Health risk assessment of environmental selenium: Emerging evidence and challenges (Review)

New data have been accumulated in the scientific literature in recent years which allow a more adequate risk assessment of selenium with reference to human health. This new evidence comes from environmental studies, carried out in populations characterized by abnormally high or low selenium intakes, and from high-quality and large randomized controlled trials with selenium recently carried out in the US and in other countries. These trials have consistently shown no beneficial effect on cancer and cardiovascular risk, and have yielded indications of unexpected toxic effects of selenium exposure. Overall, these studies indicate that the minimal amount of environmental selenium which is source of risk to human health is much lower than anticipated on the basis of older studies, since toxic effects were shown at levels of intake as low as around 260 µg/day for organic selenium and around 16 µg/day for inorganic selenium. Conversely, populations with average selenium intake of less than 13-19 µg/day appear to be at risk of a severe cardiomyopathy, Keshan disease. Overall, there is the need to reconsider the selenium standards for dietary intake, drinking water, outdoor and indoor air levels, taking into account the recently discovered adverse health effects of low-dose selenium overexposure, and carefully assessing the significance of selenium-induced proteomic changes

Anti-shock effect of ACTH-(1-24): comparison between intracerebroventricular and intravenous route of administration

In an experimental model of hypovolemic shock in rats, produced by withdrawing about 50% of the estimated total blood volume, and causing 100% deaths within 30 min, ACTH-(1-24) dose-dependently improved arterial and pulse pressure and increased survival rate. The intracerebroventricular (i.c.v.) route of administration was more effective than the intravenous (i.v.) route: at the dose of 24 micrograms/kg, 45% and 91% of rats were still surviving 2 hr after i.v. and i.c.v. treatment, respectively. At higher doses of ACTH-(1-24), the survival rate rose to 100% regardless of the route of administration, but arterial pressure increased more after i.c.v. than after i.v. injection. These data suggest that the CNS plays an important role in the anti-shock effect of ACTH

LACK OF INFLUENCE OF AROMATASE AND 5-ALPHA-REDUCTASE INHIBITION ON [H-3] IMIPRAMINE BINDING IN THE MALE-RAT BRAIN

In intact adult male rats an inhibitor of aromatase and an inhibitor of 5alpha-reductase did not change the characteristics of [H-3]imipramine binding sites in cerebral cortex, hypothalamus, and hippocampus. Testosterone, estradiol and dihydrotestosterone prevented the effect of castration on the number of [H-3]imipramine binding sites, but had no effect in non-castrated animals. These data suggest that testosterone and its major metabolites, estradiol and dihydrotestosterone, are equally effective with regard to imipramine binding sites

Mechanism of action of the anti-shock effect of CCK-8: influence of CCK antagonists and of sympatholytic drugs

In an experimental model of haemorrhagic shock that causes 100% mortality in rats within 30 min, the intravenous bolus injection (20 micrograms/kg) of sulfated cholecystokinin octapeptide (CCK-8) induces a prompt and sustained rise in blood pressure and pulse amplitude, all treated animals still surviving at the end of the experiment (2 h). This effect of CCK-8 is completely blocked by reserpine (5 mg/kg i.p.), significantly antagonized by prazosin (0.1 mg/kg i.v.) and yohimbine (1 mg/kg i.v.), and unaffected by practolol (15 mg/kg i.v.) and proglumide (0.2 mg/kg i.v.); it is completely antagonized by the intravenous (0.01-0.05 mg/kg), but not by the intracerebroventricular (0.002 mg/kg) injection of the 'peripheral' CCK antagonist, L-364,718. The present data indicate that the cardiovascular effects of CCK-8 in haemorrhagic shock involve peripheral CCK receptors, and require the functional integrity of the sympathetic nervous system

CHRONIC ADMINISTRATION OF I-SULPIRIDE AT NON-NEUROLEPTIC DOSES REDUCES THE DURATION OF IMMOBILITY IN EXPERIMENTAL-MODELS OF DEPRESSION-LIKE BEHAVIOR

It has been shown that long-term administration of l-sulpiride induces a down-regulation of beta receptor-associated adenylate cyclase activity in the frontal cortex of rats, an adaptive response that is typically associated with the chronic administration of antidepressants. Here we show that in two animal models of ''depression-like'' behavior (forced swim in rats and tail suspension in mice), the long-term (21 days) administration of l-sulpiride at a non-neuroleptic dose (2 mg/kg IP twice a day) significantly decreases the duration of immobility, the effect being similar to that of desipramine (20 mg/kg IF). The same dose (2 mg/kg) of l-sulpiride, acutely administered, has no effect at all, On the other hand, either chronic (21 days) or acute administration of neuroleptic doses of l-sulpiride have an opposite effect, and indeed increase the duration of immobility. These results are an in vivo support to the in vitro findings suggesting that low doses of l-sulpiride may have antidepressant-like activity

Brain effects of melanocortins

The melanocortins (, and -melanocyte-stimulating hormones: MSHs; adrenocorticotrophic hormone:ACTH), a family of pro-opiomelanocortin (POMC)-derived peptides having in common thetetrapeptide sequence His-Phe-Arg-Trp, have progressively revealed an incredibly wide range of extrahormonaleffects, so to become one of the most promising source of innovative drugs for many, importantand widespread pathological conditions.The discovery of their effects on some brain functions, independently made by William Ferrari andDavid De Wied about half a century ago, led to the formulation of the term “neuropeptide” at a timewhen no demonstration of the actual production of peptide molecules by neurons, in the brain, was stillavailable, and there were no receptors characterized for these molecules.In the course of the subsequent decades it came out that melanocortins, besides inducing one of themostcomplex and bizarre behavioural syndromes(excessive grooming, crises of stretchings and yawnings,repeated episodes of spontaneous penile erection and ejaculation, increased sexual receptivity), play akey role in functions of fundamental physiological importance as well as impressive therapeutic effectsin different pathological conditions.If serendipity had been an important determinant in the discovery of the above-mentioned first-noticedextra-hormonal effects of melanocortins, many of the subsequent discoveries in the pharmacology ofthese peptides (feeding inhibition, shock reversal, role in opiate tolerance/withdrawal, etc.) have been theresult of a planned research, aimed at testing the “pro-nociceptive/anti-nociceptive homeostatic system”hypothesis.The discovery of melanocortin receptors, and the ensuing synthesis of selective ligands with agonistor antagonist activity, is generating completely innovative drugs for the treatment of a potentiallyvery long list of important and widespread pathological conditions: sexual impotence, frigidity, overweight/obesity, anorexia, cachexia, haemorrhagic shock, other forms of shock, myocardial infarction,ischemia/reperfusion-induced brain damage, neuropathic pain, rheumathoid arthritis, inflammatorybowel disease, nerve injury, toxic neuropathies, diabetic neuropathy, etc.This reviewrecalls the history of these researches and outlines the pharmacology of the extra-hormonaleffects of melanocortins which are produced by an action at the brain level (or mainly at the brain level).In our opinion the picture is still incomplete, in spite of being already so incredibly vast and complex.So, for example, several of their effects and preliminary animal data suggest that melanocortins might beof concrete effectiveness in one of the areas of most increasing concern, i.e., that of neurodegenerativediseases

INFLUENCE OF ACTH-(1-24) ON INGESTIVE BEHAVIOURS

ACTH-(1-24) has a complex, direct and differentiated effect on eating behaviour which seems to be very similar to that already described for CRF. These similarities indicate that both these neuropeptides coud be putative mediators in stress-induced anorexia

EFFECTS OF THYROID STATUS ON THE CHARACTERISTICS OF ALPHA1-IMIPRAMINE, ALPHA2-IMIPRAMINE, BETA-IMIPRAMINE IMIPRAMINE AND GABA RECEPTORS IN THE RAT-BRAIN

The effects of a chronic treatment with L-triiodothyronine (T3; 100 mg/rat/day s.c. for 7 days) or with propylthiouracil (PTU; 50 mg/rat/day for 35 days by stomach tube) on the characteristics of alpha1, alpha2, beta, imipramine and GABA binding sites in different brain areas of the adult rat have been studied. T3-treatment caused an increase in the number of [H-3]dihydroalprenolol and a decrease in the number of [H-3]muscimol binding sites in the cerebral cortex. PTU-treatment caused a decrease in the number of [H-3]prazosin, [H-3]yohimbine and [H-3]dihydroalprenolol binding sites in the cerebra cortex, while the number of [H-3]imipramine binding sites was reduced in the cerebral cortex and hypothalamus, and increased in the hippocampus. Affinity constants were never modified. Concurrent experiments showed that the in vitro addition of T3 and PTU did not influence the binding of any of the ligands employed to control rat brain membranes. The present data further support the view that neurotransmission in the CNS is influenced by the thyroid status