Glycine prodrug facilitates memory retrieval in humans

Schwartz, Barbara L.; Hashtroudi, Shahin; Herting, Robert L.; Handerson, H.; Deutsch, Stephen I.

doi:10.1212/wnl.41.9.1341

Cited by 74 publications

(31 citation statements)

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“…Both the partial glycine site agonist d-cycloserine and the glycine prodrug milacemide facilitate memory in animal models 10,11) and have been tested as cognitive enhancers in both healthy subjects and patients with Alzheimer's disease. [12][13][14] Our working hypothesis is that one of the mechanisms by which nootropic drugs improve cognitive function is to modulate the nACh and/or NMDA receptor functions. Nootropic drugs improve cognitive function by increasing the activity of nACh and/or NMDA receptors in patients with Alzheimer's disease and patients with other forms of dementia who have reduced nACh and NMDA receptors; in poststroke patients who have excess glutamate release, nootropic drugs with a partial agonist action reduce the excess activation of NMDA receptors.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

Narahashi

Moriguchi

Zhao

et al. 2004

Biological & Pharmaceutical Bulletin

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No strategies for curing Alzheimer's disease have been developed yet as we do not know the exact cause of the disease. The only therapy that is available for patients is symptomatic treatment. Since Alzheimer's disease is associated with downregulation of the cholinergic system in the brain, its stimulation is expected to improve the patients' cognition, learning, and memory. Four anticholinesterases have been approved in the U.S.A. for the treatment of Alzheimer's disease patients. However, because of the inhibition of cholinesterases, these drugs have side effects and their effectiveness does not last long. Thus new approaches are needed. One approach is to stimulate directly nicotinic acetylcholine (nACh) receptors in the brain, and another is to stimulate NMDA receptors which are also known to be downregulated in Alzheimer's patients. Nefiracetam has been shown to potentiate ACh currents in the a a4b b2 receptor of rat cortical neurons with a bell-shaped dose-response relationship and the maximum effect at 1 nM. This effect was exerted via G s proteins. The a a7 receptor was almost unaffected by nefiracetam. Nefiracetam also potentiated NMDA currents with the maximum effect at 10 nM via interaction with the glycine-binding site of the receptor. Galantamine had a moderate potentiating effect on the a a4b b2 receptor and potentiated NMDA currents with the maximum effect at 1 m mM. However, galantamine did not interact with the glycine-binding site. Donepezil, a potent anticholinesterase, also potentiated NMDA currents at 1-10000 nM. In conclusion, these three drugs potentiate the activity not only of the cholinergic system but also of the NMDA system, thereby stimulating the downregulated nACh receptors and NMDA receptors to improve patients' learning, cognition, and memory.

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Section: Introductionmentioning

confidence: 99%

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

Narahashi

Moriguchi

Zhao

et al. 2004

Biological & Pharmaceutical Bulletin

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“…Both the partial glycine site agonist d-cycloserine and the glycine prodrug milacemide facilitate memory in animal paradigms (Hanndelmann et al, 1989;Baxter et al, 1994) and have been tested as cognitive enhancers in patients with Alzheimer's disease (Schwartz et al, 1991(Schwartz et al, , 1996Dysken et al, 1992).…”

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confidence: 99%

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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“…Drugs that modulate NMDA receptor-mediated neural transmission by acting at the glycine binding site of NMDA receptors are potential therapeutic agents to treat memory deficits associated with aging and Alzheimer's disease. Both the partial glycine site agonist d-cycloserine and the glycine prodrug milacemide prevent memory deficit in animal paradigms (Hanndelmann et al, 1989;Baxter et al, 1994), and have been tested as cognitive enhancers in both healthy subjects and patients with Alzheimer's disease (Schwartz et al, 1991(Schwartz et al, , 1996Dysken et al, 1992). Thus, NMDA receptors play a crucial role in learning and memory.…”

mentioning

confidence: 99%

Potentiation of N-Methyl-d-aspartate-Induced Currents by the Nootropic Drug Nefiracetam in Rat Cortical Neurons

Moriguchi

Marszalec²,

Zhao³

et al. 2003

J Pharmacol Exp Ther

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Nefiracetam is a new pyrrolidone nootropic drug being developed for the treatment of Alzheimer's type and post-stroke vascular-type dementia. In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems has been found and is thought to play an important role in impairment of cognition, learning and memory. We have previously shown that the activity of neuronal nicotinic acetylcholine receptors is potently augmented by nefiracetam. The present study was undertaken to elucidate the mechanism of action of nefiracetam on glutamatergic receptors. Currents were recorded from rat cortical neurons in long-term primary culture using the whole-cell patch-clamp technique at a holding potential of Ϫ70 mV in Mg 2ϩ -free solutions. N-Methyl-D-aspartate (NMDA)-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam resulting in a bellshaped dose-response curve. The minimum effective nefiracetam concentration was 1 nM, and the maximum potentiation to 170% of the control was produced at 10 nM. Nefiracetam potentiation occurred at high NMDA concentrations that evoked the saturated response, and in a manner independent of NMDA concentrations ranging from 3 to 1,000 M. Glycine at 3 M potentiated NMDA currents but this effect was attenuated with an increasing concentration of nefiracetam from 1 to 10,000 nM. 7-Chlorokynurenic acid at 1 M prevented nefiracetam from potentiating NMDA currents. Nefiracetam at 10 nM shifted the dose-response relationship for the 7-chlorokynurenic acid inhibition of NMDA currents in the direction of higher concentrations. ␣-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid-and kainate-induced currents were not significantly affected by application of 10 nM nefiracetam. It was concluded that nefiracetam potentiated NMDA currents through interactions with the glycine binding site of the NMDA receptor.

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Glycine prodrug facilitates memory retrieval in humans

Cited by 74 publications

References 0 publications

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

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

Potentiation of N-Methyl-d-aspartate-Induced Currents by the Nootropic Drug Nefiracetam in Rat Cortical Neurons

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