title: Species- and concentration-dependent differences of acetyl- and butyrylcholinesterase sensitivity to physostigmine and neostigmine.
abstract: Previous and more recent studies show that cholinesterase inhibitors (ChE-Is) are an important possibility for therapeutic intervention in Alzheimer's Disease, sepsis and other inflammatory syndromes. ChE-Is maintain high levels of acetylcholine (ACh) determining beneficial effects on the disease process. Despite numerous efforts to identify the appropriate choice of agents and dose of ChE-Is, a common protocol regarding concentration- and species-dependent differences in inhibitory potency (IC 50) of clinical relevant ChE-Is is still not available. To evaluate the in vitro sensitivity of Acetyl- and Butyrylcholinesterase (AChE, BChE), we compared the concentration-response effects of physostigmine and neostigmine on cholinesterases in whole blood from rat and human. A spectrophotometrical test system based on in vitro Ellman's reagent has been used to determine the kinetic properties of clinical relevant ChE-Is. In vitro, the enzyme activity of human AChE and BChE was inhibited in a concentration-dependent manner until a residual activity of 4-6% for AChE and 20-30% for BChE (IC 50 human AChE: 0.117 ± 0.007 μM physostigmine, 0.062 ± 0.003 μM neostigmine; IC 50 human BChE: 0.373 ± 0.089 μM neostigmine; 0.059 ± 0.012 μM physostigmine). The inhibition curve of rat BChE in contrast showed no concentration-dependency for physostigmine and neostigmine (87% residual activity even at high inhibitor concentrations). Rat AChE was inhibited in a concentration-dependent manner until a residual activity of 53%. The results suggest that cholinesterases from human and rat show marked species- and inhibitor-dependent differences in sensitivity to physostigmine and neostigmine. Knowledge of such differences may be critical in assessing the possible therapeutic effects of ChE-Is in both species and may guide researchers in the optimal design of future experiments regarding the application of ChE-Is.
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany. Electronic address: diane.bitzinger@ukr.de.
authors.forename: Diane I
authors.initials: DI
authors.lastname: Bitzinger
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gruber
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Tümmler
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Michels
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Anika
authors.initials: A
authors.lastname: Bundscherer
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Hopf
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Trabold
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Graf
authors.affiliation: Department of Anesthesiology, University of Regensburg, Regensburg, Germany.
authors.forename: York A
authors.initials: YA
authors.lastname: Zausig
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009388:Neostigmine / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
chemical_list: D002800:Cholinesterase Inhibitors; D009388:Neostigmine; D010830:Physostigmine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase; Alzheimer's disease; Butyrylcholinesterase; Cholinesterase inhibitors; Ellman's reagent; Inflammatory disease; Neostigmine; Physostigmine; Rat