Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When animals learn hippocampus-dependent associative and spatial tasks such as trace eyeblink conditioning and the water maze, CA1 hippocampal neurons become more excitable as a result of reductions in the post-burst, slow afterhyperpolarization. The calcium-activated potassium current that mediates this afterhyperpolarization is activated by the calcium influx that occurs when a series of action potentials fire and serves as a modulator of neuronal firing frequency. As a result, spike frequency accommodation is also reduced after learning. Neuronal calcium buffering processes change and/or voltage-dependent calcium currents increase during aging; leading to enhancements in the slow afterhyperpolarization, increased spike frequency accommodation and age-associated impairments in learning. We describe a series of studies done to characterize this learning-specific enhancement in intrinsic neuronal excitability and its converse in aging brain. We have also combined behavioral pharmacology and biophysics in experiments demonstrating that compounds that increase neuronal excitability in CA1 pyramidal neurons also enhance learning rate of hippocampus-dependent tasks, especially in aging animals. The studies reviewed here include those using nimodipine, an L-type calcium current blocker that tends to cross the blood-brain barrier; metrifonate, a cholinesterase inhibitor; CI1017, a muscarinic cholinergic agonist; and galantamine, a combined cholinesterase inhibitor and nicotinic agonist. Since aging is the chief risk factor for Alzheimer's disease, a disease that targets the hippocampus and associated brain regions and markedly impairs hippocampus-dependent learning, these compounds have potential use as treatments for this disease. Galantamine has been approved by the USDA for this purpose. Finally, we have extended our studies to the TG2576 transgenic mouse model of Alzheimer's disease (AD), that overproduces amyloid precursor protein (APP) and increases levels of toxic beta-amyloid in the brain. Not only do these mice show deficits in hippocampus-dependent learning as they age, but their hippocampal neurons show a reduced capacity to increase their levels of intrinsic excitability with reductions in the slow afterhyperpolarization after application of the muscarinic agonist carbachol. These TG2576 APP overproducing mice were crossed with BACE1 knockout mice, that do not produce beta-amyloid because cleavage of APP by the beta-site APP cleaving enzyme 1 (BACE1) is a critical step in its formation. Not only was hippocampus-dependent learning rescued in the bigenic TG2576-BACE1 mice, but the capacity of hippocampal neurons to show normal enhancements of intrinsic excitability was restored. The series of studies reviewed here support our hypothesis that enhancement in intrinsic excitability by reductions in calcium-activated potassium currents in hippocampal neurons is an important cellular mechanism for hippocampus-dependent learning.
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PMID:Pharmacological and molecular enhancement of learning in aging and Alzheimer's disease. 1645 91

Fourteen diterpenes were isolated from the n-hexane fraction of the roots of Aralia cordata (syn. = A. continentalis). Through spectroscopy, the chemical structures were determined as: ent-pimara-8(14),15-diene-19-oic acid (1); ent-kaur-16-en-19-oic-acid (2); 18-nor-ent-pimara-8(14),15-diene-4beta-ol (3); 18-nor-ent-kaur-16-ene-4beta-ol (4); ent-pimara-8(14),15-diene-19-ol (5); 7alpha-hydroxy-ent-pimara-8(14),15-diene-19-oic acid (6); 7beta-hydroxy-ent-pimara-8(14),15-diene-19-oic acid (7); ent-pimar-15-en-8alpha,19-diol (8); 7-oxo-ent-pimara-8(14),15-diene-19-oic acid (9); 16alpha-hydroxy-17-isovaleroyloxy-ent-kauran-19-oic acid (10); 17-hydroxy-ent-kaur-15-en-19-oic acid (11); 15alpha,16alpha-epoxy-17-hydroxy-ent-kauran-19-oic acid (12); 16alpha,17-dihydroxy-ent-kauran-19-oic acid (13); and 16alpha-methoxy-17-hydroxy-ent-kauran-19-oic acid (14). Compounds 4, 5, 8, 12, and 14 were first isolated from this plant. The anti-Alzheimer and antioxidant effects of ent-pimarane-type diterpenes 1, 3, 5, 8, and 9, as well as ent-kaurane-type diterpenes 2, 4, and 10-13, were evaluated via beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), peroxynitrite (ONOO(-)), and nitric oxide (NO*) assays. Of the compounds tested, 8 exerted the most effective BChE inhibition with an IC(50) value of 7.58 microM, followed by 3, 13, 11, 2, and 10. Compounds 9-11 exhibited good BACE1 inhibitory activities with IC(50) values of 18.58-24.10 microM. However, 11 showed marginal AChE inhibitory effect, and all compounds tested showed no scavenging activities on ONOO(-) and NO* at a concentration of 100 microM.
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PMID:Cholinesterase and BACE1 inhibitory diterpenoids from Aralia cordata. 1989 3

It was previously reported that certain lavandulylated flavanones from Sophora flavescens are beta-site APP cleaving enzyme 1 (BACE1) inhibitors; however, based upon their levels within the extract, their inhibitory effects should be higher than expected. Moreover, chalcones and flavonols were reported to exert higher bioactivities than flavanones. These findings have led to a further search for other possible constituents potentially contributing to the strong inhibitory activity of the S. flavescens extract. In this study, BACE1 activities were significantly inhibited by 8-lavandulylkaempferol (IC(50) 7.29 microM), kuraridinol (IC(50) 7.10 microM), kuraridin (IC(50) 6.03 microM), and kushenol C (IC(50) 5.45 microM) from the ethyl acetate fraction, along with desmethylanhydroicaritin (IC(50) 1.86 microM), xanthohumol (IC(50) 7.19 microM), and leachianone G (IC(50) 8.56 microM) from the dichloromethane fraction of the extract. The results indicate that the prenyl group, rather than the lavandulyl group, and the flavonols and chalcones, rather than flavanones, might make predominant contributions to BACE1 inhibition. In particular, 8-lavandulylkaempferol exhibited significant inhibitory effects with IC(50) values of 7.10 and 8.11 microM for butyrylcholinesterase and acetylcholinesterase, respectively, when compared to its counterpart, desmethylanhydroicaritin. This indicates that the lavandulyl group might play a predominant role in both cholinesterase inhibitions. This is the first study indicating that prenylated flavonoids exert varying degrees of inhibition primarily through their skeleton (flavonols, chalcones, flavanones), as well as their lipophilic chain length (prenyl and lavandulyl groups). Therefore, S. flavescens and its prenylated flavonoids, possessing low molecular weights and lipophilic moieties may be potent preventive and therapeutic candidates for Alzheimer's disease.
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PMID:Selective inhibition of prenylated flavonoids from Sophora flavescens against BACE1 and cholinesterases. 2038 35