title: Antimalarials inhibit human erythrocyte membrane acetylcholinesterase.
abstract: The current study examined the ability of antimalarials chloroquine (CQ), primaquine (PQ), and quinine (Q) to inhibit human erythrocyte membrane acetylcholinesterase (AChE) and the mechanisms underlying their inhibitory action. CQ was found to be the most effective inhibitor of the enzyme followed by PQ and Q. The concentrations required to obtain 33% inhibition (IC(33)) for CQ and PQ were 22 and 38 microM, respectively, whereas that for Q was 3.2 mM. The concentrations required to obtain 67% inhibition (IC(67)) were about 9 and 7 times higher for CQ and PQ, whereas that for Q was only about 2.5 times higher. Hill plot analysis revealed that CQ shows de-binding above 40 microM. The two kinetic components of AChE were inhibited by the three antimalarials, and the inhibition was of mixed type. Increasing concentrations of antimalarials caused progressive decrease in the V(max) of both components. IC(33) concentrations resulted in 1.6- to 6-fold increase in K(m) of both the components while IC(67) concentration caused 2.8- to 13-fold increases in K(m) with maximum effect being seen with Q. The K(i) values were lowest for CQ suggesting that it was the most potent inhibitor; these values were 3.3 and 60 times higher for PQ and Q. Antimalarials represent the bifunctional compounds that possess anti-inflammatory properties and also inhibit cholinesterases. The results of our studies suggest that 4-aminoquinoline-based antimalarials like CQ and hydroxychloroquine, which are both potent anti-inflammatory agents and inhibitors of cholinesterases, may have potential use as the most effective neuroprotective agents against amyloid-beta-peptide (Abeta) neurotoxicity in Alzheimer's disease.
authors.affiliation: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India. subhash-katewa@uiowa.edu
authors.forename: Subhash D
authors.initials: SD
authors.lastname: Katewa
authors.forename: Surendra S
authors.initials: SS
authors.lastname: Katyare
mesh_terms: D000110:Acetylcholinesterase / Q000097:blood*; D000328:Adult; D000962:Antimalarials / Q000493:pharmacokinetics / Q000494:pharmacology*; D002738:Chloroquine / Q000493:pharmacokinetics / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004910:Erythrocyte Membrane / Q000187:drug effects* / Q000201:enzymology*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011319:Primaquine / Q000493:pharmacokinetics / Q000494:pharmacology; D011803:Quinine / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D002800:Cholinesterase Inhibitors; D002738:Chloroquine; D011803:Quinine; D000110:Acetylcholinesterase; D011319:Primaquine