Memantine does not influence AChE inhibition in rat brain by donepezil or rivastigmine but does with DFP and metrifonate in in vivo studies

This in vivo study investigated whether the N-methyl-D-aspartate receptor antagonist, memantine (MEM), interacts with inhibition of acetylcholinesterase (AChE) by reversible (donepezil and rivastigmine) and irreversible (diisopropyl fluorophosphate (DFP) and metrifonate) AChE inhibitors (AChEls) in rat brain regions (cortex and hippocampus), which are affected in humans with Alzheimer's disease. MEM (10mg/kg, e.g., two to four times greater than the therapeutically relevant dose) was administered 15 min prior to donepezil (0.75 or 1.5 mg/kg), rivastigmine (0.35 or 0.7 mg/kg), metrifonate (55 or I 10 mg/kg), or DFP (1.5 or 3.0 mg/kg). DFP was used as positive control. Rats were sacrificed at the time of maximal AChE inhibition (determined from time course studies; 15 min after donepezil, 30 min after rivastigmine or metrifonate, 60 min after DFP) to determine AChE activity in the brain region homogenates. Neither MEM nor AChEls produced any behavioral effects at any time during the study, except metrifonate, which produced muscle tremors and fasciculations at I 10 mg/kg. The present studies showed that i) MEM itself did not inhibit AChE in any brain area; ii) MEM did not interact with AChE inhibition induced by therapeutically used AChEls (donepezil and rivastigmine) at either dose level; iii) MEM prevented AChE inhibition caused by DFP or metrifonate; and (iv) MEM prevented metrifonate-induced tremors and fasciculations. These findings indicate that MEM does not influence AChE inhibition by donepezil or rivastigmine, and therefore the possibility exists that either of the two antidementic drugs can be used concurrently with MEM. © 2005 Wiley-Liss, Inc.