Inhibition of cholinesterase activity by tetrahydroaminoacridine and the hemisuccinate esters of tocopherol and cholesterol.
The anticholinesterase properties of tetrahydroaminoacridine (THA, Tacrine), alpha-tocopheryl hemisuccinate (TS), and cholesteryl hemisuccinate (CS), given alone and in combination, were examined in vitro. Results from these studies indicate that: [1] THA is a potent inhibitor of acetylcholinesterase (AChE, IC50 of 0.40 microM) and butyrylcholinesterase (BChE, IC50 of 0.10 microM) with greatest inhibitory activity towards BChE; [2] TS and CS are weak inhibitors of BChE (IC50 of 100 microM and 168 microM, respectively) but potent inhibitors of ACHE (IC50 of 1.73 microM and 0.79 microM, respectively); [3] both TS and CS treatment in combination with THA significantly increased THA's anticholinesterase activity. The percentage AChE inhibition observed with this combination was often significantly greater than the sum of the individual values (synergistic). The addition of 0.5 microM CS or TS to an ACHE preparation reduced THA's IC50 value from 0.40 microM or 0.18 microM, respectively [4]; inhibition of AChE by THA, TS and CS are mixed non-competitive while THA inhibition of BChE is mixed non-competitive and TS and CS inhibition of BChE are simple non-competitive; and [5] inhibition of cholinesterases by TS and CS occurs immediately (50 to 75%), during the first 30 min of incubation (25 to 50%) and is dependent on the anionic charged portion of the molecule. In conclusion, our experimental data indicate that TS and CS are potent inhibitors of AChE activity and significantly potentiate the anticholinesterase activity of THA. Such potent and synergistic inhibition of AChE suggest that TS or CS, alone and in combination with THA, may prove beneficial in the treatment of organophosphate poisoning and Alzheimer's disease.
Chelliah
J
J
Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0662.
Smith
J D
JD
Fariss
M W
MW
D000110:Acetylcholinesterase / Q000378:metabolism; D002091:Butyrylcholinesterase / Q000378:metabolism; D002788:Cholesterol Esters / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004347:Drug Interactions; D007700:Kinetics; D013619:Tacrine / Q000494:pharmacology*; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
D002788:Cholesterol Esters; D002800:Cholinesterase Inhibitors; D014810:Vitamin E; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D002802:Cholinesterases; D024505:Tocopherols; C013440:cholesteryl succinate