INHIBITION OF CHOLINESTERASE ACTIVITY BY TETRAHYDROAMINOACRIDINE AND THE HEMISUCCINATE ESTERS OF TOCOPHEROL AND CHOLESTEROL

The anticholinesterase properties of tetrahydroaminoacridine (THA, Tac rine), alpha-tocopheryl hemisuccinate (TS), and cholesteryl hemisuccin ate (CS), given alone and in combination, were examined in vitro. Resu lts from these studies indicate that: [1] THA is a potent inhibitor of acetylcholinesterase (AChE, IC50 of 0.40 mu M) and butyrylcholinester ase (BChE, IC50 of 0.10 mu M) with greatest inhibitory activity toward s BChE; [2] TS and CS are weak inhibitors of BChE (IC50 of 100 mu M an d 168 mu M, respectively) but potent inhibitors of ACHE (IC50 of 1.73 mu M and 0.79 mu M, respectively); [3] both TS and CS treatment in com bination with THA significantly increased THA's anticholinesterase act ivity. The percentage AChE inhibition observed with this combination w as often significantly greater than the sum of the individual inhibiti on values (synergistic). The addition of 0.5 mu M CS or TS to an ACHE preparation reduced THA's IC50 value from 0.40 mu M to 0.05 mu M or 0. 18 mu M, respectively [4]; inhibition of AChE by THA, TS and CS are mi xed non-competitive while THA inhibition of BChE is mixed non-competit ive and TS and CS inhibition of BChE are simple non-competitive; and [ 5] inhibition of cholinesterases by TS and CS occurs immediately (50 t o 75%), during the first 30 min of incubation (25 to 50%) and is depen dent on the anionic charged portion of the molecule. In conclusion, ou r experimental data indicate that TS and CS are potent inhibitors of A ChE activity and significantly potentiate the anticholinesterase activ ity of THA. Such potent and synergistic inhibition of AChE suggest tha t TS or CS, alone and in combination with THA, may prove beneficial in the treatment of organophosphate poisoning and Alzheimer's disease.