Circadian melatonin and young-to-old pineal grafting postpone aging and maintain juvenile conditions of reproductive functions in mice and rats.

Chronic, night administration of melatonin to aging mice and transplantation of a young pineal gland into the thymic rudiment of older mice and rats have been studied with the aim of evaluating their effects on aging of gonadal, sexual, and reproductive functions. Both melatonin administration and young-to-old pineal grafting positively affect size and function of testes and maintenance of juvenile hippocampal and testicular LHRH-receptors and beta-adrenergic receptors in the tests of old rats and mice. These results demonstrate that a pineal-directed circadian function and cyclicity is fundamental for the regulation of sexual, reproductive physiology, and that proper intervention with melatonin may potentially postpone aging of both neural and gonadal sexual function.

The involvement of pineal gland and melatonin in immunity and aging: II. Thyrotropin-releasing hormone and melatonin forestall involution and promote reconstitution of the thymus in anterior hypothalamic area (AHA)-lesioned mice.

A stereotactic electrolytic lesion of the anterior hypothalamic area in mice produces a rapid involution of the thymus and a reduction of lymphocytes in the peripheral blood. This effect on the thymus and blood lymphoid compartment can be prevented by postoperational administration of thyrotropin-releasing hormone (TRH) or melatonin. These activities of TRH or melatonin are antagonized by the opioid receptor blocker naltrexone. They do not seem to depend on stimulation of the thyroid gland or of the endogenous opioid system but rather on a direct activity of TRH on thymic targets or binding sites on lymphocytes.

Iron carrier proteins facilitate engraftment of allogeneic bone marrow and enduring hemopoietic chimerism in the lethally irradiated host.

Cell-free supernatants of rabbit bone marrow were fractionated, separated, and purified by Ultrogel and Superose chromatography. A single fraction promoted engraftment of allogeneic bone marrow and enduring hemopoietic chimerism across the H-2 barrier in lethally irradiated mice. This "bio-active" fraction, analyzed by reducing SDS-PAGE electrophoresis, and transblotted on PVDF membrane, and purified by reverse-phase HPLC and SDS-PAGE electrophoresis yielded a main prealbumin band that when examined for primary structure by Edman degradation, proved to be rabbit transferrin. This was also attested by highly specific precipitation of the prealbumin band with polyclonal antibodies to rabbit transferrin. Iron-saturated human transferrin, lactotransferrin, and egg transferrin (conalbumin) were assayed in irradiated C57BL/6 mice infused with bone marrow from histoincompatible BALB/c donors. Mice treated with iron-loaded transferrins survive and develop enduring allogeneic chimerism with no discernible signs of graft-versus-host disease. Iron carrier proteins thus provide an unique means of achieving successful engraftment of allogeneic bone marrow in immunologically hostile murine H-2 combinations.

[The effect of iron carrier proteins on the transplantation of H-2 locus-incompatible bone marrow in irradiated mice]. / Vliianie zhelezonesushchikh belkov na transplantatsiiu nesovmestimogo po H-2 lokusu kostnogo mozga obluchennym mysham.

Rabbit bone marrow supernatants were fractionated and purified by Ultrogel and Superose chromatography. A unique fraction promoted engraftment of allogenic bone marrow and enduring hemopoietic chimerism across the histocompatibility (H-2) barrier in lethally irradiated mice. This fraction analysed by reducing SDS-PAGE electrophoresis and transblotted on PVDF membrane or purified by reverse-phase HPLC and SDS-PAGE electrophoresis yielded a main pre-albumin band that was examined for primary structure by Edman degradation. It appeared to be rabbit transferrin. Iron saturated human transferrin, lactotransferrin and egg transferrin (conalbumin) were then tested in irradiated C57B1/6 mice transplanted with bone marrow from histoincompatible BALB/CJ donors. Most mice treated with iron-loaded transferrins survived and developed enduring allogeneic chimerism with no discernible signs of graft-versus-host disease at 10 months posttransplant. Observation of these animals is still carried on. Iron carrier proteins seem to provide a novel unexpected means for achieving a successful engraftment of allogeneic bone marrow in immunologically hostile murine H-2 combinations and may open a new approach in the clinical area.

Inhibitory effect of cabergoline on the development of estrogen-induced prolactin-secreting adenomas of the pituitary.

Cabergoline 1-[(6-allylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea is a recently developed ergot derivative with a long-lasting dopamine agonist action. We now studied the ability of cabergoline to counteract the development of a prolactin-secreting tumor (prolactinoma) induced in female rats by long-term administration of high doses of estrogens. The effect of cabergoline was compared to that of bromocriptine. Cabergoline (0.6 mg/kg p.o.) had a marked and sustained prolactin-lowering effect in freely moving female rats, its effect still being present 3 days after a single dose. Bromocriptine, at a dose 5-fold higher (3 mg/kg s.c.), induced a strong and short-lasting prolactin inhibitory effect which, however, had completely disappeared 24 h post-injection. Intermittent administration of cabergoline (0.6 mg/kg p.o. every 3 days), starting from the first day of estrogen treatment, completely counteracted the development of the prolactinoma, as judged by the weight of the pituitary and the stimulating effect of estrogens on plasma prolactin and mitotic rate and DNA synthesis of pituitary cells. These effects of cabergoline were shared by a 5-fold higher dose of bromocriptine (3 mg/kg s.c.) given daily. The potent anti-tumorigenic effect of cabergoline, coupled to a sustained prolactin-lowering effect, the most prolonged ever seen with an ergot derivative, makes cabergoline a most suitable drug for the treatment of human macroprolactinomas.

Different regulation of growth hormone-releasing factor-sensitive adenylate cyclase in the anterior pituitary of young and aged rats.

Low basal GH secretion and reduced GH responsiveness to different GH secretagogues, including GHRF, have been reported in aged animals and humans. Parallel to the in vivo findings, an impaired GH responsiveness to GHRF is evident in somatotropes from old rats of either sex. We report here that in anterior pituitaries (APs) from aged male and female rats GHRF-induced stimulation of adenylate cyclase (AC) activity was strikingly reduced (male rats, change from baseline 700% in young and 100% in old rats) or lacking (female rats, change from baseline 430% in young and 13% in old rats) when compared to that evoked by GHRF in the APs from young counterparts. Pretreatment with GHRH (5 micrograms/rat iv for 3 days) decreased the high basal AC activity of old male rats [from 33.38 +/- 3.60 to 15.99 +/- 5.75 (SEM) pmol cAMP/min.mg protein], did not alter the GHRF-stimulated rise in AC activity in old male rats, and induced a small but unequivocal rise in AC activity in old female rats (change from baseline 35% vs. 13%, respectively). Pretreatment with GHRF markedly reduced the acute effect of GHRF in the APs from young rats of both sexes (male rats, change from baseline 360% and 700%; female rats, change from baseline 230% and 430% in GHRF-pretreated and control rats, respectively). In parallel studies performed in female rats, it was shown that in vivo pretreatment with GHRF at the same schedule markedly reduced the effect of acute GHRF stimulation on GH secretion from cultured pituitary cells of young rats but left unchanged GHRF-induced stimulation of GH secretion from pituitary cells of old rats. In all, these data suggest that deficiency of endogenous GHRF synthesis and/or release may underlie defective GH secretion in old rats and that a GHRF replacement regimen that reduces the sensitivity of the young somatotrope cells does not alter the sensitivity of (male rats) or exerts a priming effect (female rats) on the old somatotrope cell.