Mechanism of action of memantine

Johnson, Jon W.; Kotermanski, Shawn E.

doi:10.1016/j.coph.2005.09.007

Cited by 420 publications

(309 citation statements)

References 53 publications

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“…Furthermore, the inhibitory effect of YY-23 on the NMDA-induced current was not affected by membrane potential, and sustained administration of YY-23 inhibited [25,34] . This is entirely in contrast to the findings for the non-competitive antagonist, ketamine, as well as the uncompetitive channel blockers, memantine and MK-801 [25,34,[39][40][41][42] . MK-801 is poorly tolerated clinically due to its slow unblocking kinetics [34,43] .…”

Section: Discussioncontrasting

confidence: 53%

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Zhang

Guo

et al. 2015

Acta Pharmacol Sin

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Aim: N-methyl-D-aspartic acid (NMDA) receptor modulators have shown promising results as potential antidepressant agents, whereas timosaponins extracted from the Chinese herb Rhizoma Anemarrhenae exhibit antidepressant activities. In the present study we examined whether YY-23, a modified metabolite of timosaponin B-III, could affect NMDA receptors in rat hippocampal neurons in vitro, and evaluated its antidepressant-like effects in stressed mice. Methods: NMDA-induced currents were recorded in acutely dissociated rat hippocampal CA1 neurons using a whole-cell recording technique. C57BL/6 mice were exposed to a 6-week chronic mild stress (CMS) or a 10-d chronic social defeat stress (CSDS). The stressed mice were treated with YY-23 (20 mg·kg -1 ·d -1 ) or a positive-control drug, fluoxetine (10 mg·kg -1 ·d -1 ) for 3 weeks. Behavioral assessments were carried out every week. Results: In acutely dissociated rat hippocampal CA1 neurons, YY-23 selectively and reversibly inhibited NMDA-induced currents with an EC 50 value of 2.8 μmol/L. This inhibition of NMDA-induced currents by YY-23 was non-competitive, and had no features of voltagedependency or use-dependency. Treatment of the stressed mice with YY-23 not only reversed CMS-induced deficiency of sucrose preference and immobility time, and CSDS-induced reduction of social interaction, but also had faster onset as compared to fluoxetine. Conclusion: YY-23 is a novel non-competitive antagonist of NMDA receptors with promising rapid antidepressant-like effects in mouse models of CMS and CSDS depression.

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Section: Discussioncontrasting

confidence: 53%

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Zhang

Guo

et al. 2015

Acta Pharmacol Sin

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“…To date, it is the only clinically approved NMDAR antagonist for the treatment of moderateto-severe forms of AD (2002 in Europe; in the USA) (Chen and Lipton , 2006 ;Parsons et al , 2007 ). Memantine was shown to slow the cognitive decline associated with AD after as little as 2 weeks of treatment (Johnson and Kotermanski , 2006 ). Because of the defi cit in the cholinergic system in the brain of AD patients, the major alternative therapies in AD are all acetylcholinesterase inhibitors that also act on peripheral cholinergic synapses.…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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“…Increase in nerve fiber counts at the distal segment of the regenerated nerve may be due to axon-sprouting into the distal nerve (22). However, morphometric parameters such as the mean axonal of the NMDA receptor, reduces pathological overactivity of NMDA receptors while allowing physiological activation (16,21). Peripheral nerve injury results in excess release of glutamate from primary sensory neurons into the dorsal horn of the spinal cord (15).…”

Section: Histomorphometric Analysismentioning

confidence: 99%

The effect of memantine on functional recovery of the sciatic nerve crush injury in rat

Ghayour

Abdolmaleki²,

Rassouli³

2016

Turkish Neurosurgery

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ABSTRACTin turn, triggers free radical formation and multiple pathways leading to the initiation of apoptotic-like damage (1,5). Therefore, glutamate excitotoxicity is an attractive therapeutic target for attenuation of neural tissue damage (13,32). Hence, NMDA receptor antagonists could potentially provide neuroprotective effects in several neurodegenerative diseases manifesting excessive stimulation of NMDA receptors, including stroke, nerve injury and neuropathic pain syndromes (2,21). However, attempts to use potent competitive NMDA receptor antagonists as neuroprotectants have shown serious side effects in patients (42).Memantine is a non-competitive N-methyl-d-aspartate glutamate (NMDA) receptor antagonist and is capable of blocking excitotoxicity (12). This drug only reduces excessive NMDA receptor activation when it is pathologically activated for long █ INTRODUCTION P eripheral nerves injuries result in loss of motor, sensory and autonomic function of the affected nerves. Spinal neural circuits undergo continuous functional and structural changes in response to a peripheral nerve injury (2). Some recent studies show that glutamate receptors may be involved in sensory and motor neuron apoptosis following severe nerve injury in rats (14,17,25,50). Glutamate is an important excitatory neurotransmitter in the nervous system. Neural trauma triggers massive release of glutamate from injured cells (2). Overactivation of the N-methyl-Daspartate (NMDA) glutamate receptor subtype can result in a process called excitotoxicity that leads to cell death (20,32). Excitotoxicity is due to excessive calcium ion influx which, AIm: Following severe peripheral nerve injury (PNI), regeneration is often insufficient and functional recovery is incomplete. In this regard, glutamate N-methyl-D-aspartate (NMDA) receptor antagonist such as Memantine have been shown to have neuroprotective effects. We evaluated the effects of Memantine against sciatic nerve crush injury in male Wistar Rats. mATERIAl and mEThODS: Memantine or vehicle was given parenteraly to rats for 7 days postoperative. In Memantine treatment groups, a single dose of agent (5 and 10 mg/kg) was administered daily. The control group was given vehicle in the same manner. The rats were subjected to crush injury in the left sciatic nerve with non-serrated clamp for 30 seconds. Behavioural, electrophysiological and morphological alterations were evaluated during the experimental period. RESUlTS:Results showed that Memantine has no significant effect on regeneration process rate and functional recovery quality. In the sciatic functional index (SFI) test no significant difference was observed between Memantine treatment groups (5 and 10 mg/ kg) at any week. CONClUSION:Since the major neuroprotective effect of Memantine is due to its protective activity against NMDA receptormediated excitotoxicity, it seems that glutamate excitotoxicity is less important in motor impairment due to sciatic nerve crush injury. It is clear that more research is needed to confirm these findin...

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Mechanism of action of memantine

Cited by 420 publications

References 53 publications

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Timosaponin derivative YY-23 acts as a non-competitive NMDA receptor antagonist and exerts a rapid antidepressant-like effect in mice

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

The effect of memantine on functional recovery of the sciatic nerve crush injury in rat

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