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CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart.
Circ Res
V Bodart, M Febbraio, A Demers +8 more
Growth hormone-releasing peptides (GHRPs) are known as potent growth hormone secretagogues whose actions are mediated by the ghrelin receptor, a G protein-coupled receptor cloned from pituitary libraries. Hexarelin, a hexapeptide of the GHRP family, has reported cardiovascular activity. To identify the molecular target mediating this activity, rat cardiac membranes were labeled with a radioactive photoactivatable derivative of hexarelin and purified using lectin affinity chromatography and preparative gel electrophoresis. A binding protein of M(r) 84 000 was identified. The N-terminal sequence determination of the deglycosylated protein was identical to rat CD36, a multifunctional glycoprotein, which was expressed in cardiomyocytes and microvascular endothelial cells. Activation of CD36 in perfused hearts by hexarelin was shown to elicit an increase in coronary perfusion pressure in a dose-dependent manner. This effect was lacking in hearts from CD36-null mice and hearts from spontaneous hypertensive rats genetically deficient in CD36. The coronary vasoconstrictive response correlated with expression of CD36 as assessed by immunoblotting and covalent binding with hexarelin. These data suggest that CD36 may mediate the coronary vasospasm seen in hypercholesterolemia and atherosclerosis.
Impact of two or three daily subcutaneous injections of hexarelin, a synthetic growth hormone (GH) secretagogue, on 24-h GH, prolactin, adrenocorticotropin and cortisol secretion in humans.
Eur J Endocrinol
Mauro Maccario, Johannes D Veldhuis, Fabio Broglio +4 more
To extend the insights on the action of GH secretagogues (GHS) on pituitary function, we studied the impact of intermittent daily s.c. administration of a peptidyl GHS, hexarelin (HEX), on 24-h GH, PRL, ACTH and cortisol release in healthy volunteers.
Pulsatile growth hormone secretion persists in genetic growth hormone-releasing hormone resistance.
Am J Physiol Endocrinol Metab
Hiralal G Maheshwari, Suzan S Pezzoli, Asad Rahim +3 more
Growth hormone (GH) secretion is regulated by GH-releasing hormone (GHRH), somatostatin, and possibly ghrelin, but uncertainty remains about the relative contributions of these hypophysiotropic factors to GH pulsatility. Patients with genetic GHRH receptor (GHRH-R) deficiency present an opportunity to examine GH secretory dynamics in the selective absence of GHRH input. We studied circadian GH profiles in four young men homozygous for a null mutation in the GHRH-R gene by use of an ultrasensitive GH assay. Residual GH secretion was pulsatile, with normal pulse frequency, but severely reduced amplitude (<1% normal) and greater than normal process disorder (as assessed by approximate entropy). Nocturnal GH secretion, both basal and pulsatile, was enhanced compared with daytime. We conclude that rhythmic GH secretion persists in an amplitude-miniaturized version in the absence of a GHRH-R signal. The nocturnal enhancement of GH secretion is likely mediated by decreased somatostatin tone. Pulsatility of residual GH secretion may be caused by oscillations in somatostatin and/or ghrelin; it may also reflect intrinsic oscillations in somatotropes.
Novel excitatory actions of galanin on rat cholinergic basal forebrain neurons: implications for its role in Alzheimer's disease.
J Neurophysiol
Jack H Jhamandas, Kim H Harris, David MacTavish +1 more
Galanin, a 29-amino-acid neuropeptide, is generally viewed as an inhibitory neuromodulator in a variety of central systems. Galanin expression is upregulated in the cholinergic basal forebrain nuclei in Alzheimer's disease (AD) and is postulated to play an important role in memory and cognitive function. In this study, application of galanin to acutely dissociated rat neurons from the basal forebrain nucleus diagonal band of Broca (DBB), caused a decrease in whole cell voltage-activated currents in a majority of cells. Galanin reduces a suite of potassium currents, including calcium-activated potassium (I(C)), the delayed rectifier (I(K)), and transient outward potassium (I(A)) conductances, but not calcium or sodium currents. Under current-clamp conditions, application of galanin evoked an increase in excitability and a loss of accommodation in cholinergic DBB neurons. Using single-cell RT-PCR technique, we determined that galanin actions were specific to cholinergic, but not GABAergic DBB neurons The notion that galanin plays a deleterious role in AD is based, in part, on galanin hyperinnervation of cholinergic cells in the basal forebrain of AD patients, its ability to depress acetylcholine release and its inhibitory actions at other CNS sites. However, our results suggest that by virtue of its excitatory actions on cholinergic neurons, galanin may in fact play a compensatory role by augmenting the release of acetylcholine from remaining cholinergic basal forebrain neurons. This action might serve to delay the progression of AD pathology linked to a reduction in central cholinergic tone.
Leptin regulates GH gene expression and secretion and nitric oxide production in pig pituitary cells.
Endocrinology
M Baratta, R Saleri, G L Mainardi +3 more
The aim of this study was to investigate the direct effect of leptin on GH gene expression and secretion and the role of nitric oxide as a possible mediator in pig anterior pituitary cells. Pituitary cells from adult sows were treated for 4 or 24 h with rhleptin (from 0.1 nM to 1 microM) alone or in association with GHRH (10 nM) or hexarelin (10 nM). At the end of incubation, medium was collected for GH and nitric oxide determination by ELISA and Griess test, respectively. Total RNA was collected from cells, and GH gene expression was measured by RT-PCR. Leptin significantly (P < 0.001) stimulated GH secretion in both incubation periods. The maximum response was induced by 10 nM leptin; furthermore, a significant interaction (P < 0.002) between leptin and GHRH (P < 0.03) and between leptin and hexarelin was observed when the molecules were used in association. GH gene expression was significantly increased (at least P < 0.05) by hexarelin, GHRH, and leptin (1000 and 100 nM) after 24 h of treatment. Leptin (10 nM and 1 microM) significantly (P < 0.05) increased nitric oxide production, whereas S-nitroso-N-acetyl-penicillamine (from 0.01-1000 nM) significantly (P < 0.05) stimulated GH secretion. These data demonstrate that leptin directly influences GH regulation at the pituitary level, and nitric oxide may be involved in this function.
Pharmacological profile of a new orally active growth hormone secretagogue, SM-130686.
J Endocrinol
J Nagamine, R Nagata, H Seki +5 more
SM-130686, an oxindole derivative, is a novel orally active GH secretagogue (GHS) which is structurally distinct from previously reported GHSs such as MK-677, NN703 and hexarelin. SM-130686 stimulates GH release from cultured rat pituitary cells in a dose-dependent manner. Half-maximum stimulation was observed at a concentration of 6.3+/-3.4 nM. SM-130686-induced GH release was inhibited by a GHS antagonist, but not by a GH-releasing hormone antagonist. SM-130686 dose-dependently inhibited the binding of radiolabeled ligand, (35)S-MK-677, to human GHS receptor 1a (IC(50)=1.2 nM). This indicates that SM-130686 stimulates GH release through the GHS receptor. The effect of a single oral administration of SM-130686 on GH release in pentobarbital-anesthetized rats was studied. After treatment with 10 mg/kg SM-130686, plasma GH concentrations measured by radioimmunoassay significantly increased, reaching a peak at 20-45 min, and remained above baseline during the experimental period (60 min). The anabolic effect of repetitive SM-130686 administration was studied in rats. Rats received 10 mg/kg SM-130686 orally twice a day and were weighed every day for 9 days. At day 9 there was a significant increase in both the body weight and the fat free mass (19.5+/-2.1 and 18.1+/-7.5 g respectively). Serum IGF-I concentration was also significantly elevated 6 h after the last dose of SM-130686. An endogenous GHS ligand for the GHS receptor has recently been identified from stomach extract and designated as ghrelin. The GH-releasing activity in vitro relative to ghrelin (100%) was about 52% for SM-130686. It is likely that SM-130686 is a partial agonist for the GHS receptor. In summary, we describe here an orally active GHS, SM-130686, which acts through the GHS receptor. Repetitive administration of SM-130686 to rats, similar to repetitive administration of GH, significantly increased the fat free mass by an amount almost equal to the gain in body weight.
The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice.
Endocrinology
M Heffernan, R J Summers, A Thorburn +4 more
Both human GH (hGH) and a lipolytic fragment (AOD9604) synthesized from its C-terminus are capable of inducing weight loss and increasing lipolytic sensitivity following long-term treatment in mice. One mechanism by which this may occur is through an interaction with the beta-adrenergic pathway, particularly with the beta(3)-adrenergic receptors (beta(3)-AR). Here we describe how hGH and AOD9604 can reduce body weight and body fat in obese mice following 14 d of chronic ip administration. These results correlate with increases in the level of expression of beta(3)-AR RNA, the major lipolytic receptor found in fat cells. Importantly, both hGH and AOD9604 are capable of increasing the repressed levels of beta(3)-AR RNA in obese mice to levels comparable with those in lean mice. The importance of beta(3)-AR was verified when long-term treatment with hGH and AOD9604 in beta(3)-AR knock-out mice failed to produce the change in body weight and increase in lipolysis that was observed in wild-type control mice. However, in an acute experiment, AOD9604 was capable of increasing energy expenditure and fat oxidation in the beta(3)-AR knock-out mice. In conclusion, this study demonstrates that the lipolytic actions of both hGH and AOD9604 are not mediated directly through the beta(3)-AR although both compounds increase beta(3)-AR expression, which may subsequently contribute to enhanced lipolytic sensitivity.
Age-related loss of skeletal muscle function and the inability to express the autocrine form of insulin-like growth factor-1 (MGF) in response to mechanical overload.
FEBS Lett
V Owino, S Y Yang, G Goldspink
The response of insulin-like growth factor-1 (IGF-1) signalling and the capacity of skeletal muscle to adapt to mechanical overload was studied using synergistic muscle ablation. Overload of the plantaris and soleus resulted in marked hypertrophy and activation of satellite cells (as indicated by MyoD expression), particularly in young rats. Two muscle IGF-1 splice variants were measured and found to be differentially regulated at the RNA level. The significant changes associated with the inability of the older muscles to respond to mechanical overload included the considerably lower expression of the local splice variant mechano growth factor, and the failure to up-regulate IGF-1 receptor and MyoD mRNA.
[Behavioral and electrophysiological analysis of the choline-positive effect of nootropic dipeptide acylproline (GVS-111)].
Eksp Klin Farmakol
R U Ostrovskaia, T Kh Mirzoev, F A Firova +5 more
The behavioral experiments using a passive avoidance learning model showed that the new cognition-enhancing acyl-prolyn containing dipeptide GVS-111 promotes recovery of the test performance in animals with a long-term memory deficit caused by the M-cholinolytic scopolamine (1 mg/kg/day scopolamine for 20 days, followed by 0.5 mg/kg/day GVS-111 for 10 days). At the same time, GVS-111 increased the duration of tremor induced by the M-cholinomimetic arecoline. The results of electrophysicological experiments showed that GVS-111 in a concentration range from 10(-11) to 10(-9) M increased amplitude of the neural response to acetylcholine (Ach) microappications in 75% of the isolated neurons of Helix Pomatum and produced a predominantly facilitating effect upon the endoneuronal pacemaker activity. The effect of GVS-111 upon the Ach response in a part of neurons was attenuated or even blocked by scopolamine, and in the other neurons--by the N-cholinolytic d-tubocurarine. This fact indicates that both muscarinic and nicotinic receptors are involved in the mechanism of the cholino-sensitizing action of GVS-111 upon the neuronal activity.
Primary thymic endocrine failure in HIV-1-infected children.
Pathobiology
R Consolini, A Legitimo, M Milani
Thymulin, an essential hormone for the T lymphocyte differentiation process and function, was evaluated to asses thymic endocrine function in a cohort of 17 HIV-1-infected children aged between 2 months and 14 years, 18 seroreverted subjects and 47 normal controls. The rosette inhibition assay by Dardenne and Bach (1975) is the only method available to evaluate the biologically active form of this hormone (thymulin or Zn-facteur thymique sérique, Zn-FTS), as immunoassays cannot discriminate between thymulin and the inactive form of the hormone not containing Zn (FTS). HIV-1 patients presented undetectable or significantly lowered plasma levels of thymulin. Plasma zinc levels were significantly reduced in patients although inactive, zinc-unbound thymulin molecules were not demonstrated. The investigation of inhibitory anti-thymulin molecules performed in all patients was negative. Thymulin titers did not correlate with CD4+ lymphocyte count at the different disease stages. This study suggests that a primary thymic endocrine deficiency is present in HIV children. The critical importance of these results in assessing disease progression and a potential therapeutic approach are discussed.
Do growth hormone-releasing peptides act as ghrelin secretagogues?
Endocrine
I Ahnfelt-Rønne, J Nowak, U B Olsen
NN703 is an orally active and selective growth hormone secretagogue (GHS) that was derived from growth hormone-releasing peptide-1(GHRP-1) via ipamorelin by a peptidomimetic approach and has now entered into phase II clinical trials. When the disposition in rats of NN703 and GHRP-6 was studied using whole-body autoradiography following administration of an iv dose of radiolabeled material, we found that a substantial amount of these secretagogues accumulate in the glandular part of the stomach. Because this is the site of synthesis and secretion of ghrelin, the endogenous GHS, we investigated the effect of resection of the gastrointestinal (GI) tract on growth hormone (GH) release induced by GHRP-6. This procedure significantly attenuated the GH secretion response by 60-70%. By contrast, the effect of GH-releasing hormone on GH release was not inhibited. The binding of GHRPs to the glandular part of the stomach and the blunted GH response to GHRP-6 following resection of the GI tract suggest a role for ghrelin as a mediator of part of the GH-releasing effect of GHRPs.
Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues.
Biochem Biophys Res Commun
M Matsumoto, Y Kitajima, T Iwanami +7 more
Ghrelin is a 28-amino acid residue endogenous growth hormone secretagogue. Intensive investigations revealed that the N-terminus tetrapeptide, having octanoyl group at Ser(3), is the minimum active core. In this study, we further explored the structure-function relationships of the active N-terminus portion of ghrelin using a Ca(2+) mobilization assay. The smallest and most potent ghrelin derivative we have found so far is 5-aminopentanoyl-Ser(Octyl)-Phe-Leu-aminoethylamide, showing comparable activity to the natural molecule. In the process of modifying the active core, the ghrelin-derived short analogues emerged structurally close to peptidyl growth hormone secretagogues. The N-terminus modification suggested that Gly(1)-Ser(2) unit works as a spacer, forming adequate distance between N(alpha)-amino group and n-octanoyl group. Replacement of 3rd and 4th amino acid residues to D-isomer suggested that the N-terminal dipeptide contributes to shape the biologically active geometry by effecting conformation of residues in positions 3 and 4.
Immunological evaluation of patients with beta-thalassemia major.
Acta Haematol
R Consolini, A Calleri, A Legitimo +1 more
Abnormalities in the immune system and zinc homeostasis in patients with beta-thalassemia major (TM) have been reported. Since zinc ion is essential for the efficiency of the immune system and is required to induce biological activity to thymulin (Zn-FTS), a biochemically defined thymic hormone, we investigated the plasma levels of zinc and both active thymulin (Zn-FTS) and total zinc saturable thymulin (Zn-FTS+FTS) in 18 patients with TM aged between 2 and 31 years and 22 normal controls of the same age. Inhibitory molecules anti-thymulin and the distribution of lymphocyte subsets were also analyzed. Patients with TM presented significantly lowered plasma zinc and thymulin levels when compared to normal subjects. The significant enhancement of the active form of the hormone after zinc addition in vitro suggests that low thymulin values found in TM are due not to a thymic failure in synthesizing and secreting the thymic hormone, but a defect in zinc saturation of the hormone. An impairment of cell subset distribution was also demonstrated. This study shows that zinc and thymulin deficiency contribute to the complex mechanisms underlying immune dysfunction in TM.
Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease.
Proc Natl Acad Sci U S A
R A Steiner, J G Hohmann, A Holmes +9 more
Galanin is a neuropeptide with multiple inhibitory actions on neurotransmission and memory. In Alzheimer's disease (AD), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. We generated transgenic mice (GAL-tg) that overexpress galanin under the control of the dopamine beta-hydroxylase promoter to study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in AD. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that GAL-tgs displayed normal general health and sensory and motor abilities; however, GAL-tg mice showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggest that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of AD.
Different age-related effects of thymectomy in myasthenia gravis: role of thymoma, zinc, thymulin, IL-2 and IL-6.
Mech Ageing Dev
E Mocchegiani, R Giacconi, M Muzzioli +4 more
Different age-related immune pathogenetic mechanisms in myasthenia gravis (MG) have been suggested because of restoration after thymectomy (Tx) of altered zinc, thymulin (TH) and T-cell subsets exclusively in early-onset patients (younger <50 years), not in late-onset patients (older >50 years). In this context interleukin-2 (IL-2), interleukin-6 (IL-6) and thymoma are crucial because both involved in MG pathogenesis and correlated with acetylcholine receptors (AchRs) Ab production. Moreover, IL-2 and IL-6 are zinc-dependent, are altered in aging and related with zinc and TH age-dependent declines. Moreover, zinc is relevant for immune efficiency. In order to confirm these different age-related pathogenetic mechanisms further, the role of thymoma, zinc, TH, IL-2 and IL-6 is studied in MG patients with generalized MG with and without thymoma before and 1 month and 1 year after Tx. The high IL-2, IL-6, zinc, and AChR Ab levels observed before Tx are significantly correlated each other in younger MG patients (<50 years) independently by thymoma and in older MG patients (>50 years) with thymoma. No correlations exist in older MG patients without thymoma. Thymulin is not correlated with other parameters considered to be both in younger and older MG patients independently by the thymoma. Thymectomy restores zinc; immune parameters and AChR Ab are exclusively in the younger group, not in the older one. These findings suggest that IL-2 and IL-6, via zinc, rather than TH, may be involved in different age-related pathogenetic mechanisms mainly in early-onset MG. By contrast, thymoma may be involved in MG etiology in late-onset representing, as such, a useful discriminant tool for MG etiology between early and late-onset MG patients. Because autoimmune phenomena may rise in aging, a parallelism with altered immune functions during aging is discussed.
Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections.
J Nutr
E Mocchegiani, M Muzzioli
The relevance of zinc in resistance to infections by virus, fungi and bacteria is recognized because of its pivotal role in the efficiency of the entire immune system, in particular in conferring biological activity to a thymic hormone called thymulin, which has differentiation properties on T-cell lines. In infection with human immunodeficiency virus (HIV), the zinc-bound form of thymulin (active thymulin, ZnFTS) is strongly reduced in stage IV of the disease (Centers for Disease Control and Prevention classification) with concomitant decrements in CD4(+) cell count and zincemia values. The zinc-unbound form of thymulin (inactive thymulin, FTS) is, in contrast, very high. The in vitro addition of zinc to plasma samples induces a recovery of the thymulin active form, suggesting low zinc bioavailability as the cause of impaired thymic functions with consequent CD4(+) depletion. An analysis of risk factors for the incidence of recidivism opportunistic infections shows CD4(+) depletion and zinc deficiency to have significant scores. Supplementation with zinc for 1 mo (45 mg Zn(2+)/d) associated with zidovudine (AZT) therapy in stage IV induces recovery of active zinc-bound thymulin, of zincemia, of CD4(+) cells with concomitant reduction (50%) of recidivism opportunistic infections compared with the AZT-treated group. Complete disappearance of recidivism by Candida aesophagea or Pneumocystis carinii is observed after supplementation with zinc. The relative risk factors (CD4(+) depletion and zinc-deficiency) have lower scores in the HIV-positive zinc-treated group, confirming, as such, the relevance of zinc in opportunistic infections that involve extracellular matrix. Such an assumption is indirectly confirmed with new HAART, where no opportunistic infections occur. Indeed, HIV RNA is inversely correlated with both CD4(+) and zincemia values (r = -0.73, P<0.01) in HAART-treated subjects. Lower scores for the same relative factors for the appearance of opportunistic infections are present in HAART-treated subjects compared with those treated with AZT. These findings, on the one hand, show the poor efficacy of AZT therapy compared with HAART therapy for the progression of HIV, but on the other hand, they suggest that the lack of occurrence of opportunistic infections by HAART may also result from major zinc bioavailability. This further supports the key role played by zinc against opportunistic infections in HIV with a possible independent effect by either HIV or the pathogens involved.
Galanin inhibits acetylcholine release from rat cerebral cortex via a pertussis toxin-sensitive G(i)protein.
Neuropeptides
H Y Wang, K D Wild, R P Shank +1 more
Galanin has been implicated in various physiological functions including memory, feeding and pain perception. Using rat cerebral cortical slices and synaptosome preparations incubated with [(3)H]choline in Kreb's-Ringer solution, galanin was shown to inhibit both spontaneous and K(+)-stimulated [(3)H]ACh release in a concentration-related manner [EC(50)= 35 nM]. The galanin-mediated inhibition on spontaneous and K(+)-stimulated [(3)H]ACh release was respectively regulated by pertussis toxin-sensitive G(alphai3)and G(alphai1). These suggest that galanin is a negative modulator of cortical cholinergic function and most probably acting on presynaptic cholinergic terminals. Although galantide blocked the galanin-mediated inhibitory effect on [(3)H]ACh release, it mimicked galanin in blocking K(+)-stimulated [(3)H]ACh release, indicating that galantide may have a more complicated pharmacology than being a galanin receptor antagonist. In addition, we demonstrate that galanin and beta-amyloid peptide(1-42)synergistically attenuated K(+)-evoked [(3)H]ACh release from synaptosomes prepared from rat cerebral cortex. Since galanin is increased in Alzheimer's disease brain, our results suggest that galanin may be involved in cholinergic dysfunctions that occur in Alzheimer's disease.
Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model.
Behav Pharmacol
R U Ostrovskaya, G A Romanova, I V Barskov +5 more
Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by combination of the intravenous photosensitive dye Rose Bengal administration with focused high-intensity illumination of the frontal bone, was shown to provoke a pronounced deficit in step-through passive avoidance performance in rats without concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS-111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1 h after ischaemic lesion and then for 9 post-operative days, with the last administration 15 min before testing, attenuated the deficit. This treatment significantly diminished the volume of the infarcted area. Thus, post-ischaemic injection of GVS-111 demonstrated both cognition-restoring and neuroprotective properties. The cognition-restoring effect is probably based on an increase in neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS-111 combine antioxidant activity with the ability to attenuate glutamate-provoked neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates the main metabolic shifts involved in pathogenesis of brain ischaemia.
beta-Amyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology.
J Biol Chem
H Y Wang, D H Lee, M R D'Andrea +3 more
Alzheimer's disease pathology is characterized by the presence of neuritic plaques and the loss of cholinergic neurons in the brain. The underlying mechanisms leading to these events are unclear, but the 42-amino acid beta-amyloid peptide (Abeta(1-42)) is involved. Immunohistochemical studies on human sporadic Alzheimer's disease brains demonstrate that Abeta(1-42) and a neuronal pentameric cation channel, the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), are both present in neuritic plaques and co-localize in individual cortical neurons. Using human brain tissues and cells that overexpress either alpha7nAChR or amyloid precursor protein as the starting material, Abeta(1-42) and alpha7nAChR can be co-immunoprecipitated by the respective specific antibodies, suggesting that they are tightly associated. The formation of the alpha7nAChR.Abeta(1-42) complex can be efficiently suppressed by Abeta(12-28), implying that this Abeta sequence region contains the binding epitope. Receptor binding experiments show that Abeta(1-42) and alpha7nAChR bind with high affinity, and this interaction can be inhibited by alpha7nAChR ligands. Human neuroblastoma cells overexpressing alpha7nAChR are readily killed by Abeta(1-42), whereas alpha7nAChR agonists such as nicotine and epibatidine offered protection. Because Abeta(1-42) inhibits alpha7nAChR-dependent calcium activation and acetylcholine release, two processes critically involved in memory and cognitive functions, and the distribution of alpha7nAChR correlates with neuritic plaques in Alzheimer's disease brains, we propose that interaction of the alpha7nAChR and Abeta(1-42) is a pivotal mechanism involved in the pathophysiology of Alzheimer's disease.
Methylprednisolone does not inhibit the release of growth hormone after intravenous injection of a novel growth hormone secretagogue in rats.
Growth Horm IGF Res
K Malmlöf, P B Johansen, P M Haahr +2 more
The present study was undertaken to study the growth hormone-releasing properties and growth-promoting effect of a GH secretagogue ipamorelin (IPA) in rats given the synthetic glucocorticoid methylprednisolone (MP). In a first experiment, rats received either saline or MP (5.0 mg/kg) for 8 days. Treatment with MP significantly (P< 0.001) decreased body weight gain, but the acute response to either IPA or growth hormone releasing hormone (GHRH) in terms of plasma GH was not changed. In a second experiment, venous catheters were surgically implanted. On the next day, rats were randomly allocated to receive saline alone, MP alone (5.0 mg/kg) or MP plus IPA in doses of 0.4 or 1.6 mg/kg/day for 10 days. IPA was administered intravenously four times a day.MP treatment significantly (P< 0.05) retarded recovery from surgery in terms of body weight. Thus, saline treated animals lost 4.0 +/- 3.5 g over the entire experimental period, whereas animals receiving MP lost 13. 6 +/- 2.9 g. When IPA was given together with MP, losses in body weight were significantly (P< 0.05) reduced to 2.3 +/- 2.0 and 1.6 +/- 2.0 g in animals given the high and low dose of IPA, respectively. In parallel with this IGF-I levels increased. In conclusion, this work shows that MP does not disrupt the response of the GH-IGF-I axis to an exogenous stimulus like IPA, and repeated stimulation leads to increases in IGF-I and of body weight gain.