Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The extent and distribution of biochemical abnormalities thought to reflect disorders of subpopulations of neurons have been determined in the cerebral cortex from brains of patients with Alzheimer-type dementia and depressive illness who died of natural causes. In dementia, loss of gray matter from areas of the parietal and temporal lobes is most obvious. In depression, these areas are not affected, but the pars opercularis and temporal pole are smaller than in controls. Results expressed per unit mass of total protein indicate selective reductions in both disorders of serotonin 2 recognition sites in all areas examined and of somatostatin content in only the temporal pole of the six areas examined. In dementia alone a selective loss was found of somatostatin content of the superior parietal lobule and of serotonin 1A sites and choline acetyltransferase activity in all areas examined. Results for depression expressed per entire area indicate additionally reduced somatostatin content and serotonin 1A sites in the pars opercularis and serotonin 1A sites in the temporal pole. These multiple analyses performed on each sample provide further support for a prominent disorder of pyramidal neurons in dementia as well as more evidence for alterations in cortical neurons in depression, either as a result of the disease itself or its treatment.
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PMID:Circumscribed changes of the cerebral cortex in neuropsychiatric disorders of later life. 257 63

It is known that nerve growth factor (NGF) induces neurite outgrowth and elevation of the activity of adrenergic marker enzyme, tyrosine hydroxylase (TH) in clonal rat pheochromocytoma cells (PC12), whereas glioma-conditioned medium (GCM) induces neurite outgrowth and elevation of the activity of cholinergic marker enzyme, choline acetyltransferase (ChAT) in PC12 cells. In the previous study we have shown that retinoic acid (RA) induces specific elevation of ChAT activity and depression of TH activity without morphological differentiation (Matsuoka, I. et al., Brain Res., 502 (1989]. In the present study, we compared the effects of NGF, GCM and RA on the intracellular signalings in PC12 cells in relation to the mechanism of cholinergic differentiation. Addition of NGF, GCM or RA to the culture medium of PC12 cells caused a rapid rise in intracellular Ca2+ concentration [( Ca2+]i) reaching the level of almost 2.5-fold the resting condition within 3-18 h. Thereafter, [Ca2+]i of NGF-treated cells were decreased to the resting level within 12 h. On the other hand, [Ca2+]i of GCM-and RA-treated cells decreased to a level which was 1.8- to 2-fold the resting condition within 24-48 h and stayed at this level for up to 4-7 days. When homogenates of GCM- and RA-treated PC12 cells were incubated with [gamma-32P]ATP, phosphorylation of a protein with molecular mass of 27 kDa (27 K-protein) was specifically enhanced. The phosphorylation of the 27 K-protein was not seen in the homogenate of the NGF-treated cells. The phosphorylation of the 27 K-protein was dependent on Ca2+ and inhibited by inhibitors of Ca2+-dependent protein kinase, H-7 and W-7. Addition of H-7 and W-7 to the culture medium of PC12 cells abolished the elevation of ChAT activity specifically induced by GCM and RA. These observations suggested that the sustained increase of [Ca2+]i and Ca2+-dependent protein phosphorylation are involved in the intracellular signaling mechanism required for the cholinergic differentiation of PC12 cells induced by GCM and RA.
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PMID:Possible involvements of intracellular Ca2+ and Ca2+ -dependent protein phosphorylation in cholinergic differentiation of clonal rat pheochromocytoma cells (PC12) induced by glioma-conditioned medium and retinoic acid. 258

We investigated the ameliorating effects of DN-1417 (a TRH analog) on the changes of behavior, EEG, neurochemical parameters and regional cerebral blood flow (rCBF) in rats with global cerebral ischemia. Global cerebral ischemia was produced by 10-min occlusion of both common carotid arteries 24 hr after the permanent electrocauterization of bilateral vertebral arteries. DN-1417 was administered intraperitoneally as soon as possible, following recirculation of carotid blood flow. DN-1417 shortened significantly the recovery times of righting reflex (RR) and spontaneous movement (SM) at 2.5 mg/kg and higher doses, and it recovered effectively the EEG activity at 10 mg/kg during recirculation after 10-min cerebral ischemia. In addition, DN-1417 (10 mg/kg) recovered the various changes such as decrease of 5-hydroxytryptamine (5-HT) levels, increase of cyclic AMP (cAMP) levels, inhibition of [3H]-choline uptake, depression of choline acetyltransferase (CAT) and acetylcholine esterase (AChE) activities, and shortened the durations of hyperperfusion and hypoperfusion of rCBF. As a result, it is identified that DN-1417 ameliorates the disturbance of consciousness supposedly caused by behavioral and EEG abnormalities during recirculation following the temporary cerebral ischemia, and the effect of DN-1417 seems to be mediated by normalizing of alterations in the brain monoaminergic and cholinergic systems, as well as rCBF, and the effectiveness for disturbance of consciousness in clinical situations would be expected.
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PMID:[Pharmacological study of the temporary cerebral ischemic rats produced by bilateral vertebral and carotid artery occlusion. Effects of DN-1417]. 286 Nov 49

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses--reflected as an increase in ACh content--is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, L-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine on cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat. 300 39

The acetylcholine turnover rate and the enzymatic activity of choline acetyltransferase were determined in the nucleus accumbens and striatum. Whereas both apomorphine and a serotonin agonist MK 212 led to a decrease in acetylcholine turnover rate, haloperidol showed the opposite effect in the nucleus accumbens and striatum, respectively. Dopamine and serotonin agonists induced a depression of the enzymatic activity but this effect was less pronounced than the effect on acetylcholine turnover rate. It is concluded that in the nucleus accumbens and striatum the cholinergic interneurons appear to be modulated by dopaminergic and serotonergic systems in an inhibitory manner.
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PMID:Modulation by dopaminergic and serotonergic systems of cholinergic interneurons in nucleus accumbens and striatum. 383 17

The prevalence of severe dementia in the United States is about 1.3 million cases, of which at least 50 to 60% are of the Alzheimer type. Severe dementia of the Alzheimer type is found rarely in a clearly dominant pattern, although often one or more relatives are affected. Down's syndrome in adults is often associated with Alzheimer changes. The diagnosis is a clinicopathological one; there is a considerable error rate in the clinical diagnosis early in the course of the disease, especially in regard to dementia in depression. The differential diagnosis involves a great many disorders, including multi-infarct dementia, tumors, subdural hematomas, and others. Physiological aspects of Alzheimer's disease include a diffusely slow electroencephalogram, reduced cerebral blood flow, and particular patterns noted on positron emission tomographic scanning. The latter technique has also demonstrated that oxygen extraction is normal in Alzheimer's disease, thus excluding ischemia from possible pathogenetic factors. Morphological changes, that is, the presence of plaques and tangles, are widely distributed in neocortex, paleocortex, and many deep gray areas down through the pontine tegmentum, but largely exclude the basal ganglia, thalamus, and substantia nigra. Numerous plaques without neocortical tangles are found in many demented persons older than 75 years. A severe loss of large neocortical neurons is characteristic of the disease. The chemical nature of the paired helical filaments that make up the neurofibrillary tangle has not yet been ascertained. Neurons are markedly deficient in the basal forebrain nuclei, and this deficiency may account for the severe diminution of choline acetyltransferase and acetylcholine in the neocortex and paleocortex. Muscarinic cholinergic receptors are present in normal amounts. Norepinephrine is reduced in some cases, and somatostatin in most. Substance P is low in severe cases. The etiology of the disorder is unknown and the role of aluminum is disputed. Management of patients with Alzheimer's disease is difficult, and neuroleptics are to be used with great caution because of their side effects. Substrate therapy has not been effective; physostigmine improves memory but is not suitable for general use. Trophic factors, gangliosides, and aluminum chelation are being investigated for use in pharmacological intervention.
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PMID:Senile dementia of the Alzheimer type. 613 75

The uptake of [3H]choline and its conversion to [3H]acetylcholine were investigated in term human placental tissue in vitro. Although the net uptake of [3H]choline increased throughout a 45 min incubation period, intracellular [3H]choline levels reach a plateau after 2 min. There was a constant increase in [3H]acetylcholine levels throughout the incubation period. After 45 min, 36.5 per cent of the total intracellular tritium was recovered as acetylcholine by high-voltage electrophoresis. The effects of the choline acetyltransferase inhibitors, 2-benzoylethyltrimethyl-ammonium chloride (BETA) and 4-naphthylvinyl pyridine (NVP), and an inhibitor of choline uptake, hemicholinium-3 (HC-3), were also investigated for their influence on the uptake and metabolism of [3H]choline. A significant depression in both [3H]choline uptake and [3H]acetylcholine synthesis could be demonstrated with all three compounds, although with somewhat different time courses and activities. An analysis of the accumulation of [3H]acetylcholine in relation to the uptake and intracellular levels of [3H]choline as well as the patterns of inhibition produced by the inhibitors indicates that, unlike nervous tissue, the rate-limiting step in the synthesis of acetylcholine in human placental tissue is the transacetylation reaction catalysed by choline acetyltransferase.
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PMID:Investigation of the rate-limiting step in the synthesis of acetylcholine by the human placenta. 650 60

Parallel electrophysiological and neurochemical studies of development are reported for mouse spinal cord cell cultures. The time course of electrical activity and the stage-dependent effects of tetrodotoxin on levels of the neuronal enzyme choline acetyltransferase were compared to establish the presence of spontaneous electrical activity at a time when tetrodotoxin adversely affects development. The extracellular patch electrode makes it possible to examine the ongoing electrical activity of the small cells present in young cultures. A rapid increase in spontaneous electrical activity during the first 2 weeks in culture was found to correlate closely with the onset of tetrodotoxin-induced depression of choline acetyltransferase activity, supporting the idea that ongoing electrical activity plays a role in neuronal development. The development of inhibitory synaptic activity occurs gradually throughout the period of culture, whereas excitatory synaptic activity and action potentials develop in unison, reaching maximal levels during the 2nd week in culture. For all cultures tested, ranging in age from 9 to 45 days old, acute bath application of gamma-aminobutyric acid (GABA) abolished spontaneous electrical activity. Glycine is relatively ineffective in abolishing spontaneous activity in young cultures which have few inhibitory postsynaptic potentials (IPSPs), but glycine becomes as effective as GABA at a later stage of development. This suggests rather different timetables of development for GABA and glycine receptors, with glycine receptors developing in parallel with IPSPs.
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PMID:Electrical development in spinal cord cell culture. 705 Mar 10

The vulnerability of striatal and hippocampal neurons to ischemia was studied by measuring the activity of neurotransmitter-related enzymes after transient forebrain ischemia in rats. Activities of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) were measured 6 h to 8 days after 20, 30 or 40 min of forebrain ischemia, as markers for GABAergic and cholinergic neurons respectively. Transient forebrain ischemia resulted in depression of striatal GAD activity while striatal CAT and hippocampal GAD activities were unaffected. Striatal GAD activity progressively decreased during the first 24 h postischemia and remained depressed 5--8 days later, suggesting irreversible damage to this population of neurons. The stability of striatal CAT and hippocampal GAD activity indicates that these cells were resistant to the present ischemic conditions.
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PMID:The response of GABAergic and cholinergic neurons to transient cerebral ischemia. 710 39

Human spermatozoa contain choline acetyltransferase (ChA), acetylcholinesterase and acetylcholine (ACh). There is no storage pool for ACh in spermatozoa. Therefore, ChA inhibitors should exhibit dramatic effects in the alteration of levels and turnover of ACh and sperm motility. The effects of two groups of ChA inhibitors, 2-benzoylethyltrimethylammonium (BETA) and related compounds and halogenoacetylcholines (cholinesters of iodo-, bromo- and chloroacetic acids; XACh, where X = l, Br or Cl), on the motility index of human ejaculated sperm were studied. These investigations gave the following results: 1) BETA was a potent inhibitor of ChA from monkey brain (I50, 4.8 x 10(-6) M), homogenates of rat spermatozoa (I50, 6.5 x 10(-5) M) and homogenates of human spermatozoa (I50, 5.6 x 10(-5) M). It decreased the motility index of human spermatozoa (I50, 8.5 x 10(-8) M) at concentrations higher than 10(-8) M after a contact time of 5 to 60 min. It decreased the motility index of human spermatozoa by about 80% after 5 min and by 95% after 1 hr at a concentration of 10(-6) M. 2) There was a positive relationship between the inhibition of ChA and the depression of the motility index of human spermatozoa among these inhibitors. Both the number of motile cells and the graded motility were decreased. 3) All ChA inhibitors studied are quaternary ammonium compounds that do not significantly cross membrane barriers. 4) Both human sperm cells and human sperm cell homogenates had the same ChA activity. 5) Seventy-five percent of ChA activity could be washed away from human spermatozoa. 6) The same amount of ChA inhibition was observed when BETA was added to the homogenate of sperm cells or whole sperm cells. All of these observations indicate that sperm cell ChA is accessible to BETA and related quaternary ammonium compounds. These studies indicate that ACh is possibly synthesized by the tail and is a local hormone in the coordination of contraction and relaxation cycles of spermatozoan flagella.
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PMID:Inhibition of human sperm motility by inhibitors of choline acetyltransferase. 746 54


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