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)

Previous studies have demonstrated that cholinergic neurons in the adult rat forebrain, i.e., septal region, are able to respond and regenerate after damage followed by exogenous treatment with beta-nerve growth factor. Furthermore, it has been shown that an age-related loss of NGF-receptor (NGFr) immunoreactivity occurs in cholinergic septal neurons. Since the regenerative capacity of cholinergic neurons is of importance for potential therapeutic strategies during the course of age-related neurodegenerative diseases, we have compared NGFr positive neurons in young adult (3 months old) and in aging (18-24 months old) rats in their ability to produce a physiological plasticity response after surviving an excitotoxic lesion of the nucleus basalis of Meynert (NBM). In aging control rats, NGFr immunoreactivity within NBM neurons was significantly reduced, in analogy to data obtained earlier from studies about septal neurons in aged rats. After lesion with quisqualic acid, a severe cell loss as well as atrophy of remaining cholinergic neurons was observed in both groups. Investigation of the NBM at various times after the lesion demonstrated signs of axonal or dendritic sprouting and local regeneration, with a maximum seen 3 months after the lesion. No age-related differences in the response could be found. However, despite local fiber growth, no reinnervation of the frontal and parietal cortex could be noted, as demonstrated by acetylcholinesterase histochemistry. Our findings suggest that, despite a relatively early onset of NGFr decline during lifetime, cholinergic cells keep the capacity for a plastic response, although they ultimately fail to reinnervate the neocortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Quisqualic acid-induced lesion of the nucleus basalis of Meynert in young and aging rats: plasticity of surviving NGF receptor-positive cholinergic neurons. 139 63

Mouse 3T3 fibroblasts were genetically modified by transfection with a mammalian expression vector containing the rat beta-nerve growth factor (NGF) gene. The transfected cell line, designated 3E, contains several hundred copies of the rat NGF gene and secretes high levels of biologically active NGF. Pieces of collagen gel containing the NGF-secreting 3E cells were grafted to the brains of unilaterally fimbria-fornix-lesioned rats. Grafts of the genetically modified NGF-producing cells rescued axotomized basal forebrain cholinergic neurons and significantly reduced cholinergic cell death in the medial septum as compared with rats treated with grafts of the parental 3T3 cells. Grafted fibroblast cells were detected, and rescue effects were noted up to 6 weeks after grafting. Local effects of NGF secreted by grafted cells were also seen at the gel-brain border in the form of sprouting acetylcholinesterase immunoreactive host cortical fibers. We suggest that implantation of genetically modified cells producing NGF may have therapeutic applications in rescuing damaged central cholinergic neurons in senile dementia of the Alzheimer type as well as in providing trophic support for chromaffin tissue grafts in Parkinson's disease.
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PMID:Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. 232 66

Although beta-nerve growth factor is primarily known for its trophic role in the peripheral nervous system, recent reports have also revealed an inductive effect of beta-nerve growth factor on the cholinergic metabolism of the forebrain. To learn more about the significance and location of beta-nerve growth factor action in the central nervous system, the distribution of [125I]beta-nerve growth factor binding sites was studied by using the method of in situ receptor autoradiography and compared with the distribution of acetylcholinesterase, a sensitive enzyme marker of cholinergic neurons. The autoradiographic studies demonstrated strong, specific and saturable [125I]beta-nerve growth factor binding to several neuronal groupings in the forebrain and brainstem. beta-Nerve growth factor binding sites and strong acetylcholinesterase reactivity were jointly distributed in the forebrain on the medial septal nucleus, the diagonal band of Broca, the magnocellular basal nucleus and in the striatum. In the brainstem, beta-nerve growth factor binding sites were located on a number of neuronal groups in the reticular formation, the dorsolateral lemniscus and the cochlear nuclei. In contrast to the forebrain, less correlation was found with the distribution of acetylcholinesterase; no beta-nerve growth factor receptor expression was recorded on the cholinergic motor nuclei of the brainstem, while specific [125I]beta-nerve growth factor labeling could be located on the non-cholinergic cochlear nuclei. The present autoradiographic studies reveal a variety of tentatively beta-nerve growth factor receptor-positive neurons in the central nervous system. While strong correlation between the cholinergic metabolism and the presence of specific beta-nerve growth factor binding is demonstrated in the forebrain, this observation could not be extended to the brainstem, indicating the chemical diversity of central beta-nerve growth factor receptor-positive neurons.
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PMID:The localization and distribution of high affinity beta-nerve growth factor binding sites in the central nervous system of the adult rat. A light microscopic autoradiographic study using [125I]beta-nerve growth factor. 243 88

Recent reports have led to widespread interest in the role of beta-nerve growth factor (beta NGF) in the central nervous system. To learn more about the action of beta NGF in the central nervous system we have mapped the distribution of beta NGF receptors and compared it with that of acetylcholinesterase (AChE), a sensitive enzyme marker for cholinergic neurons. In situ autoradiography revealed strong and saturable beta NGF binding to several groups of neurons in basal forebrain and brainstem. They also contain significant levels of mRNA coding for beta NGF receptors. beta NGF receptors and AChE are codistributed on the medial septal nuclei and in the basal forebrain, including the striatum. In the brainstem, beta NGF receptors are present on the neurons in the lower part of the reticular formation and in cochlear nuclei but do not correspond to the distribution of AChE reactivity.
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PMID:Topography of beta NGF receptor-positive and AChE-reactive neurons in the central nervous system. 255 8

The sparse-fur (spf) mutant mouse has an X-linked deficiency of hepatic ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal period similar to that seen in human patients. We studied the effect of congenital hyperammonemia on the development of cerebral cholinergic parameters such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and high-affinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf mutant mice were significantly elevated after weaning compared with control animals. ChAT activity levels started decreasing in mutant spf mice from the age of 30 days (i.e., immediately after weaning); it reached significantly lower levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice compared with controls up to the adult stage. However, there were no marked changes in the activity of AChE between control and hyperammonemic spf mice. The levels of beta-NGF, which is essential for cholinergic differentiation and function, were significantly lower in different brain regions of adult mutant mice compared with normal controls. A treatment of spf/spf breeding females with acetyl-L-carnitine, at a dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted in a significant restoration of ChAT activity levels in some brain regions of the spf/Y offspring. The beta-NGF levels were also significantly elevated after supplementation with ALCAR in mutant mice compared with untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR during cholinergic deficiency caused by congenital hyperammonemia.
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PMID:Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: effect of acetyl-L-carnitine. 761 28

The biological activities of recombinant human nerve growth factor (rhNGF) produced by Chinese hamster ovary (CHO) cells that were transfected with human NGF gene were investigated in vitro and in vivo. rhNGF showed the same immunoreactivity as mouse NGF (mNGF) in a highly sensitive two-site enzyme immunoassay system employing mouse monoclonal antibody against mouse beta-NGF (MAb 27/21) for both the primary and the secondary antibodies. In PC12 cells, rhNGF promoted neurite extension and induced acetylcholinesterase (AChE) with the same potency as mNGF, showing an ED50 of 10-20 ng/mL. In fetal rat septal neurons cultured on a feeder layer of astroglial cells, rhNGF promoted survival and neurite extension as well as an increase in choline acetyltransferase (ChAT) activity and acetylcholine (ACh) content. At a maximal effective concentration of 30 ng/mL, rhNGF promoted a 1.4-, 2.8-, and 4-fold increase in surviving cell number, ACh content, and ChAT activity, respectively. rhNGF was five times more potent than mNGF for the increase in ChAT activity and ACh content showing an ED50 of 0.5 ng/mL, although the maximal response was the same for the two NGFs. Transection of the fimbria-fornix resulted in a loss of AChE-positive cells in the medial septum (MS) and vertical limb of the diagonal band of Broca (VDB). The administration of rhNGF or mNGF (3 or 30 micrograms in gel form) attenuated the loss of AChE-positive cells; rhNGF was as potent as or even more potent than mNGF. Radio frequency lesion of the basal forebrain (BF) including the nucleus basalis magnocellularis (NBM) resulted in severe impairment of memory and/or learning in passive avoidance and Morris' water maze tasks. Repeated injection of rhNGF (5 micrograms x 5 over 2 wk) into the lateral ventricle ameliorated the behavioral impairment in the water maze task but not in passive avoidance. rhNGF treatment increased ChAT activity in the frontal cortex and even in other subregions of the cerebral cortex where ChAT activity was not decreased by BF lesion. These results indicate that human NGF can be measured in an enzyme immunoassay system using monoclonal antibody against mNGF (MAb 27/21) and that rhNGF has potent biological activity, comparable to or greater than mNGF, both in vitro and in vivo.
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PMID:Detailed characterization of the biological activities of recombinant human nerve growth factor expressed in Chinese hamster ovary cells. 846 95

Sodium orthovanadate, an inhibitor of protein tyrosine phosphatases, causes increased levels of tyrosine phosphorylation and blocks, at noncytotoxic concentrations, the differentiative response of rat pheochromocytoma (PC12) cells to beta-nerve growth factor (beta NGF) and basic fibroblast growth factor (bFGF) in a reversible manner. It also prevents growth factor-induced neurite proliferation in primed cells and causes the retraction of previously formed neurites, even in the presence of beta NGF or bFGF. It is equally effective in blocking neurite proliferation by 8-Br-cAMP. Zinc chloride and ammonium molybdate, two other inhibitors of tyrosine phosphatases, also cause parallel decreases in neurite proliferation. Orthovanadate generally reduces the transcription of immediate early response genes (TIS 8 and c-fos) and secondary response genes (ornithine decarboxylase (ODC), acetyl-cholinesterase (AChE) and SCG 10) induced by beta NGF, bFGF, EGF, and PMA, albeit in a variable fashion. There was no observed effect on the kinetics of expression as judged by TIS 8 induction by beta NGF and protein kinase C (PKC) downregulation did not change the levels of inhibition by orthovanadate seen in control cells. Orthovanadate does not affect the production of diacylglycerol induced by beta NGF or bFGF. These observations are consistent with the view that growth factor stimulation of differentiation in PC12 cells involves at least one other PKC independent pathway, and that cAMP and PMA (and their active analogs) activate tyrosine kinases (albeit probably secondarily), which are at least partially responsible for their actions. Although the exact site(s) of action of orthovanadate that lead to the inhibition of growth factor-induced neurite proliferation are unknown, the results presented suggest that it prolongs tyrosine phosphorylations by nonreceptor tyrosine kinases that act downstream from the receptor kinases.
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PMID:Effect of nerve growth factor and fibroblast growth factor on PC12 cells: inhibition by orthovanadate. 846 55

To investigate the efficacy of nerve growth factor (NGF) in promoting recovery from cholinergic damage, young (3-4 month old) and aged (22-23 month old) Fischer 344 rats received NMDA-induced unilateral lesions of the nucleus basalis of Meynert and subcutaneous osmotic pumps (2-week duration) connected to permanently implanted cannulas directed at the lateral ventricle ipsilateral to the lesion. Pumps were filled with either artificial CSF/rat serum albumin (the vehicle) or 5.0 micrograms of angiotensin-free, beta-NGF. Fourteen days after surgery, all subjects were sacrificed and their brains regionally dissected (frontal and occipital cortices, striatum, and dorsal and ventral hippocampi) and assayed for choline acetyltransferase (CAT) and acetylcholinesterase (AChE). Results indicated that the lesion decreased CAT and AChE levels within the frontal cortex of both young (29.8% and 39.4% depletion, respectively) and aged (30.5% and 34.8% depletion, respectively) animals. Only in young animals did NGF reduce these lesion-induced CAT (by 34.2%) and AChE deficits (by 65.5%). In fact, NGF exacerbated frontal cortical CAT depletions in aged animals in that percent depletion was 11.3% more following treatment (30.5% vs. 41.8% depletion in Aged/CSF and Aged/NGF groups, respectively). Lower CAT and AChE levels were found in the striatum of aged animals, an effect not reversed by NGF treatment. In contrast, NGF in young animals enhanced striatal CAT activity on the non-lesioned side by 22.2%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cholinergic marker deficits induced by lesions of the nucleus basalis of Meynert are attenuated by nerve growth factor in young, but not in aged, F344 rats. 850 14

There are deficits in cholinergic basal forebrain neurons (CBFNs) in the aged brain and patients suffering Alzheimer's disease associated with a partial loss of the CBFNs. To mimic this partial loss and assess its long term effects on residual cholinergic activity and resultant target-derived nerve growth factor (NGF) levels, we produced a partial immunolesion to CBFNs with 192 IgG-saporin, an immunotoxin selectively taken up by p75NTR-bearing neurons. We measured two cholinergic markers, choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity, and NGF protein levels at 10 days, 1, 6 and 12 months postlesion. There were no significant changes in the cholinergic markers and the NGF protein levels in the sham-treated animal controls during the one year experiment. Ten days after 192 IgG-saporin treatment, ChAT activity decreased to 35-50% of controls in the olfactory bulb, hippocampus, and cortex. There was a minor but significant recovery of ChAT activity one year after the immunolesion in the hippocampus. Changes in AChE activity mirrored the ChAT changes but were less robust. There were transient increases in NGF protein levels in the hippocampus and cortex that returned to basal levels at 6 months and 12 months postlesion, respectively. In summary, partial immunolesions resulted in partial region-specific and time-dependent recoveries of cholinergic activity in the target areas of the basal forebrain after a partial elimination of CBFNs and a return to basal levels of NGF protein consistent with the hypothesis that the remaining CBFNs compensated for losses of ChAT and NGF due to changes in cholinergic innervation of basal forebrain target areas.
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PMID:Long term changes in brain cholinergic markers and nerve growth factor levels after partial immunolesion. 972 78

Cholinergic basal forebrain neurons (CBFNs) retrogradely transport neurotrophins released in the hippocampus and cortex as part of a general response to injury in a process that is impaired in the aged rodent and can be spared by the exogenous addition of pharmacological doses of nerve growth factor (NGF). This observation suggests that components of stress response signal transduction pathways in the aged CNS can be exogenously activated. The extent and mechanism of the endogenous stimulation of NGF in response to injury can be mimicked via treatment with 192 IgG-saporin of rat CNS, an immunolesion model. Here we report on the use of a conditioning lesion paradigm to determine if repeated partial immunolesions have a conditioning effect on the immunolesion-induced increases in NGF protein or decreases in choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity. We report that chronic repeated immunolesions, as used here, were not as effective as a one time equivalent immunolesion in terms of induced NGF protein increases or decreasing ChAT and AChE activity in the hippocampus and cortex. Thus, chronic lesions resulting in cholinergic impairment typical of the aged CNS may differ from acute toxic models as a result of desensitization due to a conditioning effect of chronic subthreshold lesioning events in the CNS.
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PMID:Repeated immunolesions display diminished stress response signal. 1071 72


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