Matilde Amico-Roxas

Amylin given by central or peripheral routes decreases gastric emptying and intestinal transit in the rat

The effect of rat amylin on gastric emptying and intestinal transit in the rat was examined. Amylin administered intracerebroventricularly (1, 2, 2.5 or 4 μg/rat) produced the maximal decrease in gastric emptying and intestinal transit at the dose of 2.5 μg/rat. Higher doses produced a lower effect. Peripheral administration (25, 50 or 100 μg/kg) produced dose-dependent effects. Pre-treatment with neostigmine blocked the effect of amylin when it was centrally injected, while the effect of amylin given peripherally was partially reduced. Pre-treatment with domperidone decreased the inhibitory effect of peripherally injected amylin, but no effect was observed when the peptide was centrally injected.

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.

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.

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.

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.

Pyrazolothiazolopyrimidine derivatives as a novel class of anti-inflammatory or antinociceptive agents: synthesis, structural characterization and pharmacological evaluation☆

Abstract As a part of a research program on anti-inflammatory-analgesic compounds, pyrazolothiazolopyrimidines 5a-f and 5g-i were prepared by cyclodehydration in 98% H 2 SO 4 or PPA of the corresponding 6-thioketomethylene-substituted-4-hydroxy-pyrazolo[3,4- d ]pyrimidines 2a-i and 2g-i . The results of the pharmacological in vivo screening indicate an interesting dissociation of the analgesic from the anti-inflammatory activity depending on aromatic or aliphatic substitution at the C4 of the thiazole ring. Analgesic activity was not associated with any narcotic effect; in addition, all the active compounds showed a remarkable systemic and gastric tolerance. This indicated a mode of action different from that of the classical nonsteroidal anti-inflammatory drugs, acting on prostaglandin biosynthesis. To clarify the mechanism or the mechanisms underlying the pharmacological activity of these and other closely related compounds, we initiated a ‘file chemical approach’ to various systems involved in the inflammatory process. At present, some of the more active in vivo compounds tested as substance P antagonists showed a moderate and possibly non-specific effect on NK 1 and NK 2 receptors.

Gastroprotective effect of adrenomedullin administered subcutaneously in the rat

Subcutaneous injections of adrenomedullin prevented reserpine-induced gastric mucosal damage in a dose-dependent manner (1-1000 ng/kg), but did not interfere with the lesions produced by ethanol administration. In pylorus-ligated rats adrenomedullin significantly reduced gastric volume, total and free acid output as well as ulcer formation. The gastroprotective activity of adrenomedullin was not present in rats pretreated with cysteamine. These results suggest that adrenomedullin exerts its antiulcer effect, when it is administered subcutaneously (s.c.), probably by a mechanism which involves somatostatin related transmission.

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.

Secretory and vascular effects of adrenomedullin in gastric ulcer: role of CGRP- and adrenomedullin-receptors.

Adrenomedullin prevents damage of gastric mucosa in either reserpine-treated or pylorus-ligated rats. Pre-treatment with CGRP(8-37) resulted in a decrease of the gastro-protective effect of adrenomedullin in both models and reversed the inhibitory effect of adrenomedullin on gastric acid output in the pylorus-ligated rats. These adrenomedullin actions were less effectively modified by pre-treatment with adrenomedullin(22-52). These data suggest that the anti-ulcer effect of adrenomedullin is mainly related to its anti-secretory action, presumably mediated through CGRP-receptors.

Effects of centrally or 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.