Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.1.7 (acetylcholinesterase)
28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathophysiology, symptomatology, and treatment of memory loss in patients with Alzheimer's disease are described. Alzheimer's disease is characterized by cerebral cortical atrophy, neuronal loss, neurofibrillary tangles, and neuritic plaques. The primary neuropharmacologic defect involves reduced activity of the enzyme choline acetyltransferase, causing reduced synthesis of acetylcholine (ACh). Other neurotransmitters known to be compromised in patients with Alzheimer's disease include norepinephrine, serotonin, dopamine, and somatostatin. Initially components of short-term memory and immediate recall are lost. Eventually, memory loss is so severe that patients lose the ability to care for themselves. A definite diagnosis of Alzheimer's disease can be made only at autopsy. Three pharmacologic approaches to enhancing cholinergic function include increasing ACh production by increasing the availability of ACh precursors (lecithin, choline); inhibiting ACh degradation by inhibiting acetylcholinesterase (physostigmine, tacrine hydrochloride); and directly stimulating cholinergic receptors by using cholinomimetic agents (arecoline, RS-86). However, results of studies involving these agents are conflicting: no consistent benefit has been shown in patients with Alzheimer's disease. Although therapy with tacrine hydrochloride has been beneficial in some patients, it has not been effective in all cases and has the potential to cause serious adverse effects. Despite the research in patients with Alzheimer's disease, no agent has yet been found that produces consistent improvement in the memory loss associated with this disease.
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PMID:Alternatives in the treatment of memory loss in patients with Alzheimer's disease. 206 22

It is well known that GH responses to GH-releasing hormone (GHRH) show marked interindividual variations in normal subjects, which have been attributed to a variable somatostatinergic tone. Recently, it has been shown that enhancement of cholinergic tone with the acetylcholinesterase inhibitor pyridostigmine (PD), which presumably acts by inhibiting somatostatin release, stimulates basal GH secretion and GH responses to a maximal dose of GHRH. In this study we have investigated the effects of PD on the dose-response relationships of GHRH-induced GH secretion in normal subjects. Our data showed that PD (120 mg, orally, at-60 min) induced a clear-cut increase in basal GH levels, significantly different from that after saline treatment, at 15, 30, 45, 60, 90, and 120 min. Moreover, PD administration markedly potentiated GH responses to GHRH at doses of 500, 100, 25, 10, and 3 micrograms/subject, as assessed by either area under the curve or maximal peak GH levels. In fact, GH responses to pyridostigmine plus 3 micrograms GHRH were similar to those to the administration of 500 and 100 micrograms GHRH alone. Our findings of marked increases in GH response to GHRH after pyridostigmine administration show that with enhancement of cholinergic tone, the dose of GHRH needed to induce a similar increase in GH is reduced 30 times.
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PMID:Effect of enhancement of endogenous cholinergic tone with pyridostigmine on the dose-response relationships of growth hormone (GH)-releasing hormone-induced GH secretion in normal subjects. 210 28

The diagnosis of growth hormone (GH) deficiency (GHD) is currently based on failure to increase plasma GH levels to an arbitrary cutoff point of 7 or 10 micrograms/l in response to two provocative stimuli. False negative responses to these tests, however, frequently occur thus reducing their diagnostic reliability. The aim of this study was to assess a combination of pyridostigmine (PD) and GH-releasing hormone (GHRH) (60 mg oral PD 60 min before 1 microgram/Kg GHRH iv) as a reliable test probing pituitary somatotropic function. In fact PD, an acetylcholinesterase inhibitor, strikingly potentiates GH response to GHRH likely by inhibiting somatostatin release. The combination PD + GHRH was tested in normal children and adolescents (NS, n = 27) and in a large group of short children classified as having familial short stature (FSS, n = 24), constitutional growth delay (CGD, n = 34) and GH deficiency (organic, oGHD, n = 6; idiopathic, iGHD, n = 10). In all groups results obtained by PD + GHRH were compared with those obtained by testing with GHRH, clonidine (CLON) and PD alone and by studying spontaneous nocturnal GH secretion over 8 hours. Assuming 7 micrograms/l as minimum normal GH peak, a positive response occurred in only 18/24, 11/12 and 12/13 NS for GHRH, CLON, and PD, respectively. In contrast even assuming a minimum normal GH peak as high as 20 micrograms/l, PD + GHRH induced a positive response in 27/27 NS all having a nocturnal GH mean concentration (MC) greater than or equal to 3 micrograms/l. Therefore PD + GHRH test gave no false negative responses and this was true not only in NS but even in all FSS and CGD having a GH MC greater than or equal to 3 micrograms/l. On the other hand, PD + GHRH induced a negative GH response in all oGHD and in 8/10 iGHD patients. In the remaining two iGHD patients, PD + GHRH demonstrated a normal pituitary GH reserve in spite of a GH MC less than 3 micrograms/l and low IGF-I level, thus pointing to a hypothalamic pathogenesis for the GHD. Considering FSS and CGD children having a GH MC less than 3 micrograms/l, PD + GHRH showed a primary pituitary GH deficiency in 3/12 CGD with low plasma IGF-I levels. In conclusion, in slowly growing children PD + GHRH test is the most reliable provocative test for the diagnosis of primary pituitary GH deficiency being capable to discriminate between an unequivocally normal and impaired somatotropic function.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A new test for the diagnosis of growth hormone deficiency due to primary pituitary impairment: combined administration of pyridostigmine and growth hormone-releasing hormone. 211 60

Glucocorticoids have been shown to inhibit GH secretion in normal man when acutely and chronically administered in pharmacological amounts. Pyridostigmine (PD), an acetylcholinesterase inhibitor, is able to elicit GH secretion when administered alone and to enhance the GH response to GHRH in normal subjects probably via a decrease in the hypothalamic release of somatostatin. The aim of the present study was to investigate the influence of glucocorticoids on the GH response to PD administered either alone or in combination with GHRH in normal adult subjects. Six healthy adult volunteers underwent six experimental protocols. They received 1) human (h) GHRH(1-29)NH2, 100 micrograms injected as an iv bolus; 2) cortisone acetate, 50 mg administered orally (po) 60 min before an hGHRH iv bolus injection; 3) PD, 120 mg administered po, 60 min before an hGHRH iv bolus injection; 4) PD and cortisone acetate, administered po 60 min before an hGHRH iv bolus injection; 5) PD, administered po 60 min before a saline iv bolus injection; 6) PD and cortisone acetate administered po 60 min before a saline iv bolus injection. Mean GH levels, peak GH levels, and GH area under the curves (AUCs) were significantly lower after GHRH + cortisone as compared to GHRH alone. However, these parameters were not significantly different after PD + GHRH + cortisone when compared to PD + GHRH and after PD + cortisone when compared to PD alone. We conclude that acute administration of pharmacological amounts of glucocorticoids cannot inhibit the GH response to PD alone or in combination with GHRH. Thus, we hypothesize that the inhibitory action of glucocorticoids on the GH response to GHRH in man may be mediated by an enhancement of either somatostatin release by the hypothalamus or somatostatin action on the pituitary.
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PMID:Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone-releasing hormone stimulated growth hormone secretion in normal man. 211 35

We have found that interleukin 3 (IL-3), a growth factor for hematopoietic cells, is a novel trophic factor for mouse and rat central cholinergic neurons. It enhanced neurite outgrowth and elevated choline acetyltransferase activity. The effect seems to be specific for cholinergic neurons, since somatostatin release and glutamic acid decarboxylase and 2',3'-cyclic nucleotide 3'-phosphodiesterase activities were not significantly influenced by IL-3. In vivo, IL-3 was infused into the lateral ventricles of rats after unilateral axotomy of the septohippocampal pathways. Two weeks later, the IL-3-treated animals showed significant numbers of acetylcholinesterase-positive neurons remaining in the septal region.
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PMID:Interleukin 3 as a trophic factor for central cholinergic neurons in vitro and in vivo. 215 41

In 11 elderly normal subjects and in 17 young healthy subjects we studied the response of plasma growth hormone to GH-releasing hormone (GHRH(29), 1 microgram/kg iv) alone and preceded by pyridostigmine (120 mg orally 60 min before GHRH), a cholinesterase inhibitor likely able to suppress somatostatin release. The GH response to pyridostigmine alone was also examined. Basal plasma GH levels were similar in elderly and young subjects. In the elderly, GHRH induced a GH rise (AUC, median and range: 207.5, 43.5-444.0 micrograms.l-1.h-1) which was lower (p = 0.006) than that observed in young subjects (548.0, 112.5-2313.5 micrograms.l-1.h-1). The pyridostigmine-induced GH rise in the elderly was similar to that in young subjects (300.5, 163.0-470.0 vs 265.0, 33.0-514.5 micrograms.l-1.h-1). Pyridostigmine potentiated the GH responsiveness to GHRH in both elderly (437.5, 152.0-1815.5 micrograms.l-1.h-1; p = 0.01 vs GHRH alone) and young subjects (2140.0, 681.5-4429.5 micrograms.l-1.h-1; p = 0.0001 vs GHRH alone). However, the GH response to pyridostigmine + GHRH was significantly lower (p = 0.0001) in elderly than in young subjects. In conclusion, the cholinergic enhancement by pyridostigmine is able to potentiate the blunted GH response to GHRH in elderly subjects, inducing a GH increase similar to that observed after GHRH alone in young adults. This finding suggests that an alteration of somatostatinergic tone could be involved in the reduced GH secretion in normal aging. However, a decreased GH response to combined administration of pyridostigmine and GHRH in elderly subjects suggests that other abnormalities may coexist, leading to the secretory hypoactivity of somatotropes.
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PMID:Pyridostigmine partially restores the GH responsiveness to GHRH in normal aging. 222 Feb 58

In order to explore the mechanisms by which free fatty acids (FFA) inhibit GH secretion, we studied the effect of the acetylcholinesterase inhibitor pyridostigmine (120 mg p.o.) on the FFA blockade of GH responses to the administration of GHRH (100 micrograms i.v.) in seven normal subjects. GHRH-induced GH secretion was significantly reduced following elevation of circulating FFA levels by lipid-heparin infusion and significantly potentiated by previous pyridostigmine treatment. Peak GH levels following combined administration of pyridostigmine plus lipid-heparin plus GHRH were significantly higher (P less than 0.01) than after GHRH alone and significantly lower than after pyridostigmine plus GHRH (P less than 0.01). In conclusion, central cholinergic activation by pyridostigmine, with the presumed reduction in somatostatin discharge, reversed the blocking effect of FFA on GHRH-stimulated GH release. Conversely, FFA were able to reduce even a maximal GH stimulation by pyridostigmine plus GHRH.
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PMID:Role of cholinergic muscarinic pathways on the free fatty acid inhibition of GH responses to GHRH in normal men. 222 76

In the present study we investigated the effects of the acetylcholinesterase inhibitor pyridostigmine (PD), which is hypothesized to decrease hypothalamic somatostatin tone, alone and in association with GH-releasing hormone (GHRH) on GH secretion in 18 type 1 diabetic patients and 12 normal subjects using a randomized double blind placebo-controlled protocol. All subjects received either 120 mg oral PD or placebo 60 min before iv injection of either human GHRH-(1-29) NH2 (100 micrograms) or sterile water (2 mL). In normal subjects both PD alone and GHRH alone caused a significant increase in GH. PD and GHRH acted in a synergistic fashion when combined. In diabetic patients the GH response to GHRH was variable. To segregate the responses, the ratio between the GH increase after GHRH plus PD and after GHRH alone was calculated for each subject. In 10 diabetic patients (group A) the ratio was lower than 2 SD (P less than 0.05) from the mean response of normal subjects. These patients showed an exaggerated GH increase after GHRH and a lower GH increase after PD with respect to normal subjects. Eight diabetic patients (group B) showed a ratio similar to that in normal subjects and similar GH responses to the stimuli. No significant differences were found between groups A and B with respect to age, body mass index, and blood glucose levels. Duration of diabetes was longer and basal GH levels were higher in group A. Hemoglobin-A1c was higher in group A, but of only borderline statistical significance (P = 0.052). Our data demonstrate that in diabetic patients with exaggerated GH responses to GHRH an increase in cholinergic tone does not affect GH secretion. These data suggest that in some type 1 diabetic patients an altered somatostatinergic control of GH secretion may contribute to their abnormal GH response to GHRH.
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PMID:Impaired growth hormone (GH) response to pyridostigmine in type 1 diabetic patients with exaggerated GH-releasing hormone-stimulated GH secretion. 222 5

Knowledge about the distribution and origins of peptide-containing nerves in the innervated and transplanted heart is lacking. Immunohistochemical and histochemical techniques were used to visualize human cardiac innervation before and after transplantation. In the recipient heart cardiac nerve fibers and fascicles displayed immunoreactivity for general neural (protein gene product 9.5 and synaptophysin) and Schwann cell markers (S-100). A major proportion of cardiac nerves displayed neuropeptide tyrosine and tyrosine hydroxylase immunofluorescence staining. Subpopulations of nerves contained somatostatin, vasoactive intestinal polypeptide, calcitonin gene-related peptide, substance P- or neurokinin-like immunoreactivity, and acetylcholinesterase activity. Tissues from cardiac allografts (5 weeks to 63 months after transplantation) contained nerves and ganglion cells that were acetylcholinesterase positive and immunoreactive for the general neural markers. These nerves were less numerous than in recipient hearts and rarely displayed neuropeptide immunostaining. Atrial natriuretic peptide immunoreactivity was localized to myocardial cells in transplanted hearts as well as explanted recipient and postmortem hearts. While most human cardiac allografts remain functionally extrinsically denervated, they appear to contain viable intrinsic nerves, and myocardial cells retain the capacity to produce atrial natriuretic peptide.
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PMID:Immunohistochemical demonstration of human cardiac innervation before and after transplantation. 231 94

Hippocampal CA3 neurons from fetal rats were grafted to excitotoxic lesions in the CA3 subfield of the adult rat hippocampus and the formation of graft-host brain nerve connections examined. The excitotoxic lesions were induced by localized, stereotaxic injection of ibotenic acid (IA), a glutamic acid agonist, into CA3 of the dorsal hippocampus. The result was a so-called axon-sparing lesion with localized degeneration of nerve cells, but preservation of the extrinsic afferent fibers, now deprived of their targets. One week after the lesion a suspension of embryonic (E18-20) CA3 cells was grafted to the lesion site. Six weeks or more later the recipient brains were processed and analyzed by ordinary cell stains, histochemistry for acetylcholinesterase (AChE) and heavy metals (Timm staining), immunohistochemistry for the neuropeptides cholecystokinin and somatostatin and glial fibrillary acidic protein (GFAP) for astroglia, electron microscopy, and axonal tracing with retrogradely axonal transported fluorescent dyes or lesion-induced, anterograde degeneration combined with silver staining or electron microscopy. More than 90% of the grafts survived. They contained the normal types of CA3 neurons, which are mainly pyramidal cells, in addition to some normal, peptidergic, cholecystokinin- and somatostatin-reactive neurons. The grafts were innervated by AChE-positive, host cholinergic fibers, Timm-positive mossy fiber terminals from the host fascia dentata, and host commissural fibers traced by axonal degeneration. Efferent transplant projections were traced to the ipsilateral host CA1 (Schaffer collaterals) and the contralateral host hippocampus by retrograde axonal transport of fluorochromes injected into these host brain areas. All grafts analyzed by electron microscopy contained axonal varicosities resembling axonal growth cones even after long survival times. The results demonstrate that fetal rat hippocampal neurons, grafted to excitotoxic, axon-sparing lesions in the adult brain, can become both structurally and connectively well incorporated in the mature host central nervous system.
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PMID:Grafting of fetal CA3 neurons to excitotoxic, axon-sparing lesions of the hippocampal CA3 area in adult rats. 239 68


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