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

  title={Memantine Blocks $\alpha$7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-D-aspartate Receptors in Rat Hippocampal Neurons},
  author={Yasco Aracava and Edna F. R. Pereira and Alfred Maelicke and Edson X. Albuquerque},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={1195 - 1205}
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 Ca2+-conducting α7* nAChR, in cultured hippocampal neurons. Memantine caused a concentration-dependent reduction of… 

Activation of Brain Histaminergic Neurotransmission: A Mechanism for Cognitive Effects of Memantine in Alzheimer's Disease

The increase in brain t-MeHA levels after single or repeated administration of therapeutic doses of memantine suggests that the drug exerts its beneficial effects on cognitive deficits of Alzheimer's disease, at least partly, by activating histamine neurons.

Response: Comments on “Memantine Blocks α7* Nicotinic Acetylcholine Receptors More Potently Than N-Methyl-d-aspartate Receptors in Rat Hippocampal Neurons”

The clinical findings and the presently available preclinical data on the inhibitory actions of memantine in the nicotinic cholinergic system in the brain suggest that the prospect of using this drug for treatment of mild-to-moderate AD should be examined with a great deal of awareness and caution.

Memantine Inhibits ATP-Dependent K+ Conductances in Dopamine Neurons of the Rat Substantia Nigra Pars Compacta

Results highlight KATP channels as possible relevant targets of Memantine effects in the brain and suggest another mechanism of action underlying the protective role of memantine in Parkinson's disease.

Cognitive Enhancer Effects of Low Memantine Doses Are Facilitated by an Alpha7 Nicotinic Acetylcholine Receptor Agonist in Scopolamine-Induced Amnesia in Rats

The results suggest that memantine and PHA-543613 may exert their cognitive enhancer effects on the same target, possibly on the alpha7 nAChRs.

Cholinergic direct inhibition of N‐methyl‐D aspartate receptor‐mediated currents in the rat neocortex

It is found that the application of ACh and of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR‐mediated currents (INMDA), ranging from 20 to 90% of the control amplitude, which could supply a new interpretation to previous studies on the role of A Ch at the glutamatergic synapse.

Mg2+ Imparts NMDA Receptor Subtype Selectivity to the Alzheimer's Drug Memantine

The results suggest that currently hypothesized mechanisms of memantine and ketamine action should be reconsidered and that NR1/2C and/or NR 1/2D receptors play a more important role in cortical physiology and pathology than previously appreciated.

Alpha7 Nicotinic Acetylcholine Receptor Is a Target in Pharmacology and Toxicology

  • M. Pohanka
  • Biology, Medicine
    International journal of molecular sciences
  • 2012
The α7 nAChR is associated with a cholinergic anti-inflammatory pathway in the termination of the parasympathetic nervous system and is suitable for treatment of multiple cognitive dysfunctions such as Alzheimer’s disease or schizophrenia.

Memantine Inhibits α3β2-nAChRs-Mediated Nitrergic Neurogenic Vasodilation in Porcine Basilar Arteries

By directly inhibiting α3β2-nAChRs located on the sympathetic nerve terminals, memantine blocks nicotine-induced neurogenic vasodilation of the porcine basilar arteries, decreasing its clinical efficacy in the treatment of Alzheimer’s disease.



Inhibition of human α7 nicotinic acetylcholine receptors by open channel blockers of N‐methyl‐D‐aspartate receptors

Evidence is provided that human α7 receptors are inhibited by memantine and cerestat and it is suggested that caution should be applied when using these compounds to study systems in which NMDA and nACh receptors co‐exist.

The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.

Channel-level factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.

Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. I. Pharmacological and functional evidence for distinct structural subtypes.

Differences observed in the pharmacological and functional properties of the Nicotinic currents imply the expression of at least three structurally distinct nicotinic acetylcholine receptor subtypes in hippocampal neurons, which may involvement in the transduction of signals is discussed.

Memantine inhibits efferent cholinergic transmission in the cochlea by blocking nicotinic acetylcholine receptors of outer hair cells.

Synaptic transmission in OHCs is inhibited by memantine block of Ca(2+) influx through nAChRs, which means prolonged receptor activation and consequently massive Ca( 2+) influx, is blocked at low micromolar concentrations, whereas the fast IPSCs initiated by short receptor activation are only blocked at concentrations above 10 microM.

Mechanism of memantine block of NMDA‐activated channels in rat retinal ganglion cells: uncompetitive antagonism.

The predominant mechanism of open‐channel blockade by memantine is uncompetitive, and the degree of blockade at various concentrations of agonist for "pure' non‐competitive vs. uncompetitive inhibition was computer simulated.

Unconventional ligands and modulators of nicotinic receptors.

The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nA ChR function/expression is known to be altered.

NMDA and AMPA receptors contribute to the nicotinic cholinergic excitation of CA1 interneurons in the rat hippocampus.

In the hippocampus, glutamatergic inputs to pyramidal neurons and interneurons are modulated by alpha7* and alpha3beta4* nicotinic acetylcholine receptors (nAChRs), respectively, present in