Research reportModulation of the neuronal nicotinic acetylcholine receptor-channel by the nootropic drug nefiracetam
Introduction
Nootropic drugs may be classified into two groups, cholinergic agonists and pyrrolidone derivatives. The latter includes oxiracetam, aniracetam, and piracetam. Despite a number of studies that have been undertaken in an attempt to understand the mechanism of action of nootropic drugs, our knowledge about their cognitive enhancing action is far from satisfactory. The biochemical effects of nootropic drugs that have been disclosed include, but are not limited to, the enhancement of dopamine release, choline uptake, cholinergic transmission, AMPA receptor function, phosphatidylinositol turnover, and phosphatase A2 activity 2, 8, 10, 27, 33, 38. Nootropic drugs also facilitate long-term potentiation [39]and enhance synaptic transmission by increasing the neurotransmitter release from presynaptic nerve terminals 6, 25or by increasing the postsynaptic response to neurotransmitters 13, 14, 43. Ca2+ influx into postsynaptic cells may be increased by nootropic drugs through the potentiation of the AMPA-sensitive glutamate receptors [3], leading to facilitation of long-term potentiation.
Nefiracetam (DM-9384), a pyrrolidone derivative, is a nootropic drug being developed for the treatment of dementia [27]. It has been shown to ameliorate various types of amnesia in rodents 18, 28, 36, 44. Our previous study has clearly demonstrated that nefiracetam modulates the activity of the γ-aminobutyric acid (GABA)A receptor-channel via interactions with G proteins and protein kinase A (PKA) [11]. Nefiracetam interactions with G proteins and PKA predict that it acts on other receptors and ion channels which are regulated by these systems. In fact, this was already shown to be the case in voltage-gated L/N-type calcium channels [51]. Along this line, one of the most likely receptors/channels that would be modulated by nefiracetam is the neuronal nicotinic acetylcholine (ACh) receptor-channel, since there are structural similarities between the ACh and GABAA receptors 21, 23, 26, 40. A variety of nootropic drugs structurally related to nefiracetam are known to affect the cholinergic system (reviewed by Gouliaev and Senning [10]; Pepeu and Spignoli [33]). Furthermore, the neuronal nicotinic ACh receptor, which is also regulated by G proteins and protein kinases, is known to be altered in various neurological disorders including Alzheimer's disease [1]. Thus, we have undertaken a patch clamp study of the nefiracetam modulation of the neuronal nicotinic ACh receptor-channel. It was found that the response of the ACh receptor-channel to nefiracetam was very similar to that of the GABAA receptor-channel. Nefiracetam had a dual effect on the ACh receptor-channel, current potentiation and suppression depending on the ACh concentration, and the potentiating effect was exerted via G proteins and PKA, but not PKC.
Section snippets
Materials
PC12 cells were used as a model for the neuronal nicotinic ACh receptors which are known to be different from the muscle-type nicotinic ACh receptors with respect to the molecular structure, physiology and pharmacology 7, 17, 21, 26. The PC12 cell line was kindly provided by Drs. Edson X. Albuquerque and Edna F.R. Pereira of the University of Maryland School of Medicine in Baltimore. Cells were cultured in Dulbecco's modified Eagles' medium containing fetal bovine serum (0.1 mg/ml, Sigma, St.
Mechanism of dual action of nefiracetam
Nefiracetam was found to cause a dual action on ACh-induced currents depending on the concentration of ACh. At a low (10 μM) ACh applied for 2 s, 10 μM nefiracetam applied to the bath clearly augmented the current, and the effect was reversed after washing with nefiracetam-free solution (Fig. 1). Little or no suppression of current was observed during the application of nefiracetam. Since ACh-induced currents in PC12 cells have been shown to be blocked by hexamethonium or d-tubocurarine 29, 30,
Discussion
Nefiracetam has been found to modulate the neuronal nicotinic ACh receptor-channel in a manner very similar to the modulation of the GABAA receptor-channel reported previously [11]. It has a dual action, augmentation of the currents induced by low concentrations of ACh and suppression of the currents induced by high concentrations of ACh. Currents induced by a low concentration (10 μM) of ACh are reversibly augmented by 0.1 μM, 1 μM, and 10 μM nefiracetam, although only the effect of 10 μM
Acknowledgements
This work was supported in part by Daiichi Pharmaceutical and by a grant from the National Institutes of Health (NS 14144). The authors wish to thank Drs. Edson X. Albuquerque and Edna F.R. Pereira of the University of Maryland School of Medicine for providing us with PC12 cell line, Nayla Hasan for technical assistance and Julia Irizarry for secretarial assistance.
References (51)
- et al.
Pharmacology of neuronal nicotinic acetylcholine receptor subtypes
Adv. Pharmacol.
(1997) - et al.
A decrease in brain catecholamines prevents oxiracetam antagonism of the effects of scopolamine on memory and brain acetylcholine
Pharmacol. Res.
(1991) - et al.
Piracetam and other structurally related nootropics
Brain Res. Rev.
(1994) - et al.
Effects of the nootropic drug nefiracetamon the GABAA receptor-channel complex in dorsal root ganglion neurons
Neuropharmacology
(1996) Structure of nicotine acetylcholine receptors
Curr. Opin. Neurobiol.
(1993)- et al.
Effect of DM-9384 on extracellular acetylcholine in the rat frontal cortex measured with microdialysis
Eur. J. Pharmacol.
(1990) - et al.
A receptor for protons in the nerve cell membrane
Neuroscience
(1980) - et al.
Oxiracetam increases the release of endogenous glutamate from depolarized rat hippocampal slices
Eur. J. Pharmacol.
(1990) - et al.
Potent modulation of neuronal nicotinic acetylcholine receptor-channel by ethanol
Neurosci. Lett.
(1996) - et al.
Lead modulation of the neuronal nicotinic acetylcholine receptor in PC12 cells
Brain Res.
(1997)
Nicotinic receptors in the development and modulation of CNS synapses
Neuron
Effects of N-(2, 6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl)acetamide (DM-9384) on learning and memory in rats
Jpn. J. Pharmacol.
Oxiracetam prevents mecamylamine-induced impairment of active, but not passive, avoidance learning in mice
Pharmacol. Biochem. Behav.
Taking stock of cognition enhancers
Trends Pharmacol. Sci.
Aniracetam augments, and midazolam inhibits, the long-term potentiation in guinea-pig hippocampal slices
Neurosci. Lett.
Functional domains of GABAA receptors
Trends Pharmacol. Sci.
Interactions between oxiracetam, aniracetam and scopolamine on behavior and brain acetylcholine
Pharmacol. Biochem. Behav.
DM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortex
Eur. J. Pharmacol.
Presynaptic nicotinic ACh receptors
Trends Neurosci.
Enhancement of neuronal calcium channel currents by the nootropic agent, nefiracetam (DM-9384), in NG108-15 cells
Brain Res.
(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: 1. In vitro characterization
J. Pharmacol. Exp. Ther.
Nootropic drugs positively modulate α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-sensitive glutamate receptors in neuronal cultures
J. Neurochem.
A patch-clamp study of bovine chromaffin cells and of their sensitivity to acetylcholine
J. Physiol.
Changes of dopamine metabolism by hypoxia and effect of nootropic drugs
Biomed. Biochem. Acta
Cited by (32)
The cognition-enhancer nefiracetam is protective in BDNF-independent neuronal cell death under the serum-free condition
2002, Neurochemistry InternationalPyrrolidone derivatives
2001, LancetCitation Excerpt :Most, however, influence cholinergic function, but these cholinergic effects are complex. Acetylcholine production and turnover are stimulated by most pyrrolidones but with varying actions at both muscarinic and nicotinic receptors.6,7,11,12,15,22,25,26,38,39 This may be state-dependent; nefiracetam, for instance, enhances low concentration acetylcholine currents at nicotinic receptors but suppresses high concentration currents (effects which are postulated to be mediated by protein kinase A or G proteins).36
Nefiracetam improves Morris water maze performance following traumatic brain injury in rats
2001, Pharmacology Biochemistry and Behavior