Nefiracetam Modulates Acetylcholine Receptor Currents via Two Different Signal Transduction Pathways

Nishizaki, Tomoyuki; Matsuoka, Toshifumi; Nomura, Tamotsu; Sumikawa, Katumi; Shiotani, Tadashi; Watabe, Shigeo; Yoshii, Mitsunobu

doi:10.1124/mol.53.1.1

Cited by 54 publications

(58 citation statements)

References 21 publications

(26 reference statements)

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“…A recent study by Nishizaki et al (1998) has indeed demonstrated an important feature of nefiracetam-acetylcholine receptor interactions. Using Torpedo californica nicotinic AChRs expressed in Xenopus laevis oocytes, nefiracetam at 0.01 to 0.1 M caused a short-term depression of ACh-induced currents and a long-term potentiation at higher concentrations (1 to 10 M).…”

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confidence: 99%

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

et al. 2001

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Nefiracetam (DM-9384) is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and poststroke vascular-type dementia. Because the cholinergic system plays an important role in cognitive functions and Alzheimer's disease dementia, the present study was conducted to elucidate the mechanism of action of nefiracetam and aniracetam on neuronal nicotinic acetylcholine receptors (nnAChRs). Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell, patch-clamp technique. Two types of currents were evoked by acetylcholine (ACh): ␣-bungarotoxin-sensitive, ␣7-type currents and ␣-bungarotoxin-insensitive, ␣4␤2-type currents. Although nefiracetam and aniracetam inhibited ␣7-type currents only weakly, these nootropic agents potentiated ␣4␤2-type currents in a very potent and efficacious manner. Nefiracetam at 1 nM and aniracetam at 0.1 nM reversibly potentiated ␣4␤2-type currents to 200 to 300% of control. Nefiracetam at very high concentrations (ϳ10 M) also potentiated ␣4␤2-type currents but to a lesser extent, indicative of a bell-shaped dose-response relationship. Nefiracetam markedly increased the saturating responses induced by high concentrations of ACh. However, human ␣4␤2 subunits expressed in human embryonic kidney cells were inhibited rather than potentiated by nefiracetam. The specific protein kinase A inhibitors (H-89, KT5720, and peptide 5-24) and protein kinase C inhibitors (chelerythrine, calphostin C, and peptide 19 -63) did not prevent nefiracetam from potentiating ␣4␤2-type currents, indicating that these protein kinases are not involved in nefiracetam action. The nefiracetam potentiating action was not affected by 24-h pretreatment of neurons with pertussis toxin, but was abolished by cholera toxin. Therefore, G s proteins, but not G i /G o proteins, are involved in nefiracetam potentiation. These results indicate that nnAChRs are an important site of action of nefiracetam and G s proteins may be its crucial target.

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confidence: 99%

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

et al. 2001

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“…The mechanism underlying the bellshaped dose-response relationship of nefiracetam potentiation of NMDA-induced currents remains to be clarified. Bell-shaped dose-response curves were also obtained in other in vitro studies even involving other receptors (4,23,24, and in behavioral experiments with nootropic drugs (25). Therefore, nefiracetam's ability to potentiate the glycine binding site of NMDAR is deemed to contribute to cognitive enhancing action.…”

Section: Resultsmentioning

confidence: 68%

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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“…In the studies on a cognition-enhancing mechanism, it has been reported that nefiracetam facilitates cholinergic, GABAergic and monoaminergic neurotransmissions (Nabeshima et al, 1991, Luthman et al, 1992, Watabe et al, 1993, Abe et al, 1994, Yoshii and Watabe, 1994, Huang et al, 1996, Yoshii et al, 1997, Nishizaki et al, 1998.…”

Section: Discussionmentioning

confidence: 99%

“…Nefiracetam caused the GABA-evoked chloride currents at a low concentration of GABA to increase and caused a reduction at a high concentration (Huang et al, 1996). The submicromolar concentration of nefiracetam decreased acetylcholine-evoked currents and the micromolar concentration enhanced them (Nishizaki et al, 1998). It was suggested that these effects were caused by the regulation of protein kinase A, C and G-protein.…”

Section: Discussionmentioning

confidence: 99%

“…This drug improved the learning and memory functions in several experimental amnesia models and is currently undergoing experimental and clinical studies (Sakurai et al, 1990, Nabeshima et al, 1991, Luthman et al, 1992, Watabe et al, 1993, Abe et al, 1994, Gouliaev and Senning, 1994, Yoshii and Watabe, 1994, Huang et al, 1996, Yoshii et al, 1997, Nishizaki et al, 1998, Sakurai K. HASHIZUME 4 et al, 1998. However, from its chemical structure, it seemed possible that nefiracetam had a potential anticonvulsive effect like piracetam and levetiracetam.…”

Section: Introductionmentioning

confidence: 99%

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Antiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in rats

et al. 2000

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Nefiracetam is being studied as a novel cognition-enhancing agent; however, it has been suggested from studying its chemical structure that it has a potential anticonvulsive effect. We examined the antiepileptic effect of nefiracetam on kainic acid (KA)-induced seizures. KA was infused into the left basolateral amygdaloid nucleus, and focal limbic seizures were induced in 43 male Wistar rats. During status epilepticus, 10, 50, 100 or 200 mg/kg of nefiracetam was intravenously injected. Nefiracetam inhibited KA-induced limbic seizures at doses over 100 mg/kg while it had a sedative effect on the animals. In [ 14 C] deoxyglucose autoradiographic studies, the propagation of seizure-induced hypermetabolic areas was also suppressed dose-dependently. From the results, it was indicated that nefiracetam has an antiepileptic effect and that its application may suppress seizure propagation. Further study is required whether this agent is available as a novel anticonvulsant.

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Nefiracetam Modulates Acetylcholine Receptor Currents via Two Different Signal Transduction Pathways

Cited by 54 publications

References 21 publications

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

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

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

Antiepileptic effect of nefiracetam on kainic acid-induced limbic seizure in rats

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