Biomedical subjects

E E Muller

Publications and source records attributed to E E Muller.

At least 37 records · Page 2Linked to original sources

PubMed1999

Long-term neuroprotective effects of glycosaminoglycans-IGF-I cotreatment in the motor neuron degeneration (mnd) mutant mouse.

This study shows that cotreatment with insulin-like growth factor-I (IGF-I) and glycosaminoglycans (GAGs) prevents the onset of neuromuscular deficit in the m/m mutant mouse. These mice show a mid-to-late-life onset of progressive paralysis of the hind limb, that is correlated with altered innervation and reduced nerve-evoked isometric twitch tension in the extensor digitorum longus (EDL) muscle. Almost 50% of EDL nerve endings are negative for antisynaptophysin staining, while retrograde labelling with beta-cholera-toxin coupled to type IV horseradish and quantitative histological analysis show a small loss of EDL and lumbar cord motor neurons. At 10 months of age also forelimb function evaluated as grip strength is significantly reduced. Animals treated either with glycosaminoglycans alone or with IGF-I alone at low and high doses showed only a partial improvement of their condition. However, cotreatment of m/m mice with IGF-I and GAGs fully prevented the neuromuscular abnormalities, the twitch tension loss, the motor neuron decrease and the reduction of forelimb grip strength.

Animals↗

PubMed1999

Hexarelin, a growth hormone - releasing peptide, counteracts bone loss in gonadectomized male rats.

The age-related decline in growth hormone (GH) secretion has been implicated in the pathogenesis of involutional bone loss. Whether restoration of GH secretion might be helpful in maintaining and/or improving bone mass during aging is still unsettled. The aim of the present study was to examine the effects of 30-day treatment with hexarelin (HEXA, 50 microg/kg subcutaneously b.i.d.), a highly effective GH-releasing compound, on bone metabolism and bone mineral density (BMD) in intact and osteopenic gonadectomized (GDX) mature male rats. Serum total alkaline phosphatase (ALP, bone formation marker) and bone resorption markers (lysylpyridinoline, LP and hydroxylysylpyridinoline, HP) were measured before and 7, 14 and 30 days after treatment. BMD was measured by dual-energy X-ray absorptiometry at lumbar vertebrae, femoral metaphysis and diaphysis before and at the end of the experiment. In intact rats, HEXA significantly (P<0.05) decreased LP (-36.3%) and HP (-22.8%) excretion at day 7, whereas it did not change serum ALP activity and BMDs. In GDX rats, HEXA completely prevented the significant (P<0. 01) increase in urinary excretion of both LP (+143.8%) and HP (+119. 4%), the early decrease in ALP activity (-26.5%) and the significant (P<0.05) decrease in BMDs in the femoral metaphysis (-7.9%) and lumbar vertebrae (-6.8%) caused by androgen deficiency. The bone-protective effects of HEXA could be attributed, at least in part, to its GH-releasing activity since chronic-treated rats maintained the GH response to an acute challenge with HEXA. The evidence that HEXA, unlike GH, inhibits bone resorption indicates that other mechanisms contribute to the bone sparing effect of HEXA.

Alkaline Phosphatase↗

PubMed1999

Radionuclide angiocardiographic evaluation of the cardiovascular effects of recombinant human IGF-I in normal adults.

OBJECTIVE: IGF-I possesses specific myocardial receptors and is able to promote cardiac remodelling and even inotropic effects in both humans and other animals. In fact, reduced cardiac mass and performance are present in GH deficiency and these alterations are counteracted by recombinant human (rh) GH replacement, restoring IGF-I levels. Recently, the acute administration of 60 microg/kg rhIGF-I has also been reported to be able to improve cardiac performance evaluated by echocardiography or impedance cardiography in normal subjects. The aim of our study was to verify the effects of a subcutaneous low dose of rhIGF-I (20 microg/kg) on cardiac performance in humans. METHODS: In six healthy male adults (mean+/-S. e.m.: 35.7+/-4.3 years of age), the effects of rhIGF-I on left ventricular function evaluated by radionuclide angiocardiography and on circulating IGF-I, GH, insulin, glucose and catecholamines levels were studied. RESULTS: Administration of rhIGF-I increased circulating IGF-I (peak at +150 min vs baseline: 330.2+/- 9.6 vs 199. 7+/-8.7 microg/l, P<0.03) to levels which persisted similarly up to +180min. Neither GH nor catecholamine levels were modified by rhIGF-I administration, while insulin and glucose levels showed a slight but significant decrease. Basal left ventricular ejection fraction (61.8+/-2.0%) significantly increased at +180 min after rhIGF-I (65.3+/-2.7%, P<0.03). No change was recorded in mean blood pressure while a non-significant trend towards a reduction of heart rate was present by +120 min. CONCLUSIONS: These findings indicate that even subcutaneous administration of a low dose of rhIGF-I has acute inotropic effects as evaluated by radionuclide angiocardiography in healthy adults.

Adult↗

PubMed1998

Systemic administration of insulin-like growth factor decreases motor neuron cell death and promotes muscle reinnervation.

Neonatal sciatic nerve axotomy causes motoneuron death and muscle denervation atrophy. The aim of the present study was to determine whether insulin-like growth factor-I (IGF-I) administration promotes muscle reinnervation and counteracts motor neuron loss after such an injury. Six weeks after sciatic nerve axotomy performed in 2-day-old pups, the number of motor neurons, as assessed by retrograde transport of horseradish peroxidase injected into the extensor digitorum longus (EDL) muscle, was reduced from 52 +/- 3 to 26 +/- 3. Subsequent administration of IGF-I at the doses of 0.02 mg/kg or 1 mg/kg increased the number of motor neurons to 35 +/- 2 and 37 +/- 5, respectively. The effect on motoneuron survival was accompanied by improved muscle fibre morphometry and restoration of indirect EDL muscle isometric twitch tension, which was about 80 % of control values for both doses of IGF-I compared with 60% observed with saline treatment. Reinnervated EDL muscle from saline-treated rats cannot hold tetanic tension, which is, however, achieved after IGF-I treatment at either dose. Thus, both high and low doses of IGF-I counteracted motoneuron death and improved muscle reinnervation following neonatal sciatic nerve axotomy. IGF-I at 5 microg/kg failed to increase muscle reinnervation.

Animals↗

PubMed1998

Muscle reinnervation following neonatal nerve crush. Interactive effects of glycosaminoglycans and insulin-like growth factor-I.

This study shows that glycosaminoglycans promote muscle reinnervation following neonatal sciatic nerve injury. Such an effect appears to be mediated by insulin-like growth factor-1. The glycosaminoglycan moiety of proteoglycans is a constituent of the basal lamina active on nerve regeneration by means of the interaction with laminin and with several growth factors. We have previously shown that supplementation of glycosaminoglycans affects neuronal degeneration and regeneration. In this study we report that following neonatal lesion of the rat sciatic nerve glycosaminoglycan treatment promoted extensor digitorum longus muscle reinnervation with consequent improvement of muscle morphology. In saline-treated rats, reinnervation was only partial and there was a marked muscle fibre atrophy. In addition glycosaminoglycan treatment of lesioned rats increased insulin-like growth factor-I messenger RNA and protein in the reinnervated muscle, and insulin-like growth factor-I and insulin-like growth factor binding protein-3 plasma levels. Similarly, treatment of nerve lesioned rats with insulin-like growth factor-I promoted muscle reinnervation and prevention of muscle fibre atrophy, higher levels of insulin-like growth factor-I in the reinnervated muscle and of insulin-like growth factor-I and insulin-like growth factor binding proteins in plasma. These data suggest that glycosaminoglycans are potent stimulants of muscle reinnervation and that their effects may be mediated by increased levels of insulin-like growth factor-I.

Acetylcholinesterase↗

PubMed1997

Effects of low doses of glycosaminoglycans and insulin-like growth factor-I on motor neuron disease in wobbler mouse.

In this study we examined the effects of insulin-like growth factor-I (IGF-I) and of glycosaminoglycans (GAGs) on the progressive motor neuron disease in wobbler mice. After clinical diagnosis at age 3 weeks, mice received daily subcutaneous injections of IGF-I, or GAGs, or saline for 3 weeks. The histometric analysis revealed that biceps muscle fiber diameter was reduced in wobbler mice and that treatments with GAGs and IGF-I prevented such a drop. The number of atrophic small fibers was markedly reduced and that of the larger ones augmented. No effects on body growth and biceps muscle weight were observed. The combined AChE-silver staining revealed that both treatments promoted intramuscular axonal sprouting. The typical decline of grip strength in wobbler mice was also prevented. This study suggests that GAGs and IGF-I administrations can retard the onset of motor deficit, and reduce muscle atrophy in wobbler mice.

Acetylcholinesterase↗

PubMed1996

In vivo microdialysis of the hypothalamus: a suitable method to study the function of hypophysiotropic neurons in the rat.

Brain microdialysis is a method commonly exploited by neuropharmacologists to study the mechanism of action and preclinical features of centrally acting drugs. It allows measurement of chemical messengers released into the extracellular space, providing a first approximation of neuronal function in selected areas. In this study we have applied the microdialysis of the hypothalamus to evaluate the release of somatostatin from neurosecretory neurons which are involved in growth hormone regulation and validated this method with different challenges.

Animals↗

PubMed1996

Growth hormone-releasing factor (GRF) regulates expression of its own receptor.

Recent studies have demonstrated that passive immunization of neonatal rats to GRF inhibited their somatic growth through the suppression of GH secretion. In this study, we investigated the changes in pituitary GRF receptor (GRFR) expression in GRF antibody (GRF-ab) treated rats. Neonatal rats were treated from day 1 to day 10 after birth with every other day sc injection of 50 microliters of normal rabbit serum (groups I: control & III) or rabbit serum containing GRF-ab (groups II & IV). In addition, groups III & IV received twice daily injection of recombinant human GH (0.4 microgram/kg, sc). The rats were sacrificed on day 11 and pituitaries were removed. The pituitary weights in all treatment groups were decreased compared to the control group (I). Total pituitary RNA was extracted and GRFR mRNA levels were determined by RNase protection assay. Receptor RNA levels were quantitated and normalized to an internal standard, glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The ratios of GRFR mRNA to GAPDH mRNA were significantly decreased to 49.6 +/- 4.9 (mean +/- SD), 73.0 +/- 8.7, 43.6 +/- 9.5% of control group I in the experimental groups II, III, and IV, respectively (P < 0.01). These data suggest that (1) suppression of GH secretion in GRF-ab treated animals was due, at least in part, to a decrease in GRFR expression, (2) GRF may be necessary for its own receptor expression, (3) exogenous administration of GH suppresses pituitary GRFR mRNA.

Animals↗

PubMed1996

Effects of single and short-term administration of clonidine on hypothalamic-pituitary somatotropic function of the adult male rat: an in situ hybridization study.

The effects of the alpha-2 adrenoceptor agonist clonidine (CLO) on the growth hormone (GH) regulatory neuronal systems, growth hormone-releasing hormone (GHRH) and somatostatin (SS), were studied in adult male rats given a single or a short-term administration (1, 3 and 6 days) of the drug. Acute administration of CLO significantly decreased hypothalamic GHRH content [leaving unaltered GHRH messenger RNA (mRNA) levels] and increased plasma GH levels; hypothalamic SS content/mRNA levels and pituitary GH content/mRNA levels remained unchanged. In 1- and 3-day CLO-treated rats, by contrast, decreased hypothalamic GHRH content was coupled with a significant reduction in GHRH mRNA levels. In these rats, pituitary GH content and mRNA levels were also significantly increased, whereas hypothalamic SS content and mRNA levels remained unaltered. In 6-day CLO-treated rats, hypothalamic GHRH content and mRNA levels were still significantly reduced, plasma GH levels were increased, but to a lesser extent than in 1- and 3-day CLO-treated rats, and pituitary GH content and mRNA reverted to control levels. Hypothalamic SS content and mRNA levels remained unaltered. These results indicate that 1) functional activation of alpha-2 adrenergic receptors by CLO increases GHRH release from the hypothalamus, 2) CLO, via GHRH, increases GH secretion and biosynthesis, which in turn feeds back in the hypothalamus to reduce GHRH biosynthesis, and 3) reduction of hypothalamic GH-stimulatory activity tones down the initial pituitary somatotropic hyperfunction. Unaltered hypothalamic SS content and mRNA levels in all CLO-treated rats suggests that the somatostatinergic system is less sensitive than the GHRH system to changes in circulating GH levels.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1995

Effect of 15-day treatment with growth-hormone-releasing hormone alone or combined with different doses of arginine on the reduced somatotrope responsiveness to the neurohormone in normal aging.

It is well known that both spontaneous and growth hormone-releasing hormone (GHRH)-stimulated GH secretion undergo an age-related decrease; in addition, there is supportive evidence that the GH hyposecretory state of aging is of hypothalamic origin. The aims of the study in 35 normal elderly subjects (20 males and 15 females aged 65-89 years) were to verify whether the low somatotrope responsiveness to GHRH (1 microgram/kg) can be primed by a daily GHRH treatment and whether the potentiating effect of both high intravenous (0.5 g/kg) and low oral (8 g) doses of arginine (ARG) on GH response to GHRH is maintained with time. In group A (N = 14) the GH response to GHRH on day 1 (AUC: 373.5 +/- 78.5 micrograms.l-1.h-1) was unchanged after 7 (3720 +/- 38 micrograms.l-1.h-1) and 15 days (377.9 +/- 63.8 micrograms.l-1.h-1) of daily GHRH administration. In group B (N = 6) the GH response to GHRH co-administered with iv ARG on day 1 (1614.2 +/- 146.2 micrograms.l-1.h-1) was higher (p < 0.05) than that of GHRH alone (group A) and persisted unchanged after 7 (1514.7 +/- 366.5 micrograms.l-1.h-1) and 15 days (1631.7 +/- 379.1 micrograms.l-1.h-1) of treatment. In group C (N = 15) the GH response to GHRH co-administered with oral ARG on day 1 (950.6 +/- 219.4 micrograms.l-1.h-1) was higher (p < 0.03) than that of GHRH alone (group A) but lower (p < 0.05) than that to GHRH plus iv ARG (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats.

In recent years several synthetic peptides have been shown to be active in inducing GH secretion in different mammalian species. Among them GHRP-6, GHRP-1 and GHRP-2 have demonstrated high effectiveness and high selectivity in stimulating GH release. In the present paper we report studies on the GH-secreting properties of a GHRP analog in which Trp was substituted with the chemically more stable 2-Methyl-Trp. In studies performed in conscious 10-day old rats, the hexapeptide Hexarelin (His-D-2Me-Trp-Ala-Trp-D-Phe-Lys-NH2) resulted very active in stimulating GH secretion. In anesthetized adult male rats, i.v. administration of GHRP-6 or Hexarelin elicited prompt GH release with peak GH levels occurring within 10 min At all the doses tested, the 2 peptides possessed similar effectiveness in stimulating GH release. Hexarelin given s.c. elicited a long-lasting GH release and was slightly more effective than GHRP-6. In conclusion, these findings indicate that Hexarelin is a highly effective GH releaser and might represent a valuable diagnostic and/or therapeutic tool in clinical practice.

Aging↗

PubMed1993

Effect of acute and short-term administration of cholinomimetic drugs on corticosterone secretion in the rat.

Centrally acting cholinomimetic drugs have been proposed for the therapy of cognitive disorders in aged subjects. Among the possible adverse side effects of this class of compounds, of great relevance is the stimulatory action on the adrenocortical axis, in view of the toxicity of glucocorticoids for hippocampal neurons and the immune system. The aim of the present study was to evaluate in conscious male rats the effect of acute and short-term administration of three novel cholinomimetic drugs on the release of corticosterone. The potent agonist of muscarinic receptors RU 35963 strikingly increased corticosterone levels after acute but not after short-term (6 days) administration. Similar results were obtained after administration of the reversible inhibitor of cholinesterase, eptastigmine. In contrast to RU 35963 and eptastigmine, acute administration of a choline precursor, L-alpha-glycerylphosphorylcholine, only slightly affected plasma corticosterone concentrations after both acute and short-term administration. It is concluded that activation of adrenocortical function by cholinomimetic drugs is a short-lasting event which does not represent an important side effect of these compounds when given on a long-term basis.

Analysis of Variance↗

PubMed1990

Long-term follow-up of 'cured' prolactinoma patients after successful adenomectomy.

The long-term follow-up (greater than or equal to 4 years) of clinical, hormonal and radiological aspects in 22 'cured' prolactinoma patients after adenomectomy was studied. Dynamic secretion of PRL and TSH was also evaluated, in order to identify the persistence of any underlying abnormality of hypothalamic pituitary control and to predict relapses. A relapse into hyperprolactinaemia was shown in 36% of patients 5-90 months (mean 46) after surgery. This was accompanied by reappearance of clinical symptoms but not by the radiological demonstration of the adenoma in any patients. A significant PRL rise after domperidone, a dopaminergic antagonist drug, was shown in cured patients after surgery (mean +/- SEM peak, 2977 +/- 645 mU/l) but this was markedly lower than that observed in control subjects (5732 +/- 440 mU/l). In fact, normal PRL increments were shown in only 6/16 (37%) patients. TSH hyper-responsiveness to domperidone normalized in only 46% of patients. Similar PRL responses to those obtained with domperidone were shown when a TRH test was given. A relapse into hyperprolactinaemia was observed in six of ten (60%) non-responders to domperidone and in four of seven (57%) non-responders to TRH, whereas six normal responders to domperidone and TRH had not relapsed at that time. Plasma PRL levels during pregnancy showed increments lower than those observed in normal pregnant women only in domperidone and TRH non-responder patients. These results indicate that a relapse into hyperprolactinaemia and a blunted PRL rise during pregnancy were present only in patients with persistently reduced PRL response to dynamic tests.

Adenoma↗

PubMed1988

Impaired growth hormone secretion in neonatal hypothyroid rats: hypothalamic versus pituitary component.

In 10-day-old rats made hypothyroid by giving dams propylthiouracil (PTU) in the drinking water since the day of parturition, simultaneous radioimmunoassay (RIA) determinations of basal and stimulated growth hormone (GH) secretion, hypothalamic GH-releasing hormone (GHRH)-like immunoreactivity (LI) content, immunocytochemical localization of somatotrophs, and hypothalamic GHRH-LI-positive structures were performed. The frequency of somatotrophs was also determined. One-day-old hypothyroid rats, whose mothers had been given PTU since the 14th day of pregnancy, were also used for comparison. In 10-day-old hypothyroid rats, pituitary and plasma GH levels and the number of somatotrophs were considerably lower and plasma TSH levels were significantly higher than those in age-matched control rats; however, GHRH-LI titers in the mediobasal hypothalamus and the morphology of GHRH-LI-positive structures were unaltered. In 1-day-old rats the only alteration present, in addition to elevated plasma TSH levels, was a clear-cut decrease in plasma GH levels. An acute challenge with GHRH (20 ng/100 g body wt, sc) or clonidine (15 micrograms/100 g body wt, sc) induced a clear-cut rise in plasma GH levels 15 min postinjection in 10-day-old control rats but failed to do so in age-matched hypothyroid rats. Both compounds failed to rise plasma GH in both hypothyroid and control 1-day-old rats. Taken together these data indicate that in neonatal and infant rats deprivation of thyroid hormones acts primarily to depress pituitary somatotroph function and that possible changes in GHRH-secreting structures represent a later postnatal event.

Animals↗

PubMed1986

The effect of oxandrolone on the growth hormone response to growth hormone releasing hormone in children with constitutional growth delay.

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH-releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11.0-17.1 years were given oxandrolone 0.1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1-40, 1 microgram/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously-released neurohormone.

Adolescent↗

PubMed1986

Effects of sodium valproate and diazepam on beta-endorphin, beta-lipotropin and cortisol secretion induced by hypoglycemic stress in humans.

Evidence that gamma-aminobutyric acid (GABA) and benzodiazepine receptors play a role in the inhibition of ACTH-cortisol secretion in humans has until now been drawn only from data indicating that sodium valproate, a GABA mimetic, and diazepam, a benzodiazepine, decrease hypothalamus-pituitary-adrenal (HPA) axis secretion in patients affected by pathological hypersecretion of the axis. Therefore, the present study investigated the effects, in the same healthy subjects, of sodium valproate or diazepam, on both basal and stress-stimulated concentrations of beta-endorphin (beta-EP), beta-lipotropin (beta-LPH) and cortisol. A single maximal dose of sodium valproate (400 mg) or diazepam (10 mg) did not significantly modify basal concentrations of beta-EP, beta-LPH and cortisol. On the other hand, in the same subjects, pretreatment with sodium valproate (20 mg X 3) or diazepam (10 mg X 2) blocked the increases in these hormones produced by hypoglycemic stress in all patients tested (p less than 0.01 vs. placebo at 45, 60 and 90 min after insulin injection), without affecting the decrease in blood glucose levels. The present data show that sodium valproate and diazepam inhibit stress-induced beta-EP, beta-LPH and cortisol secretion in humans, suggesting that endogenous GABA and benzodiazepine receptors participate in physiological mechanisms regulating the activity of the HPA axis.

Adult↗

PubMed1984

Prolactin control by the tubero-infundibular GABAergic system: role of anterior pituitary GABA receptors.

Anterior pituitary (AP) GABA receptors have been shown to play a functional role in the inhibitory control of prolactin (PRL) secretion by this amino acid. However, the physiological significance and the pharmacological characteristics of these receptors have yet to be determined. In normal male rat AP's incubated in vitro, GABA (10(-6) M) is effective in decreasing PRL release only when incubated in the presence of ethanolamine-O-sulphate (EOS), a potent GABA-transaminase (GABA-T) blocker. The failure of GABA alone to inhibit PRL release in vitro could be explained by the rapid degradation of the amino acid when added to the medium by AP-GABA-T. Central nervous system (CNS)- and AP-GABA receptors present similar affinity constants when evaluated by Scatchard analysis. However, displacement studies show that AP-GABA receptors have 10- and 100-times less affinity for muscimol (M), a GABA agonist, and for bicuculline, a GABA antagonist, respectively, than have GABA receptors. The low affinity of the agonist towards the AP receptors could also account for the relatively poor sensitivity of lactotrophs to GABA-mimetic compounds. Failure of chronic treatment with aminooxyacetic acid, a GABA-T inhibitor, to modify the PRL-lowering effect of GABA-mimetic compounds, despite the decrease in the number of AP-GABA receptors, indicates that in normal conditions only a reduced number of receptors are operative. These studies of AP-GABA receptors provide insight for a better understanding of the mechanisms involved in the regulation of PRL secretion by the hypothalamic GABAergic system.

Animals↗

PubMed1984

Inhibitory action of the alpha 1-adrenergic receptor on growth hormone secretion in the dog.

Intravenous administration of methoxamine ( METHOX , 5 mg, iv), a specific alpha 1-adrenergic agonist, reduced baseline GH levels of four unanesthetized beagle dogs 45 and 60 min post-injection and completely abolished the GH-releasing effect of the alpha 2-adrenergic agonist clonidine ( CLON , 4/ micrograms/kg, iv). Prazosin (PRA, 0.1 mg/kg, iv), an alpha 1-adrenergic antagonist, administered before METHOX re-instituted the GH-releasing effect of CLON . METHOX administered at the starting of an arginine infusion (ARG, 10% solution, 3.3 ml/min X 30 min) reduced consistently the GH releasing effect of the latter while, conversely, pretreatment with PRA, strikingly potentiated the GH-releasing effect of the amino acid (2 dogs). METHOX did not alter the GH-releasing effect of human pancreatic GH-releasing factor (hpGRF-40, 1/microgram/kg, iv), though it consistently delayed the occurrence of the GH secretory peak following hpGRF-40. These data indicate that alpha 1-adrenergic receptors located in the central nervous system, inhibit in the dog tonic and stimulated GH secretion.

Animals↗