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Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram.

ABSTRACT: Many persons with Alzheimer's disease (AD) treated with galantamine appear to receive additional cognitive benefit from citalopram. Both drugs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These enzymes co-regulate acetylcholine catabolism. In AD brain, AChE is diminished while BuChE is not, suggesting BuChE inhibition may be important in raising acetylcholine levels. BuChE is subject to activation at high acetylcholine levels reached at the synaptic cleft. The present study explores one way combining galantamine and citalopram could be beneficial in AD.Spectrophotometric studies of BuChE catalysis in the absence or presence of galantamine or citalopram or both, were performed using the Ellman method. Data analysis involved expansion of our previous equation describing BuChE catalysis.Galantamine almost completely inhibited BuChE at low substrate concentrations (V(S)=43.6 ?M/min; V(S(gal))=0.34 ?M/min) without influencing the substrate-activated form of the enzyme (V(SS)=64.0 ?M/min;V(SS(gal))=62.3 ?M/min). Conversely, citalopram inhibited both un-activated (V(S)=43.6 ?M/min; V(S(cit))=10.2 ?M/min) and substrate-activated (V(SS)=64.0 ?M/min; V(SS(cit))=47.3 ?M/min) forms of BuChE. Combined galantamine and citalopram increased inhibition of un-activated BuChE (V(S)=43.6 ?M/min; V(S(gal)(cit))=2.73 ?M/min) and substrate-activated form (V(SS)=64.0 ?M/min; V(SS(gal)(cit))=42.2 ?M/min).Citalopram and galantamine produce a combined inhibition of BuChE that is considered to be synergistic.Clinical benefit from combined galantamine and citalopram may be related to a synergistic inhibition of BuChE, facilitating cholinergic neurotransmission. This emphasizes the importance of further study into use of drug combinations in AD treatment.

SUBMITTER: Walsh R

PROVIDER: S-EPMC3263522 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram.

Walsh Ryan R Rockwood Kenneth K Martin Earl E Darvesh Sultan S

Biochimica et biophysica acta 20110819 12

<h4>Background</h4>Many persons with Alzheimer's disease (AD) treated with galantamine appear to receive additional cognitive benefit from citalopram. Both drugs inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These enzymes co-regulate acetylcholine catabolism. In AD brain, AChE is diminished while BuChE is not, suggesting BuChE inhibition may be important in raising acetylcholine levels. BuChE is subject to activation at high acetylcholine levels reached at the synaptic c ...[more]

PMID: 21872646

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Project description:When exposed to ultraviolet radiation, the human skin produces profuse reactive oxygen species (ROS), which in turn activate a variety of biological responses. Mounting ROS levels activate tyrosinase by mobilizing ?-melanocyte-stimulating hormone in the epidermis and finally stimulates the melanocytes to produce melanin. Meanwhile, the Keap1-Nrf2/ARE pathway, which removes ROS, is activated at increased ROS levels, and antioxidant compounds facilitates the dissociation of Nrf2. In this study, we explored the possible suppressing effects of antioxidant compounds and tyrosine inhibitors on melanin formation and the promotory effects of these compounds on ROS scavenging. The antioxidant activity of glabridin (GLA), resveratrol (RES), oxyresveratrol (OXYR), and phenylethylresorcinol (PR) were investigated via the stable free radical 2,2-diphenyl-1-picrylhydrazyl method. The inhibitory effects of the four compounds and their mixtures on tyrosinase were evaluated. l-Tyrosine or 3-(3,4-dihydroxyphenyl)-l-alanine (l-DOPA) was used as a substrate. The results showed that all mixtures did not exhibit synergistic effects with the l-tyrosine as a substrate, suggesting that l-tyrosine is not suitable as a substrate. However, the mixtures of "GLA:RES," "GLA:OXYR," "OXYR:RES," and "PR:RES" demonstrated synergistic effects (CI < 0.9, p < 0.05), whereas "GLA:RES" and "PR:OXYR" indicated an additive effect (0.9 ditive1, p < 0.05). Furthermore, we used a molecular docking strategy to study the interactions of the four compounds with tyrosinase and l-DOPA. The molecular docking result is consistent with that of the experiment. Finally, we selected RES + OXYR and used PIG1 cells to verify whether OXYR synergistically promotes RES activity on tyrosinase. The two agents had a synergistic inhibitory effect on tyrosinase activity. These results provided a novel synergistic strategy for antioxidants and tyrosinase inhibitors, and this strategy is useful in skin injury treatment.

Project description:PurposeAlzheimer's disease (AD) is a multifaceted neurodegenerative disease. To target simultaneously multiple pathological processes involved in AD, natural-origin compounds with unique characteristics are promising scaffolds to develop novel multi-target compounds in the treatment of different neurodegenerative disease, especially AD. In this study, novel chromone-lipoic acid hybrids were prepared to find a new multifunctional lead structure for the treatment of AD.MethodsChromone-lipoic acid hybrids were prepared through click reaction and their neuroprotection and anticholinesterase activity were fully evaluated. The anti-amyloid aggregation, antioxidant and metal-chelation activities of the best compound were also investigated by standard methods to find a new multi-functional agent against AD.ResultsThe primary biological screening demonstrated that all compounds had significant neuroprotection activity against H2O2-induced cell damage in PC12 cells. Compound 19 as the most potent butyrylcholinesterase (BuChE) inhibitor (IC50 = 7.55 μM) having significant neuroprotection activity as level as reference drug was selected for further biological evaluations. Docking and kinetic studies revealed non-competitive mixed-type inhibition of BuChE by compound 19. It could significantly reduce formation of the intracellular reactive oxygen species (ROS) and showed excellent reducing power (85.57 mM Fe+2), comparable with quercetin and lipoic acid. It could also moderately inhibit Aβ aggregation and selectively chelate with copper ions in 2:1 M ratio.ConclusionCompound 19 could be considered as a hopeful multifunctional agent for the further development gainst AD owing to the acceptable neuroprotective and anti-BuChE activity, moderate anti-Aβ aggregation activity, outstanding antioxidant activity as well as selective copper chelation ability. A new chromone-lipoic acid hybrid was synthesized as anti-Alzheimer agent with BuChE inhibitory activity, anti-Aβ aggregation, metal-chelation and antioxidant properties.

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Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram.

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Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram.

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