Memantine Blocks α7^*Nicotinic Acetylcholine Receptors More Potently ThanN-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons

Abstract

The N-methyl-D-aspartate (NMDA) receptor antagonist memantine is an approved drug for treatment of Alzheimer's disease (AD). Other such treatments are cholinesterase inhibitors and nicotinic acetylcholine receptor (nAChR)-sensitizing agents such as galantamine. The present study was designed to test whether memantine exerts any effect on the cholinergic system, in particular the Ca 2ϩ -conducting ␣7* nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of the amplitudes of whole-cell currents evoked by the ␣7* nAChR-selective agonist choline (10 mM) or by N-methyl-D-aspartate (NMDA) (50 M) plus glycine (10 M). It also inhibited tonically activated NMDA receptors. Memantine was more potent in inhibiting ␣7* nAChRs than NMDA receptors; at Ϫ60 mV, the IC 50 values for memantine were 0.34 and 5.1 M, respectively. Consistent with an open-channel blocking mechanism, memantine-induced NMDA receptor inhibition was voltage and use-dependent; the Hill coefficient (n H ) was ϳ1. Memantine-induced ␣7* nAChR inhibition had an n H Ͻ 1 and showed a variable voltage dependence; the effect was voltage-independent at 0.1 M, becoming voltage-dependent at Ն1 M. Thus, memantine interacts with more than one class of sites on the ␣7* nAChRs. One is voltage-sensitive and therefore likely to be within the receptor channel. The other is voltage-insensitive and therefore likely to be in the extracellular domain of the receptor. It is suggested that blockade of ␣7* nAChRs by memantine could decrease its effectiveness for treatment of AD, particularly at early stages when the degrees of nAChR dysfunction and of cognitive decline correlate well.

Preclinical Investigation of the Functional Effects of Memantine and Memantine Combined with Galantamine or Donepezil

“…In cultured hippocampal neurons, memantine also caused a concentrationdependent reduction of the amplitudes of whole-cell currents evoked by a7 nAChRs, and in this study memantine was more potent in inhibiting a7 nAChRs than NMDA receptors (Aracava et al, 2005). Blockade of a7 nAChRs by memantine may have decreased its efficacy in the model system of eyeblink classical conditioning.…”

“…Donepezil, a cholinesterase inhibitor with four to eight times the potency of galantamine, has no demonstrated allosteric effect on a7 nAChRs (eg Dajas-Bailador et al, 2003). Memantine, an NMDA antagonist also blocks a7 nAChRs (eg Aracava et al, 2005;Maskell et al, 2003). Galantamine and donepezil were equated for cholinesterase inhibition, and galantamine was the only drug to show a significant amelioration of learning impairment in older rabbits.…”

Memantine for prevention of migraine: a retrospective study of 60 cases

“…This potential mechanism is supported by our observation that memantine reduced the frequency of aura as well as headache. Memantine also blocks other ligand gated ion channels, including nicotinic acetylcholine receptors and 5HT3 receptors [6,7]. It could therefore have multiple other mechanisms of action that may modulate migraine.…”

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

“…When memantine is administered to adult rats in a neuroprotective dose (i.e., a dose that effectively blocks NMDA receptors) typical NMDA antagonist type of neurotoxic side effects are readily demonstrable, despite the unique binding kinetics described for this agent in rat brain. Therefore, we propose that: 1) if the doses of memantine used in AD patients were neuroprotective by virtue of blocking NMDA receptors, typical NMDA antagonist type of side effects, including memory impairment, locomotor disturbances and psychotic reactions, would be encountered; 2) absence of such side effects may indicate that memantine, at these doses, does not block NMDA receptors; 3) this interpretation is more compelling than the unique binding kinetics interpretation for explaining memantine's favorable safety profile in humans; 4) the unique binding kinetics interpretation is problematic because it may mislead physicians into thinking that it is safe to treat refractory AD patients with escalating doses of memantine, together with donepezil, and this could have unfortunate consequences; 5) if continuing clinical experience with memantine proves that it is definitely beneficial in AD, and there continues to be no evidence that the benefit in humans is mediated by NMDA receptor blockade, it would be wise to determine the real mechanistic basis for this beneficial effect (for example, memantine reportedly [2] binds with greater affinity to the α-7 nicotinic receptor than to the NMDA receptor), and develop new drugs that are safer and more effective in acting by this beneficial mechanism; 6) for safe therapy of AD, NMDA receptor blockade should be avoided, especially in the presence of cholinesterase inhibitors; 7) for developing a rational therapy of AD, it should be remembered that there is no evidence that NMDA receptors are hyperactive in AD or that NMDA receptor-mediated excitotoxicity plays a role in the neuropathology of AD, but there is ample basis for believing that NMDA receptors are hypoactive in the AD brain and that NMDA receptor hypoactivity can trigger neurodegenerative reactions in the normal adult mammalian brain, reactions that can be markedly potentiated by drugs that inhibit cholinesterase activity. Quantitation of neuronal injury in the retrosplenial cortex four hours following administration of memantine alone or together with tacrine (A) or with donepezil (B).…”