Nootropic Drug Modulation of Neuronal Nicotinic Acetylcholine Receptors in Rat Cortical Neurons

Zhao, Xilong; Kuryatov, Alexander; Lindstrom, Jon; Yeh, Jay Z.; Narahashi, Toshio

doi:10.1124/mol.59.4.674

Cited by 51 publications

(69 citation statements)

References 51 publications

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“…2B). The situation is in sharp contrast with nefiracetam potentiation of the ␣4␤2 AChR currents (Zhao et al, 2001) and NMDA receptor currents (Moriguchi et al, 2003a), in which currents were increased beyond the saturating response produced by high concentrations of ligands.…”

Section: Resultsmentioning

confidence: 67%

“…1D). The bell-shaped dose-response curve was also observed in nefiracetam potentiation of the ␣4␤2 AChR currents (Zhao et al, 2001) and the NMDA receptor currents (Moriguchi et al, 2003a), and animal behavioral responses to nefiracetam (Nabeshima et al, 1994).…”

Section: Resultsmentioning

confidence: 88%

“…Nefiracetam potentiates the activity of the ␣4␤2 nAChR via G s proteins, but not G i /G o proteins, PKA, or PKC (Zhao et al, 2001). To assess the roles of these G proteins and kinases in galantamine potentiation of NMDA currents, the following experiments were conducted using specific chemicals agents.…”

Section: Role Of Pka Pkc and G Proteins In Galantaminementioning

confidence: 99%

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

Moriguchi¹,

Marszalec²,

Zhao³

et al. 2004

J Pharmacol Exp Ther

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Galantamine, a new Alzheimer's drug approved in the United States, is known to inhibit acetylcholinesterase and potentiate acetylcholine-induced currents in brain neurons. However, because both cholinergic and N-methyl-D-aspartate (NMDA) systems are down-regulated in the brain of Alzheimer's patients, we studied the effects of galantamine on NMDA receptors. NMDA-induced whole-cell currents were recorded from the rat multipolar cortical neurons in primary culture. NMDA currents recorded in Mg 2ϩ -free media without addition of glycine were reversibly potentiated by bath and U-tube applications of galantamine at 10 to 10,000 nM, showing a bell-shaped doseresponse relationship. However, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate currents were not affected by galantamine. The maximum potentiation of NMDA currents to ϳ130% of the control was obtained at 1 M galantamine. The potentiation was due to a shift of the NMDA doseresponse curve in the direction of lower NMDA concentrations. Glycine at 1 to 3000 nM enhanced NMDA currents, and potentiation by 1 M galantamine and 1 to 300 nM glycine was additive. The glycine site antagonist 7-chlorokynurenic acid did not prevent the galantamine action. These results suggested that galantamine did not interact with the glycine binding site. Experiments with various concentrations of Mg 2ϩ indicated that galantamine did not affect the Mg 2ϩ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, G i /G o proteins, and G s proteins were not involved. Potentiation of the activity of NMDA receptors is deemed partially responsible for the improvement of cognition, learning, and memory in Alzheimer's patients.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 88%

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

Moriguchi¹,

Marszalec²,

Zhao³

et al. 2004

J Pharmacol Exp Ther

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“…However, the clinical trials on nefiracetam in the treatment of post-stroke VaD were halted for lack of efficacy in Phase III [60] . This failure may be attributable to the opposing effect of nefiracetam on rat and human nAChRs [61] . Another reason for the ineffectiveness of nicotinic agonists in VaD treatment may be due to desensitization of nAChRs, which leads to tolerance and loss of efficacy after long-term use [62,63] .…”

Section: Acetylcholine Receptor Agonistsmentioning

confidence: 99%

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

2009

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Vascular dementia (VaD) is a progressive neurodegenerative disease with a high prevalence. Several studies have recently reported that VaD patients present cholinergic deficits in the brain and cerebrospinal fluid (CSF) that may be closely related to the pathophysiology of cognitive impairment. Moreover, cholinergic therapies have shown promising effects on cognitive improvement in VaD patients. The precise mechanisms of these cholinergic agents are currently not fully understood; however, accumulating evidence indicates that these drugs may act through the cholinergic anti-inflammatory pathway, in which the efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, although regulation of oxidative stress and energy metabolism, alleviation of apoptosis may also be involved. In this paper, we provide a brief overview of the cholinergic treatment strategy for VaD and its relevant mechanisms of anti-inflammation.

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“…By contrast, we have focused on the novel pyrrolidone derivative nootropic drug nefiracetam as shown in the present study. Nefiracetam also potentiates ACh-induced currents in α4β2-type nAChR in rat cortical neurons (4). Thus, direct potentiation of nAChR activity is a promising ap proach.…”

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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Nootropic Drug Modulation of Neuronal Nicotinic Acetylcholine Receptors in Rat Cortical Neurons

Cited by 51 publications

References 51 publications

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

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

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

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

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