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

Effective prophylactic treatments of migraine lower plasma glutamate levels

The role of glutamate in migraine treatment has not been much studied, even if this amino acid seems to be crucial in the pathogenesis of migraine. Our aim was to determine if there were differences in the plasma levels of glutamate between migraine patients and control subjects and if plasma levels of glutamate in migraine patients modified after 8 weeks of prophylactic treatment. We studied 24 patients with diagnosis of migraine without aura according to International Classification of Headache Disorders, 2nd edn criteria, and 24 age- and sex-matched healthy subjects, as controls. In migraineurs the level of glutamate was measured before and after 8 weeks of prophylactic treatment (topiramate 50 mg/day, five patients; amitriptyline 20 mg/day, seven patients; flunarizine 5 mg/day, seven patients; propranolol 80 mg/day, five patients). Venous blood samples were taken in the morning, after overnight fasting, and at least 3 days after the last migraine day. Glutamate levels were measured by means of a fluorimetric detector high-pressure liquid chromatographic method. Plasma levels of glutamate were significantly higher in migraine patients-either before (61.79 +/- 18.75 mu mol/l) or after prophylactic treatment (17.64 +/- 5.08 mu mol/l)-than in controls (9.36 +/- 2.1 mu mol/l) (P < 0.05, anova followed by Newman-Keuls' test). After prophylactic treatment, with headache frequency reduced, plasma glutamate levels were significantly lower in the same patient with respect to the prior baseline level (P < 0.0001, Student's t-test for paired data), without any differences depending on the kind of prophylactic drug. Effective prophylactic treatments reducing high glutamate plasma levels found in migraine patients could act on the underlying mechanism that contributes to cause migraine. Plasma glutamate level monitoring in migraine patients might serve as a biomarker of response to treatments and as an objective measure of disease status

Preference for palatable food is reduced by the gamma-hydroxybutyrate analogue GET73, in rats

Palatability and variety of foods are major reasons for “hedonic” eating, and hence for overeating and obesity. Palatable food and drugs of abuse share a common reward mechanism, and compounds that block the reinforcing effect of drugs of abuse preferentially suppress the intake of palatable foods. This research was aimed at studying the influence of the gamma-hydroxybutyrate analogue N-(4-trifluoromethylbenzyl)-4¬methoxybutanamide (GET73) – that inhibits alcohol consumption – on consumption and reinforcing effect of palatable food. Adult male rats were used. For place preference conditioning, sweetened corn flakes were used as the reinforcer, and GET73 (50, 100 and 200 mg kg−1) or vehicle were orally (p.o.) administered either 30 min before each training session and the test session, or only before the test session. To study the influence on con¬sumption, GET73 was given p.o. at the same doses once daily for 12 days to rats given free access to both palatable and varied food (cafeteria diet) or to standard chow. Both acquisition and expression of palatable food-induced conditioned place preference were inhibited by GET73, either adminis¬tered throughout the conditioning period or only before the test session. GET73 reduced also the consumption of cafeteria food, while that of standard chow was increased. At these doses, GET73 had no detrimental effect on open-field behaviour. GET73 seems to specifically attenuate the gratification produced by varied and palatable food, without affecting the consumption of not particularly palatable chow. Since, overweight and obesity are mostly due to the overeating of palatable and varied foods, drugs like GET73 could represent a somewhat ideal and rational approach to obesity treatment

Nanoparticles as drug delivery agents specific for CNS: in vivo biodistribution

The pharmacological treatment of neurological disorders is often complicated by the inability of drugs to pass the Blood Brain Barrier. Recently we discovered that polymeric nanoparticles (Np) made of poly(D,L-lactide-co-glycolide) surface-decorated with the peptide Gly-L-Phe-D-Thr-Gly-L-Phe-L-Leu-L-Ser(O--D-Glucose)-CONH2 are able to deliver, after i.v. administration, the model drug loperamide into Central Nervous System (CNS). This new drug delivery agent is able to ensure a strong and long-lasting pharmacological effect, far greater than that previously observed with other nanoparticulate carriers. Here, we confirmed the effectiveness of this carrier for brain targeting comparing the effect obtained by the administration of loperamide-loaded Np with the effect of an intracerebroventricular administration of the drug; moreover, the biodistribution of these Np showed a localization into CNS in a quantity about two orders of magnitude greater than that found with the other known Np drug carriers. Thus, a new kind of Np that target CNS with a very high specificity was discovere

Peptide-decorated nanoparticles as carriers for drug delivery to CNS

Peptide-decorated nanoparticles as carriers for drug delivery to CN

Peptide-derivatized nanoparticles as carriers of drugs into the central nervous system

Peptide-derivatized nanoparticles as carriers of drugs into the central nervous syste

Oral delivery of insulin loaded into polymeric nanoparticles in rats.

Diabetes prevalence is steadily increasing and both type 1 and type 2 contribute to this “diabetes epidemic”. Insulin is the sole therapeutic, life-saving option for type 1 diabetes with patients self-injecting the hormone every day for life. In this study, insulin has been loaded into polymeric nanoparticles (Np) of poly (D,L-lactide-co-glycolide) and different amounts of insulin-loaded Np (1, 3 or 10 I.U./kg) were administered by oral gavage to normal and diabetic rats, s.c. pre-treated with omeprazole (5 mg/Kg). In normal rats, the in vivo results highlighted a dose-related decrease of blood glucose levels in normal rats at the end of the observation period (20-50% depending on the doses of insulin delivered by Np). In diabetic rats, the dose of 3 I.U./kg produced a 50% decrease of the glycaemia 90 min after the treatment, with an effect stable up to the end of the observation period; a higher dose of insulin delivered by Np (10 I.U./kg) developed a significant decrease of glycaemia (65%). Correspondently, in diabetic rats, plasma insulin levels increased in a dose-related manner (3, 5, and 7-folds with respect to the basal level, depending on insulin doses delivered by NPs) with still significant values 2 h after administration. Thus, these Np are able, after pre-treatment with omeprazole, to transport insulin across the intestinal barrier, preserving the biological activity of the hormone in rats and if replicated in humans, it could suggest the concrete possibility of oral administration of insulin

Glycopeptide-decorated nanoparticles as drug carriers for CNS: effects of surface coverage and carbohydrate type

n order to study the ability of peptide-decorated PLGA Np to act as CNS drug delivery agents, the effect of various degrees of Np surface coverage by the peptide H2N-Gly-L-Phe-D-Thr-Gly-L-Phe-L-Leu-L-Ser(O-R)-CONH2 (R = -D-glucose) and of the type of carbohydrate present on Ser (R= H, -D-glucose, -D-xylose, -D-lactose, -D-Mannose) were evaluated. Loperamide was used as a model drug and its presence on rat CNS was evaluated by means of its pharmacological effect (antinociceptive assay, hot-plate test). The pharmacological effect exerted by loperamide loaded into Np demonstrated to be strongly dependent on the degree of peptidic surface coverage of Np. Thus, in the presence of a high surface coverage, a very short effect is observed, which appears early on (0.5 min) after Np iv administration. Moreover, the sugar moiety influences markedly the CNS effect of loperamide loaded into the peptide-decorated Np: among the carbohydrates here examined, the presence of Beta-D-glucose on the Ser of the peptide showed the best results, both in terms of the maximum effect and length

Engineered polylactide-co-glycolide(PLGA) Np as drug delivery systems for the Central Nervous System

Nanoparticulate polymeric systems (nanoparticles, Np) have been widely studied for the delivery of drugs to a specific target site. Np have been recently considered for the therapy of various brain diseases. The major problem in accessing the central nervous system (CNS) is due to the presence of the Blood-Brain Barrier (BBB). Recently, it has been shown the possibility to reach the CNS district crossing the BBB using nanoparticles (Np) made of polylactide-co-glycolide (PLGA), modified with a simil-opioid sequence and different glycosidic moieties. Firstly, PLGA was modified with different glycol-heptapetides (Glucose, Lactose, Xylose, and Mannose as sugar moieties and with a single [P] or a triple sequence of heptapeptides [3P]). Then, after i.v. administration, Np, labeled with covalent linkage with a fluorescent dye, were demonstrated to be able to cross the BBB by using confocal microscopy. A strong analgesic effects due to the encapsulated Loperamide, a P-glycoprotein (P-gp) substrate model drug, demonstrated the ability of modified PLGA Np to cross the BBB, after i.v. administration. The effect was different in the intensity and in the time period according to the different surface modification, being the Glucose preferable when compared with the other ones. When 3P-PLGA Np were used, a different profile in the pharmacological activity was assessed, i.e. a sudden maximum analgesic effect followed by a fast decrease over the time. Finally, the biodistribution of Np loaded with Rhodamine-123 (P-gp substrate) was analyzed quantifying the fluorescent intensity in the different organs including brain, in order to better understand the fate of these modified Np

Targeting the Central Nervous System: in vivo experiments with peptide-derivatized nanoparticles loaded with Loperamide and Rhodamine-123

Polymeric nanoparticles (Np) represent one of the most innovative non-invasive approaches for the drug delivery to the central nervous system (CNS). It is known that the ability of the Np to cross the Blood Brain Barrier (BBB), thus allowing the drugs to exert their pharmacological activity in the central nervous district, is linked to their surface characteristics. Recently it was shown that the biocompatible polyester poly(D,L-lactide-co-glycolide) (PLGA) derivatized with the peptide H2N-Gly-L-Phe-D-Thr-Gly-L-Phe-L-Leu-L-Ser(O--D-Glucose)-CONH2 [g7] was an useful starting material for the preparation of Np (g7-Np); moreover, fluorescent studies showed that these Np were able to cross the BBB. In this research, g-7 Np were loaded with Loperamide in order to assess their ability as drug carriers for CNS, and with Rhodamine-123, in order to qualitatively determine their biodistribution in different brain macro-areas. A pharmacological evidence is given that g7-Np are able to cross the BBB, ensuring, for the first time, a sustained release of the embedded drug, and that these Np are able to reach all the brain areas here examined. The ability to enter the CNS appears to be linked to the sequence of the peptidic moiety present on their surface