Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the present work was to evaluate the effect on the growth hormone (GH) secretion of eptastigmine, a new long-acting cholinesterase inhibitor, in unanesthetized beagle dogs. In a first study, 5 young dogs were given single doses (0.5, 1.0, and 2.0 mg/kg, i.m.) of the drug or saline in a randomized cross-over manner. Blood samples were collected immediately before and, at regular intervals, until 150 min after drug injection. GH plasma concentrations were determined by radioimmunoassay. Plasma cholinesterase activity was measured with a potentiometric method. There was a significant logistic relationship (r = 0.601, P < 0.01) between the administered dose of eptastigmine and the log-transformed areas under the GH plasma concentration-time curve (AUC) with a calculated ED50 for eptastigmine of 0.63 +/- 0.36 mg/kg. There was also a significant linear relationship (r = 0.630, P < 0.01) between log-transformed AUC of GH levels and AUC of plasma cholinesterase activity. In a second study we evaluate the ability of eptastigmine (2.0 mg/kg, i.m.) to potentiate the GH-releasing effect of the GH-releasing hormone (GHRH, 2.0 micrograms/kg, i.v.) in young and old dogs. Eptastigmine was administered 45 min before GHRH and blood collected every 15 min until 90 min after GHRH injection. In young dogs, maximum GH plasma levels (Cmax) were 6.1 +/- 1.0 ng/ml after GHRH compared to 22.5 +/- 2.3 ng/ml after GHRH preceded by eptastigmine (P < 0.01). In old animals, Cmax were 4.6 +/- 1.4 ng/ml after GHRH vs 13.2 +/- 7.4 ng/ml after combined administration of GHRH and eptastigmine (P < 0.05). These data indicate that eptastigmine is very effective in augmenting basal and stimulated GH secretion in old dog. The good activity also shown in old animals suggests a potential use of this drug to reverse the age-dependent decline in GH secretion responsible for many involutional changes of aging.
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PMID:Eptastigmine augments basal and GHRH-stimulated growth hormone release in young and old dogs. 833 17

There is evidence suggesting that androgens influence GH secretion in man. Our aim was to verify whether the GH releasable pool is preserved and influenced by testosterone replacement in male hypogonadism. To this goal, in eight male hypogonadal patients (HP, age 32.2 +/- 5.0 yr; Body Mass Index 23.9 +/- 1.1 kg/m2) before and after 3 months testosterone therapy, we studied the GH response to GHRH (1 microgram/kg iv) alone and combined with pyridostigmine (PD, 120 mg po), a cholinesterase inhibitor which likely inhibits hypothalamic somatostatin release allowing exploration of the maximal somatotrope secretory pool. Sixteen normal subjects (NS, age 30.1 +/- 3.5 yr; Body Mass Index 22.5 +/- 1.8 kg/m2) were studied as controls. The GH response to GHRH in HP was similar to that in NS (AUC, mean +/- SE: 1238 +/- 362 vs 1018 +/- 182 micrograms/L/h). PD potentiated to the same extent the GH response to GHRH in both groups (2092 +/- 807 and 2840 +/- 356 micrograms/L/h). After three month testosterone therapy, in HP the GH responses to GHRH alone (1352 +/- 612 micrograms/L/h) and combined with PD (1948 +/- 616 microgram/L/h) were unchanged. Also IGF-I levels in HP were similar to those in NS (222 +/- 42 vs 210.6 +/- 55.8 micrograms/L) and were unchanged during testosterone replacement (280 +/- 31 micrograms/L). As androgens have been reported to modulate sympathoadrenal activity in the rat, both before and during testosterone replacement, we also measured plasma catecholamine levels. Basal NE (p < 0.05) but not E levels were lower in HP than in NS; testosterone restored basal NE levels to normal without affecting basal E. delta absolute increase of NE and E (p < 0.05 and 0.01 vs baseline, respectively) after PD in HP were similar to those in NS and were unchanged during testosterone replacement. In conclusion, these results demonstrate that the GH releasable pool is preserved in male hypogonadism. As in this condition a reduction of spontaneous GH secretion has been reported, it could be due to neurosecretory dysfunction but not to pituitary impairment. Subtle alterations of sympathoadrenal activity seem to be present in male hypogonadism and reversed by testosterone replacement.
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PMID:Effect of testosterone replacement therapy on the somatotrope responsiveness to GHRH alone or combined with pyridostigmine and on sympathoadrenal activity in patients with hypogonadism. 871 99

Cholinergic agonists are known to potentiate GHRH-induced GH secretion, probably acting via inhibition of hypothalamic somatostatin release. Their effect is reduced in aging and in patients with Alzheimer's disease. This may be the consequence of age-related cholinergic impairment, which, in turn, could cause somatostatinergic hyperactivity leading to GH hyposecretion. As in Down syndrome (DS) neural alterations have been reported similar to those in aging, including cholinergic impairment, we verified the GH response to GHRH (1 microgram/kg i.v. at 0 min) alone or combined with pyridostigmine (PD), a cholinesterase inhibitor (60 and 120 mg, respectively, in children and adults, orally at -60 min) in 15 DS children (13.5 +/- 0.6 years) and in 11 DS young adults (24.0 +/- 1.2 years). Fifteen normal children (11.9 +/- 0.5 years), 15 normal adults (27.3 +/- 0.9 years) and 16 normal elderly (76.3 +/- 1.5 years) were studied as controls. IGF-I levels showed an age-related reduction both in DS (children vs. adults, mean +/- SEM:354.8 +/- 44.9 vs. 204.4 +/- 29.4 micrograms/l, p < 0.02) and in controls (normal children vs. normal adults vs. normal elderly:281.4 +/- 36.3 vs. 175.4 +/- 11.2 vs. 72.5 +/- 6.6 micrograms/l, p < 0.001). The GH response to GHRH in DS children was higher than in DS adults (areas under curve: 1,197.6 +/- 241.5 vs. 434.4 +/- 83.3 micrograms/l/h, p < 0.01). On the other hand, in normal subjects the GHRH-induced GH rise was similar in children and adults (1,056.2 +/- 128.4 vs. 800.8 +/- 124.5 micrograms/l/h) and both were higher than that in elderly subjects (296.0 +/- 61.0 micrograms/l/h, p < 0.001). PD enhanced the GH response to GHRH both in DS and in normal subjects (p < 0.005). The GH response to PD+GHRH was lower in DS adults than in DS children (1,068.1 +/- 145.7 vs. 1,897.4 +/- 198.8 micrograms/l/h, p < 0.001) as well as in normal elderly subjects with respect to that in normal children and normal adults (832.3 +/- 144.7 vs. 2,172.1 +/- 156.1 and 2,347.6 +/- 322.4 micrograms/l/h, respectively, p < 0.001). The GH response to GHRH alone or combined with PD in DS adults was lower (p < 0.01) than that in normal adults and similar to that in normal elderly subjects. In conclusion, the present data demonstrate that the stimulated GH secretion in DS undergoes an accelerated age-related reduction. They also suggest the existence of a precocious impairment of central cholinergic activity in DS, which, in turn, could cause somatostatinergic hyperactivity and reduced GH secretion.
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PMID:The enhancing effect of pyridostigmine on the GH response to GHRH undergoes an accelerated age-related reduction in Down syndrome. 887 21

Previous studies have shown that food ingestion is not capable of inhibiting the GHRH-induced GH release in anorexia nervosa, at variance with what is observed in normal subjects. Moreover, a cholinergic alteration has been hypothesized in this disorder. In a group of 24 anorectic patients in a stabilized phase of the illness, we tested, before and after a standard meal, the GH response to GHRH alone and after pre-treatment with pyridostigmine, an inhibitor of acetylcholinesterase, and, on a different day, with oxiracetam, which stimulates the central cholinergic neurones. The GH response to GHRH was significantly increased by both drugs in a fasting state. The postprandial response was not significantly modified by pyridostigmine nor by oxiracetam. Neither of these compounds was able to enhance the postprandial GH 'paradoxical' response to GHRH in anorectic patients. The lack of effect of both groups postprandially also suggests a suppression of somatostatinergic activity.
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PMID:Pre- and postprandial pyridostigmine and oxiracetam effects on growth hormone secretion in anorexia nervosa. 904 45

In human, arginine (ARG) induces growth hormone (GH) release, probably via a decrease in somatostatinergic tone. To assess the mechanism by which ARG mediates GH release in pigs, the effects on plasma GH release of ARG (1 g/kg body weight, infused between times -15 and -5 min), growth hormone-releasing hormone (GHRH, 2 micrograms/kg, at time 0 min) and neostigmine, a cholinesterase inhibitor (NEO, 50 micrograms/kg, at time 4 min), administered intravenously singly or in paired combinations were investigated in piglets between times -30 and 100 min. ARG and GHRH had additive effects on GH release. No potentialization was observed between the two treatments. GH response was higher following the combination of NEO and GHRH treatments than after NEO or GHRH given alone. NEO had no further effect on ARG-induced GH secretion. Therefore, our results suggest that the mechanism by which ARG stimulates GH secretion in pig is the same as in human.
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PMID:Effects of arginine, growth hormone-releasing hormone (GHRH) and neostigmine administered singly or in paired combinations on growth hormone (GH) release in pigs. 943 57

GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period. Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007). This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.
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PMID:The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease. 1576 92

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive impairment with insidious onset. Neuropathological analysis of AD-affected brains reveals extensive atrophy and an accumulation of neurofibrillary tangles. Taken together, the neurochemical changes in the brain in patients with AD indicate multiple disturbances, and it seems likely that the changes are secondary to more fundamental changes in the brain. The IGF-I is a potent neurotrophic as well as a neuroprotective factor found in the brain, with a wide range of actions in both the central and the peripheral nervous systems. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing, and the possibility that the GH/IGF-I axis is involved in cognitive deficits has been recognized for several years. IGF-I is a critical promoter of brain development and neuronal survival, and plays a role in neuronal rescue during degenerative diseases. The investigations of GH-releasing stimulation tests, and especially of GHRH in AD, are equivocal and in some cases contradictory. The results of several studies addressing this point show varied results: superimposable response of GH to GHRH than response of GH to GHRH in controls; blunted GH to GHRH response in AD patients; higher GH concentrations in the morning; greater increase of GH to GHRH in AD patients than in controls. When an acetylcholinesterase inhibitor, such as rivastigmine, a drug for AD, is acutely administered, the area under the curve of the GH response to GHRH doubles, showing that rivastigmine is a powerful drug in the enhancement of GH release. Consequently, an emerging clinical target for improving the clinical manifestations of AD may be the activation of GH/IGF-I, which rejuvenates the axis, so resulting in an overall physiological benefit.
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PMID:Growth hormone and insulin-like growth factor-I as an endocrine axis in Alzheimer's disease. 1853

Alzheimer's disease (AD) has been traditionally conceptualized as a clinicopathological entity, its definite diagnosis requiring the presence of characteristic pathology together with a dementia clinical picture. The fact that certain AD biomarkers show an acceptable sensitivity and specificity to detect AD pathology has shifted the diagnostic paradigm towards a clinicobiological approach. Neuropathological analysis of AD-affected brains reveals extensive atrophy due to neuronal loss, and accumulation of neurofibrillary tangles and neuritic plaques, surrounded by a tract of neuroinflammation and loss of neurons. Recently, emerging evidence supports the concept that AD is also a disorder of metabolic degeneration. Taken together, the neurochemical changes in the brain from patients with AD indicate multiple disturbances and it seems likely that the changes are secondary to more fundamental changes into the brain. There is a physiological decline of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis with ageing and the possibility that the GH/ IGF-I axis is involved in cognitive deficits has been recognized for several years. The IGF-I is a potent neurotrophic as well neuroprotective factor found in the brain with a wide range of actions in both central and peripheral nervous system. IGF-I is a critical promoter of brain development and neuronal survival and plays a role in neuronal rescue during degenerative diseases. The investigations of GH releasing stimulation tests especially to GHRH in AD are equivocal and in some cases contradictory. When a cholinesterase inhibitor as rivastigmine, a drug for AD, is acutely administered the area under the curve of the GH response to GHRH doubled, showing that rivastigmine is a powerful drug to enhance GH release. Starting with a more accurate diagnosis not of the clinical syndrome, but of underlying molecular defects, that may eventually lead to a personalized, more effective treatment. Hence, the development of novel therapeutic approaches is urgently needed.
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PMID:Possible usefulness of growth hormone/insulin-like growth factor-I axis in Alzheimer's disease treatment. 2252 98

The pathological phenomenon of somatopause, noticeable in hypogonadal ageing subjects, is based on the growth hormone (GH) production and secretion decrease along with the fall in GH binding protein and insulin-like growth factor 1 (IGF-1) levels, causing different musculoskeletal, metabolic and mental issues. From the perspective of safety and efficacy, GH treatment is considered to be highly controversial, while some other therapeutic approaches (application of IGF-1, GH secretagogues, gonadal steroids, cholinesterase-inhibitors or various combinations) exhibit more or less pronounced weaknesses in this respect. Soy isoflavones, phytochemicals that have already demonstrated the health benefits in treated elderly, at least experimentally reveal their potential for the somatopausal symptoms remediation. Namely, genistein enhanced GHRH-stimulated cAMP accumulation and GH release in rat anterior pituitary cells; refreshed and stimulated the somatotropic system (hypothalamic nuclei and pituitary GH cells) function in a rat model of the mild andropause, and stimulated the GH output in ovariectomized ewes as well as the amplitude of GH pulses in the rams. Daidzein, on the other hand, increased body mass, trabecular bone mass and decreased bone turnover in the animal model of severe andropause, while both isoflavones demonstrated blood cholesterol-lowering effect in the same model. These data, which necessarily need to be preclinically and clinically filtered, hint some cautious optimism and call for further innovative designing of balanced soy isoflavone-based therapeutics.
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PMID:Somatopause, weaknesses of the therapeutic approaches and the cautious optimism based on experimental ageing studies with soy isoflavones. 2974 65


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