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:3.1.1.8 (cholinesterase)
12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acetylcholine (ACh) was found here to be a strong modulator of swimming activity in the isolated spinal cord preparation of the adult lamprey (Ichthyomyzon unicuspis). During fictive swimming induced with either D-glutamate or N-methyl-D-aspartate, addition of ACh (200 microM) significantly reduced the cycle period of ventral root bursts to 54%, intersegmental phase lag to 32%, and ventral root burst proportion to 80% of control levels. Effects of ACh were apparent at concentrations as low as 1 microM. Both nicotinic and muscarinic receptors are involved, in that application of either nicotinic or muscarinic agonists alone significantly reduced cycle period. There is sufficient endogenous ACh in the spinal cord to modulate ongoing fictive swimming, as shown by application of the cholinesterase inhibitor eserine (physostigmine). Eserine (20 microM) significantly reduced the cycle period to 78% and phase lag to 58% of control levels, and these effects were reversed with the addition of cholinergic blockers. Addition of only a nicotinic or muscarinic antagonist, mecamylamine (10 microM) or scopolamine (20 microM), respectively, to the spinal cord during fictive swimming produced significant increases in cycle period and phase lag, suggesting that both types of cholinergic receptors participate in endogenous cholinergic modulation. It is concluded that ACh is an endogenous modulator of the locomotor network in the lamprey spinal cord and that ACh may take part in the regulation of cycle period, intersegmental coupling, and ventral root burst duration.
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PMID:Cholinergic modulation of the locomotor network in the lamprey spinal cord. 1515 24

By some estimates moderate-to-severe Alzheimer's disease accounts for 50% of all patients with Alzheimer's disease. However, there are numerous issues that remain to be resolved in the management of patients with more advanced Alzheimer's disease. The first prospective, randomised, controlled trial of the cholinesterase inhibitor donepezil in more advanced Alzheimer's disease has reported quite encouraging results, with further studies being undertaken. Post-hoc analyses of rivastigmine and galantamine in patients with more advanced Alzheimer's disease have supported the hypothesis that acetylcholinesterase inhibitors are likely be efficacious in this subgroup. Memantine, a glutamate NMDA receptor antagonist, is newly licensed in Europe for the treatment of more advanced Alzheimer's disease and will provide the first non-cholinesterase inhibitor option for the treatment of Alzheimer's disease. The combination of donepezil and memantine has been shown to have superior efficacy than donepezil alone in this severe Alzheimer's disease subgroup, potentially supporting a role for dual treatment in more advanced Alzheimer's disease. Further studies of all aspects of more advanced Alzheimer's disease are clearly needed. The problems of translating clinical trial results to routine clinical practice are even more complex and challenging in this patient group, with the true impact of any one given treatment ranging over a spectrum of clinical domains from improved cognition to reduced caregiver burden. Increased attentiveness by clinicians to treatment response across this multidisciplinary spectrum in more advanced Alzheimer's disease is warranted.
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PMID:What are the treatment options for patients with severe Alzheimer's disease? 1522 74

Memantine is an NMDA receptor antagonist with moderate affinity, which results in neuroprotective potential due to reducing overstimulation caused by glutamate (excitotoxicity) and simultaneous lack of adverse events (especially psychosis) typical for an antagonist with higher affinity like phencyclidine. In randomized, controlled studies it has been shown that memantine is beneficial in the treatment of moderate to severe dementia of Alzheimer's type and it became the very first compound to be registered for this purpose both in Europe (including Poland) and in the United States. Further investigation require usefulness of memantine in less advanced stages of Alzheimer's disease as well as other types of dementia especially vascular; promising results are shown in dual therapy: memantine + cholinesterase inhibitor.
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PMID:[The clinical relevance of memantine use]. 1530 96

Podophyllotoxin, 10(-3) (M), inhibits the respiration in vitro of rat lymph nodes, thymus, kidney, tumor, spleen, liver, brain, testis, and chicken embryo. Lymph node and spleen respiration are most sensitive, and the degree of inhibition increases with time. The injection of podophyllotoxin into tumor-bearing mice (20 mg. per kg.) causes a dramatic reduction in the respiration of tumor slices. Within 6 hours, the respiration approaches zero. Inhibition is evident 2 hours after injection of the drug. Spleen respiration is reduced 50 per cent within 6 hours. Kidney and liver respirations remain within normal limits. Marked reductions in the respiration of spleen, lymph nodes, and thymus glands of normal rats are produced by the injection of 15 mg. per kg. Thymus gland is the most sensitive of these three tissues, and its respiration is reduced 66 per cent 24 hours after injection of the drug. The injection of 0.8 microgram podophyllotoxin into the yolk sac of chicken eggs bearing 5 day embryos has no effect on the respiration of the embryo within 8 hours, although this is a sufficiently toxic dose to kill 80 per cent of the embryos (within 24 hours). Kidney respiration in the presence of acetate, glucose, alanine, and glutamate is inhibited to approximately the same degree as in the absence of added substrate. Succinate and pyruvate oxidation by rat kidney slices appear to be less sensitive. Oxidation of acetate and butyrate by rabbit kidney homogenate is more sensitive to podophyllotoxin than oxidation by rabbit kidney homogenate without added substrate. Glucose oxidation by this preparation is not inhibited by 10(-3)M podophyllotoxin. The anaerobic glycolysis of chicken embryo, rat brain, and rat testis is stimulated by 10(-5) and 10(-6)M podophyllotoxin, and is inhibited by 10(-3)M. The following enzymes are not inhibited by 10(-3)M podophyllotoxin: succinoxidase from pigeon breast muscle, choline, xanthine and tyrosine oxidase from rat liver homogenate, and leucine oxidase from Proteus vulgaris; alkaline and acid phosphatase from dog serum; adenosine triphosphatase from rat liver; choline esterase from rat brain homogenate; ribonucleodepolymerase from spleen mince and thymonucleodepolymerase from dog serum. High concentrations of podophyllotoxin do not influence the viscosity and degree of polymerization of thymonucleic acid.
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PMID:The effect of podophyllotoxin on tissue metabolism and enzyme systems. 1539 71

Alzheimer's disease is the fourth largest cause of death for people over 65 years of age. Dementia of Alzheimer's type is the commonest form of dementia, the other two forms being vascular dementia and mixed dementia. At present, the therapy of Alzheimer's disease is aimed at improving both, cognitive and behavioural symptoms and thereby, quality of life for the patients. Since the discovery of Alzheimer's disease by Alois Alzheimer, many pathological mechanisms have been proposed which led to the testing of various new treatments. Until recently the available drugs for the treatment of Alzheimer's disease are cholinesterase inhibitors, which have limited success because these drugs improve cognitive functions only in mild dementia and cannot stop the process of neurodegeneration. Moreover, drugs of this category show gastrointestinal side effects. As the cells of central and peripheral nervous system cannot regenerate, newer strategies are aimed at preserving the surviving neurons by preventing their degeneration. NMDA-receptor-mediated glutamate excitotoxicity plays a major role in Abeta-induced neuronal death. Hence, it was thought that NMDA receptors could be a promising target for preventing the progression of Alzheimer's disease. All the compounds synthesized initially in this category showed toxicity mainly because of their high affinity for NMDA receptors. Memantine (1-amino adamantane derivative), NMDA-receptor antagonist was reported to be effective therapeutically in Alzheimer's disease. It was available in Germany as well as European Union and has been approved for moderate to severe dementia in United States of America recently. It is an uncompetitive, moderate affinity antagonist of NMDA receptors that inhibits the pathological functions of NMDA receptors while physiological processes in learning and memory are unaffected. Memantine is also reported to have beneficial effects in other CNS disorders viz., Parkinson's disease (PD), stroke, epilepsy, CNS trauma, amyotrophic lateral sclerosis (ALS), drug dependence and chronic pain. Mechanisms of neuroprotection, preclinical and clinical evidence for effectiveness of memantine have been provided. Pharmacology and pharmacokinetics of memantine and other NMDA-receptor antagonists in comparison with currently approved drugs for dementia treatment have been discussed. The focus is on 'glutamate excitotoxicity' and glutamate receptors as drug target. Various other novel strategies for the treatment of dementia of neurodegenerative disorders have also been discussed.
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PMID:Dementia of Alzheimer's disease and other neurodegenerative disorders--memantine, a new hope. 1551 30

Extracellular amyloid plaques, intracellular neurofibrillary tangles, and loss of basal forebrain cholinergic neurons in the brains of Alzheimer's disease (AD) patients may be the end result of abnormalities in lipid metabolism and peroxidation that may be caused, or exacerbated, by beta-amyloid peptide (Abeta). Apolipoprotein E (apoE) is a major apolipoprotein in the brain, mediating the transport and clearance of lipids and Abeta. ApoE-dependent dendritic and synaptic regeneration may be less efficient with apoE4, and this may result in, or unmask, age-related neurodegenerative changes. The increased risk of AD associated with apoE4 may be modulated by diet, vascular risk factors, and genetic polymorphisms that affect the function of other transporter proteins and enzymes involved in brain lipid homeostasis. Diet and apoE lipoproteins influence membrane lipid raft composition and the properties of enzymes, transporter proteins, and receptors mediating Abeta production and degradation, tau phosphorylation, glutamate and glucose uptake, and neuronal signal transduction. The level and isoform of apoE may influence whether Abeta is likely to be metabolized or deposited. This review examines the current evidence for diet, lipid homeostasis, and apoE in the pathogenesis of AD. Effects on the cholinergic system and response to cholinesterase inhibitors by APOE allele carrier status are discussed briefly.
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PMID:Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. 1571 86

Intracerebroventricular (ICV) injection of streptozotocin (STZ) causes cognitive impairment in rats. ICV STZ is known to impair cholinergic neurotransmission by decreasing choline acetyltransferase (ChAT) levels, glucose and energy metabolism in brain and synthesis of acetyl CoA. However, no reports are available regarding the cholinesterase inhibitors in this model. In aging brain, reduced energy metabolism increases glutamate release, which is blocked by L-type calcium channel blockers. These calcium channel blockers have shown beneficial effects on learning and memory in various models of cognitive impairment. The present study was designed to investigate the influence of chronic administration of donepezil (cholinesterase inhibitor, 1 and 3 mg/kg) and lercanidipine (L-type calcium channel blocker, 0.3 and 1 mg/kg) on cognitive impairment in male Sprague-Dawley rats injected twice with ICV STZ (3 mg/kg) bilaterally on days 1 and 3. ICV STZ injected rats developed a severe deficit in learning and memory indicated by deficits in passive avoidance paradigm and elevated plus maze as compared to control rats. Cholinesterase activity in brain was significantly increased in ICV STZ injected rats. Donepezil dose-dependently inhibited cholinesterase activity and improved performance in memory tests at both the doses. Lercanidipine (0.3 mg/kg) showed significant improvement in memory. When administered together, the effect of combination of these two drugs on memory and cholinesterase activity was higher than that obtained with either of the drugs when used alone.
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PMID:Effect of donepezil and lercanidipine on memory impairment induced by intracerebroventricular streptozotocin in rats. 1584 14

Previously, we have demonstrated that decreases in blood pressure induced by intravenous nitroprusside increase the firing rate of angiotensin II-sensitive neurons in the anterior hypothalamic area (AHA) of rats and that this increase of neural firing rate is blocked by the pressure application of losartan onto the same neurons. It has been suggested that acetylcholine in the posterior hypothalamic nucleus (PHN) serves as a neurotransmitter in a pathway which can modulate baroreceptor reflexes. In the present study, we examined whether acetylcholine in the PHN is involved in the nitroprusside-induced increase of the firing of angiotensin II-sensitive neurons in the AHA of rats. Male Wistar rats were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Decreases in blood pressure induced by intravenous nitroprusside (100 ug/kg) increased the firing rate of AHA angiotensin II-sensitive neurons. The nitroprusside-induced increase of firing rate of AHA neurons was inhibited by PHN microinjection of the cholinoceptor antagonist scopolamine and potentiated by PHN microinjection of the cholinesterase inhibitor physostigmine. Microinjections of carbachol and glutamate into the PHN caused increases of firing rate of AHA neurons. The carbachol-induced but not glutamate-induced increase of unit firing was abolished by the pre-microinjection of scopolamine into the same sites of the PHN. These findings suggest that the nitroprusside-induced increase of firing of AHA neurons is mediated via acetylcholine at the level of the PHN.
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PMID:Cholinergic systems in the posterior hypothalamic nucleus are involved in blood pressure decrease-induced excitation of anterior hypothalamic area neurons in rats. 1611 37

Defining the regions of the brain displaying the neuropathological lesions that cause Alzheimer's disease (AD) will facilitate deeper investigation into their pathophysiology. In addition, this would allow the effects of AD treatment to be specifically monitored in those regions. Cognitive decline in AD begins with failings of episodic memory and spatial orientation in patients with very mild AD. Clinical and experimental data show that the brain regions primarily involved in memory impairment early in AD are the hippocampus and the medial temporal lobe. Is it possible to prevent the development of pathophysiology in these regions? The neuroprotective effect of cholinesterase inhibitors has been demonstrated in a number of different models, including protection of cortical neurons in models of oxygen-glucose deprivation and glutamate-induced toxicity, and protection against the effects of hippocampal mitochondrial dysfunction in transgenic mouse models of AD. These preclinical data are supported by extensive clinical data indicating that maximum benefit is gained through early initiation of treatment with donepezil and suggest that the benefits afforded by donepezil may extend beyond those of a purely symptomatic treatment.
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PMID:Cholinergic treatment: what are the early neuropathological targets? 1614 31

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) are tonically activated by endogenous angiotensins in rats and that activities of these AHA neurons are enhanced in spontaneously hypertensive rats (SHR). In addition, we have demonstrated that cholinergic mechanisms in the posterior hypothalamic nucleus (PHN) are involved in the activation of AHA angiotensin-II-sensitive neurons. It has been suggested that cholinergic function in the posterior hypothalamus is enhanced in SHR and that this hyperactivity plays a role in hypertension in SHR. In the present study, we examined whether the PHN cholinergic stimulation-induced activation of AHA angiotensin-II-sensitive neurons is altered in SHR. Male 15- to 16-week-old SHR and age-matched Wistar Kyoto rats (WKY) were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Microinjection of the cholinoceptor agonist carbachol, the cholinesterase inhibitor physostigmine and the excitatory amino acid glutamate into the PHN caused increases in firing rate of AHA angiotensin-II-sensitive neurons in anesthetized WKY and SHR. The increase in firing rate of AHA neurons induced by these drugs was enhanced in SHR as compared to WKY. The enhancement of the physostigmine-induced activation of AHA neurons in SHR was similar to that of the carbachol-induced activation of AHA neurons in SHR. The enhancement of the glutamate-induced activation of AHA neurons in SHR was similar to that of the carbachol-induced activation of AHA neurons in SHR. Microinjection of scopolamine, a cholinoceptor antagonist, into the PHN caused a small but significant decrease of firing rate of AHA angiotensin-II-sensitive neurons in SHR but not in WKY. These findings indicate that the PHN cholinergic stimulation-induced activation of AHA angiotensin-II-sensitive neurons is enhanced in SHR and that PHN cholinergic mechanisms are involved in tonic activation of angiotensin-II-sensitive neurons in the AHA of SHR. It appears that the enhancement of the PHN cholinergic stimulation-induced activation of AHA neurons in SHR results mainly from the enhanced neural reactivity to angiotensins in AHA neurons of SHR.
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PMID:Posterior hypothalamus cholinergic stimulation-induced activation of anterior hypothalamic area neurons is enhanced in spontaneously hypertensive rats. 1621 27


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