a precipitating dose of naloxone. It is concluded that the analgesic activity of medprotine may be mediated through either the opiate receptors or activation of endogenous opioidergic systems.

Inhibitory effects of propionyl-L-carnitine on plasma extravasation induced by irritants in rodents.

The effects of propionyl-L-carnitine (PLC) in various models of inflammation were studied in rats and mice. PLC (50-200 mg/kg i.p.) dose-dependently inhibited the granuloma pouch induced by croton oil in rats, but failed to inhibit either cotton pellet granuloma or carrageenin-induced paw oedema and peritonitis. PLC (100 mg/kg i.p.) significantly reduced mouse ear oedema induced by croton oil, tetradecanoylphorbol acetate and arachidonic acid; in these models, PLC concomitantly reduced plasma extravasation, as evaluated by the leakage of Evans blue. In all the tested models, L-carnitine and acetyl-L-carnitine were ineffective, suggesting a specific protective role of PLC in the vascular component of the inflammatory process.

Influence of sodium valproate and carbamazepine on GSH levels in rat cerebral cortex.

The effects of sodium valproate (150 mg/kg) and carbamazepine (300 mg/kg), alone and in combination, on the content of glutathione (GSH) were investigated in the rat cerebral cortex. No modification was found either 4, 12 or 16 hours after treatment, suggesting that sodium valproate and carbamazepine do not affect the cortical GSH metabolism in rats.