Calcitonin-induced anorexia in rats: A structure-activity study by intraventricular injections.

Abstract

Abstract-The anorectic potency of salmon, porcine and human calcitonins (sCT, pCT and hCT, respectively) and two sCT-fragments were compared in rats. Intraventricular injections of sCT (0.062 and 0.031 nmole/animal) significantly reduced the normal feeding and body weight. The effect appeared to be dose-dependent, reversible and lasted longer than 6 hr. No anorexia ensued, however, on injections of mammalian hormones though tested in relatively high doses (pCT: up to 3.7 nmole, hCT: 3.7 nmole). The C-terminal fragments of sCT, sCT (10-32) and sCT (22-32) were also found to be devoid of anorectic activity; but when administered with sCT, the longer fragment (1.2 nmole) significantly decreased the effect of sCT and even the shorter one (18 nmole) tended to act as an antagonist. This property was not recorded with pCT and hCT in the doses examined. On the one hand, these results indicate a novel specificity of the anorectic receptor in rat brain; and on the other hand, they seem to strongly argue against the hypothesis that in mammals thyroidal calcitonin secreted postprandially might participate in the regulation of subsequent feeding, unless the presence of the sCT-like molecule can be detected in mammals. All the more because detection of such a molecule must await development of a specific assay, the antagonistic property of the sCT fragment found herein would have use for clarifying the physiological significance of the anorectic receptor which is possibly in the hypothalamus.The anorectic effect of salmon calcitonin (sCT) was first reported by Freed et al. (1, 2). When injected subcutaneously, the fish hormone strongly reduced food intake in rats and rhesus monkeys and reduced the body potency by direct injection into rat brain has led them to suggest that the peptide would exert its effect by directly acting on the central nervous system. Later, using a synthetic derivative of eel calcitonin, Miyahara and Oomura (3) electrophysiologically identified a group of glucose-sensitive neurons in the rat hypothalamus as a possible locus of the anorectic effect. Since it has been demon strated that the calcitonin-like immuno activity increases postprandially in adult and

A novel effect of salmon calcitonin on in vitro Ca-uptake by rat brain hypothalamus: The regional and hormonal specificities.

“…The lowest dose of sCT which Freed et al (5) employed to decrease feeding of rats was 0.20 U (0.015 nmole) per animal. Later we confirmed that the minimum effective dose would be above 0.2 U per rat (6). Assuming the distribution volume as 2.0-0.2 ml, injection of 0.20 U would give 7.5 nM or higher as the final concentration which cor responds to the minimum effective concen tration estimated herein for the novel in vitro effect.…”

“…Recently, we have compared the anorectic potency of the three calcitonins and the two sCT fragments used in this experiment (6 …”

Calcitonin-Induced Analgesia: An Unusual Hormone Specificity

“…Com parative studies (4,5) on the anorectic potency of calcitonins of various animal origins have provided the results supporting the classical concept established for the hypocalcemic activity that the hormone of fish origin is biologically far more potent than the mammalian congeners (6).…”

“…sCT (4500 U/mg) was the synthetic product and pCT (170 U/mg) the natural one from the Armour Pharmaceutical Co. (Kankakee, IL, U.S.A.). Intracerebroven tricular cannulation was done as described previously (4). The antinociceptive activity was evaluated by the method of Randall and Selitto (8).…”

Converting the Highly Amyloidogenic Human Calcitonin into a Powerful Fibril Inhibitor by Three-dimensional Structure Homology with a Non-amyloidogenic Analogue

“…Moreover, aggregation stimulates undesirable immune responses, resulting in resistance or allergic reactions in patients (13,14), and drug-induced cytotoxicity (15). On the contrary, sCT shows a higher potency combined with a longer in vivo half-life when compared with hCT and a substantially lower propensity to aggregate (7,11), but it has been shown to develop side effects such as anorexia and vomiting (16,17). When aggregation is prevented by drastic chemical conditions, hCT shows a much higher potency than sCT (18); however, those conditions are difficult to implement during the production, storage, and administration to patients, explaining why hCT has never been extensively used as a therapeutic.…”