Mechanism of Action of Galantamine on<i>N</i>-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Moriguchi, Shigeki; Marszalec, William; Zhao, Xilong; Yeh, Jay Z.; Narahashi, Toshio

doi:10.1124/jpet.104.067603

Cited by 51 publications

(53 citation statements)

References 50 publications

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“…8 Unlike other AChE inhibitor drugs, 1 has a postulated dual mechanism of action: in addition to inhibiting AChE, 1 has shown a facilitating effect on the nicotinic receptor-mediated transmission via allosteric modulation of the α-subunit of nicotinic receptors. 9 In particular, 1 can enhance synaptic NMDAR activity 10,11 by activating α7 nicotinic receptors located on presynaptic glutamatergic neurons. 12 Working together, 1 and 2 may thus improve neurophysiological responses in AD patients, 13 and their combination might offer a promising therapeutic strategy for AD treatment.…”

Section: ■ Introductionmentioning

confidence: 99%

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

et al. 2012

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Herein we report on a novel series of multitargeted compounds obtained by linking together galantamine and memantine. The compounds were designed by taking advantage of the crystal structures of acetylcholinesterase (AChE) in complex with galantamine derivatives. Sixteen novel derivatives were synthesized, using spacers of different lengths and chemical composition. The molecules were then tested as inhibitors of AChE and as binders of the N-methyl-D-aspartate (NMDA) receptor (NMDAR). Some of the new compounds were nanomolar inhibitors of AChE and showed micromolar affinities for NMDAR. All compounds were also tested for selectivity toward NMDAR containing the 2B subunit (NR2B). Some of the new derivatives showed a micromolar affinity for NR2B. Finally, selected compounds were tested using a cellbased assay to measure their neuroprotective activity. Three of them showed a remarkable neuroprotective profile, inhibiting the NMDAinduced neurotoxicity at subnanomolar concentrations (e.g., 5, named memagal, IC 50 = 0.28 nM).

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Section: ■ Introductionmentioning

confidence: 99%

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

et al. 2012

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“…Whereas nefiracetam (Moriguchi et al, 2003a,b), galantamine (Moriguchi et al, 2004b), and donepezil (present study) all are capable of modulating the activity of NMDA receptors, their mechanisms of action appear to be different Fig. 7.…”

Section: Discussionmentioning

confidence: 99%

“…However, galantamine differs from nefiracetam in three aspects (Moriguchi et al, 2004b). First, the effect was much less potent, with the maximum effect occurring at 1 M; second, the receptor affinity for NMDA is increased without change in the maximum saturating responses; and third, there is no interaction with the glycine binding site of the NMDA receptor.…”

Section: Donepezil On Nmda Receptors 131mentioning

confidence: 96%

“…The latter action appeared to be exerted via nefiracetam interactions with the glycine binding site on the NMDA receptor. We have recently found that galantamine, which is known to inhibit cholinesterases and potentiate the activity of ␣7 and ␣4␤2 nAChR (Schrattenholz et al, 1996;Maelicke and Albuquerque, 2000;Maelicke et al, 2001;Samochocki et al, 2003), potentiates NMDA-evoked currents in rat cortical neurons (Moriguchi et al, 2004b). This action appeared to be exerted via the protein kinase C (PKC) system.…”

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confidence: 99%

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Modulation of N-Methyl-d-aspartate Receptors by Donepezil in Rat Cortical Neurons

Moriguchi

Zhao²,

Marszalec³

et al. 2005

J Pharmacol Exp Ther

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Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of Ϫ70 mV in Mg 2ϩ -free solutions. In multipolar neurons, NMDA currents were decreased by bath and U-tube applications of 1 to 10 M donepezil but were increased by 30 to 100 M donepezil. Donepezil suppression occurred in a manner independent of NMDA concentrations ranging from 3 to 1000 M. The donepezil suppression of NMDA currents was prevented by inhibition of protein kinase C (PKC) but unaffected by protein kinase A (PKA) and G proteins. In bipolar neurons, however, NMDA currents were potently augmented by bath and U-tube applications of 0.01 to 100 M donepezil. Donepezil potentiation occurred at high NMDA concentrations that evoked the saturating responses and in a manner independent of NMDA concentrations ranging from 3 to 1000 M. The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01-1 M) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease.

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“…We previously reported that galantamine potentiates NMDAR activity in rat cortical neurons (6). Potentiation of nAChR and enhancement of NMDAR activity may synergistically antagonize deficits in memory and cognitive function in AD.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Study on Alzheimer’s Drugs Targeting Calcium/Calmodulin-Dependent Protein Kinase II

Moriguchi

2011

J Pharmacol Sci

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Abstract. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems have been found and is thought to play an important role in impairment of cognition, learning, and memory. Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as a cognitive-enhancing effect. The present study was undertaken to elucidate mechanisms underlying the action of nefiracetam on glutamatergic receptors and intracellular protein kinases. N-Methyl-D-aspartate (NMDA)-evoked currents were recorded from rat cortical neurons in long-term cultured primary neurons using the whole-cell patch-clamp technique. NMDA-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam, resulting in a bell-shaped dose-response curve. The maximum potentiation of 170% relative to the control was produced at 10 nM. Treatment with an inhibitor of the glycine binding site of the NMDA receptor, 7-chlorokynurenic acid, at 1 μM prevented augmentation of NMDAevoked currents by nefiracetam. In rat hippocampal CA1 slices, field excitatory postsynaptic potentials were recorded by stimulation of Schaffer collateral/commissural pathways. Nefiracetam treatment significantly enhanced long-term potentiation (LTP) with the same bell-shaped doseresponse curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with calcium/calmodulin-dependent protein kinase II (CaMKII) activation with concomitant increase in phosphorylation of AMPA-type glutamate receptor subunit 1 (GluA1) (Ser-831) as a postsynaptic CaMKII substrate. In conclusion, nefiracetam enhances NMDA-receptor function through stimulation of its glycine binding site and nefiracetam-induced CaMKII activation likely contributes to improvement of cognition, learning, and memory.

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Mechanism of Action of Galantamine onN-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

Cited by 51 publications

References 50 publications

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

Modulation of N-Methyl-d-aspartate Receptors by Donepezil in Rat Cortical Neurons

Pharmacological Study on Alzheimer’s Drugs Targeting Calcium/Calmodulin-Dependent Protein Kinase II

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