Synergistic inhibition of butyrylcholinesterase by galantamine and citalopram

Background: 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.

Methods: 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.

Results: Galantamine almost completely inhibited BuChE at low substrate concentrations (V(S)=43.6 μM/min; V(S(gal))=0.34 μM/min) without influencing the substrate-activated form of the enzyme (V(SS)=64.0 μM/min;V(SS(gal))=62.3 μM/min). Conversely, citalopram inhibited both un-activated (V(S)=43.6 μM/min; V(S(cit))=10.2 μM/min) and substrate-activated (V(SS)=64.0 μM/min; V(SS(cit))=47.3 μM/min) forms of BuChE. Combined galantamine and citalopram increased inhibition of un-activated BuChE (V(S)=43.6 μM/min; V(S(gal)(cit))=2.73 μM/min) and substrate-activated form (V(SS)=64.0 μM/min; V(SS(gal)(cit))=42.2 μM/min).

Conclusion: Citalopram and galantamine produce a combined inhibition of BuChE that is considered to be synergistic.

General significance: 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.