Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

“…Here we report that administering memantine to adult rats at 20 mg/kg ip, which is the dose required for neuroprotection in the rat brain [5,10], induced mild neurotoxic injury regionally confined to the retrosplenial cortex. The cholinesterase inhibitors, tacrine and donepezil, in a dose range that inhibits cholinesterase activity by 20% to 70%, were relatively non-toxic by themselves, but when combined with non-toxic or barely toxic doses of memantine (10 to 30 mg/kg), a potentiated neurotoxic reaction occurred that killed neurons throughout many regions of the brain.…”

“…Regarding the previously reported rodent data, the contradiction may be more apparent than real. Chen et al [5] reported that memantine did not produce a neurotoxic reaction at 20 mg/ kg, but this is the highest dose they tested. We believe a more complete dose-response evaluation would have produced evidence for a neurotoxic reaction at all doses above 20 mg/ kg, in which case equivocal findings at 20 mg/kg, the dose required for neuroprotection, does not attest to the safety of this agent as a neuroprotective drug.…”

“…In rats, it reportedly exerts a protective effect against hypoxic/ischemic neurodegeneration beginning at a dose of 20 mg/kg, and at this dose no neurotoxic side effects were described [5]. Many human adults in Europe, and more recently in the United States, have been treated with memantine at doses in the range of 20 -30 mg per day without serious side effects being reported, except for occasional case reports of psychotic reactions or seizures [27,56,57].…”

“…Interestingly, prior memantine researchers have not attempted to explain the safety profile of memantine in terms of species specificity. Rather, they have argued that memantine in both rats and humans has kinetics of binding to the NMDA receptor that are different from any other NMDA antagonist, and this putatively confers the unique ability to protect neurons against excitotoxic injury at doses that do not have adverse neurotoxic consequences in either rats or humans [5,11,52]. It is unknown whether humans are more or less sensitive than rats to donepezil potentiation of memantine neurotoxicity, but a factor that could unfavorably influence the equation is that the half-life of memantine is reportedly much longer in humans (60-80 h) than in rats (3-5 h) [11,18,52,66,67].…”

“…They have described memantine as a unique NMDA antagonist with special receptor binding kinetics that allow it to block NMDA receptors without neurotoxic consequences [5,11,52]. Memantine has been evaluated in human clinical trials and reportedly is beneficial for AD patients at doses that are free from neurotoxic side effects [55,61].…”