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Mechanisms of action of GH
No full textThe process of growth, which is common to all multicellular organisms, is complex and involves the interaction of a multiplicity of factors; despite this, the GH/IGF function still maintains its preminence, and, in turn, the same is true for all approaches aimed at reducing the consequences of GH/IGF excess. In this review paper, we will deal briefly with some aspects of GH/IGF mechanism of action which are instrumental to the appreciation of a novel class of a "designer" GH antagonist, for use in conditions characterized by excess GH action and elevated serum IGF-I
The GABA(B) receptor and recognition memory: Possible modulation if its behavioral effects by the nitrergic system
No full textFunctional activation of the GABA(B) receptor inhibits learning and memory processes, though discrepant findings, in this context, have also been reported. The present study was designed to investigate the role of the GABA(B) receptor on recognition memory in the rat. For this purpose, the effects induced by the GABA(B) agonist baclofen and the GABA(B) antagonist P-(3-aminopropyl)-p-diethoxymethylphosphinic acid (CGP 35348) on memory were assessed by using the object-recognition task. In addition, the possible involvement of the nitrergic system on GABA(B) receptor's effects was also evaluated by using the same behavioral procedure. This is a working-memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, baclofen (0.5, 2, and 4 mg/kg, i.p.), dose-dependently impaired animals' performance in this task, suggesting a modulation of acquisition and storage of information. CGP 35348 (100 and 300 mg/kg, i.p.), counteracted these baclofen-induced performance deficits. The nitric oxide donor molsidomine, at the dose of 4 but not 2 mg/kg, i.p, successfully antagonized the deficits on cognition induced by the highest dose of baclofen (4 mg/kg). These results indicate a) that the GABA(B) receptor is involved in recognition memory and b) that an NO component modulates the effects of the GABA(B) receptor on learning and memory. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved
GABAERGIC CONTROL OF ANTERIOR PITUITARY HORMONE SECRETION
No full textAnatomical and biochemical studies have identified a hypothalamic tubero-infundibular GABAergic system, which plays a functional role on anterior pituitary hormone secretion. Experimental and clinical evidence support the presence of a dual component in the action of GABA; one mediated via the central nervous system and the other exerted directly at the anterior pituitary level. The two sites of action may be responsible for the excitatory and inhibitory effects of GABA on pituitary hormone and especially prolactin secretion. The future characterization of this system will provide a better understanding of the involvement of GABA in the physiology of anterior pituitary hormone secretion and will contribute to the developent of new pharmacological agents for the therapy of neuroendocrine disorders
The 5-HT1A receptor antagonist WAY 100635 improves rats performance in different models of amnesia evaluated by the object recognition task
No full textThe effects of the 5-HT1A receptor antagonist WAY 100635 on recognition memory were investigated in two different amnestic models in the rat by using the object recognition task. WAY 100635 at I mg/kg, but not at 0.3 mg/kg, counteracted scopolamine-induced performance deficits in the acquisition version of this behavioral paradigm. At the same dose, WAY 100635 antagonized extinction of recognition memory in the normal rat, suggesting that it affected acquisition, storage and retrieval of information. These results support and extend prior findings that interactions between the serotonergic and cholinergic systems are relevant to cognition and indicate that WAY 100635 modulates different aspects of recognition memory. (C) 2003 Elsevier B.V. All rights reserved
Maintenance of a Normal Meal-induced Decrease in Plasma Ghrelin Levels in Children with Prader-Willi Syndrome
No full textGhrelin is a 28-amino acid peptide recently identified in the stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a potent stimulator of GH secretion. It was recently shown that circulating ghrelin levels in humans rise shortly before and fall shortly after every meal, and that ghrelin administration increases voluntary food intake. The hypothesis that ghrelin hypersecretion might contribute to genetic obesity has never been investigated. In this context, Prader-Willi syndrome is the most common form of human syndromic obesity. As ghrelin affects appetite as well as GH secretion and both are abnormal in PWS, it has been surmised that these alterations might be due to ghrelin dysregulation. The aim of the study was to investigate whether ghrelin is suppressed by the meals differently in PWS children than in PWS adults. Overnight circulating fasting ghrelin levels and ghrelin levels 120 min after breakfast were assayed in 7 PWS children (10.2 ± 1.7 yr), 7 subjects with morbid obesity (10.3 ± 1.3 yr), and 5 normal controls (8.4 ± 1.4 yr). Because of the data spread, no statistical difference was observed in fasting ghrelin levels between PWS and control children (p = NS); anyway, fasting ghrelin levels were significantly lower in obese children than in the other groups (p < 0.05 vs. control and PWS children). Ghrelin levels were slightly suppressed by the meal in control subjects (mean fasting ghrelin: 160.2 ± 82 pg/ml; after the meal, 141.2 ± 57 pg/ml, p = NS); the meal failed to suppress ghrelin levels in obese children (mean fasting ghrelin: 126.4 ± 8.5 pg/ml; after the meal, 119.1 ± 8.3 pg/ml, p = NS). Interestingly, the meal markedly suppressed ghrelin levels in PWS children (mean fasting ghrelin: 229.5 ± 70.4 pg/ml; after the meal, 155.8 ± 34.2 pg/ ml, p < 0.01). In conclusion, since a lack of decrease in circulating ghrelin induced by the meal was previously reported in PWS adults, the finding of a meal-induced decrease in ghrelin levels in our population of young PWS would imply that the regulation of the ghrelin system involved in the orexigenic effects of the peptide is operative during childhood, although it progressively deteriorates and is absent in adulthood when hyperphagia and obesity progressively worsen
Somatostatin infusion withdrawal: studies in the acute and recovery phase of anorexia nervosa, and in obesity
No full textObjective: Changes in GH/IGF-I axis activity occur in both anorexia nervosa (AN) and obesity (OB). A GH hypersecretory state with very low plasma IGF-I levels is present in AN, whereas in morbid OB, GH secretion is dull and plasma IGF-I levels are generally preserved. Endogenous GHRH activity in AN and OB has never been directly studied, although indirect evidence would indicate that GHRH function is altered in either condition, possibly enhanced and reduced respectively. Somatostatin (SS) infusion withdrawal (SSIW) is followed by a rebound rise of plasma GH in animals and humans, an event which, allegedly, is mediated by endogenous GHRH release. Methods: In the present study, 28 young women, eight with active AN (A-AN), six with AN in the recovery phase (R-AN), eight with morbid OB, and six healthy age-matched normal weight subjects (NW), were studied. All subjects underwent, on different occasions, the following two tests: (i) acute GHRH injection (1 μg/kg, i.v.); (ii) infusion of SS (9 μg/kg per h i.v. over 60 min), with blood samples drawn prior to and at different intervals after drug injections. Plasma GH levels were measured at each time interval in all sessions, and, in addition, baseline plasma estradiol, free triiodothyronine, TSH, IGF-I and insulin were measured at - 30 min. Results: Baseline plasma GH concentrations were significantly higherin A-AN than in NW (4.7±0.7 vs 2.1±0.6 μg/l, P < 0.01). Baseline GH levels in R-AN were also higher than in NW, but the difference did not reach statistical significance (5.6±1.7 μg/l, not significant (NS)). Baseline plasma GH concentrations were significantly lower in OB than in NW (0.3±0.1 μg/l, P < 0.01). GHRH-stimulated GH release was significantly higher in A-AN than in NW (mean change in area under the curve (ΔAUC) 1904.9±626.1 vs 613.9±75.9 μg/l per min, P < 0.01), whereas no statistically significant difference was present between R-AN and NW (mean ΔAUC 638.2±293.0 μg/l per min, NS); in OB, GHRH failed to evoke a plasma GH rise (mean ΔAUC 239.8±89.9 μg/l per min vs A-AN, R-AN, and NW, P < 0.01). SS infusion markedly reduced plasma GH concentrations in both A-AN and R-AN and, to a lesser extent, in NW, but failed to do so in OB. In A-AN, SSIW was followed by a plasma GH rise markedly higher than that present in NW (mean ΔAUC 193.0±42.3 vs 60.1±11.4 μg/l per min, P < 0.01), whereas in R-AN the GH response after SSIW was nearly superimposable on that registered in NW (mean ΔAUC 72.9±22.8 μg/l per min, NS). There were no changes in plasma GH levels after SSIW in OB (mean ΔAUC 22.8±9.7 μg/l per min). In all groups, ΔAUCs of the GH response to GHRH and after SSIW were highly positively correlated (r = 0.7, P < 0.01). Conclusions: These data support the view that a high endogenous GHRH tone, which subsides in the recovery phase of the disease, is present in AN, whereas GHRH hypofunction, possibly associated with pituitary impairment, might indicate OB
Effects of molsidomine on scopolamine-induced amnesia and hypermotility in the rat
No full textNitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing.Nitric oxide (NO) is hypothesized to be a novel intracellular messenger in the central nervous system. Recently, NO involvement in learning and memory processes has been proposed. Compounds that inhibit nitric oxide synthase, the key synthesizing enzyme, may block cognition, while NO donors may facilitate it. The aim of this study was to assess in the rat the effects of the NO donor molsidomine (2 and 4 mg/kg, i.p.) on memory deficits caused by scopolamine. For this purpose, the object recognition task and the step-through passive avoidance procedure were chosen. In addition, the effects of molsidomine in antagonizing the scopolamine-induced hypermotility were also examined. Scopolamine at 0.2 mg/kg (object recognition) and 0.75 mg/kg (passive avoidance) disrupted acquisition in both the tasks and induced locomotor hyperactivity at the dose of 0.2 mg/kg. Molsidomine at either dose reversed the scopolamine-induced deficits in the object recognition paradigm but did not counteract the hypermotility and the deficits occurred in the passive avoidance test. These results suggest that to some extent, the NO donor molsidomine is involved in memory processing
The leukocyte expression of CD36 is low in patients with Alzheimer's disease and mild cognitive impairment
No full textCD36, a scavenger receptor of class B (SR-B), helps mediate microglial and macrophage response to beta-amyloid fibrils (betaA), and seems to play a key role in the proinflammatory events associated with Alzheimer disease (AD) in many tissues. Peripheral leukocytes express many molecules and multiple receptors which undergo the same regulatory mechanisms as those operative in the brain. Thus, these cells, easily obtainable through peripheral blood sampling, may be used as a tool to investigate changes occurring in inaccessible brain areas. Based on these premises, we investigated the leukocyte expression of CD36 in 70 AD patients and in 30 subjects with mild cognitive impairment (MCI). Results were compared to those of 20 young and 40 age-matched control subjects. Leukocyte expression of CD36 was significantly reduced versus controls in both AD and MCI patients, while in young and old controls there were no age-related changes. Although preliminary, these data indicate that the reduction of CD36 expression in leukocytes is a disease-related phenomenon, occurring since the early stages of AD (MCI). Irrespective of the mechanism(s) underlying such changes, assessment of leukocyte CD36 expression might represent an useful tool to support the diagnosis of AD and to screen MCI patients candidates to develop the disease
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