Learning deficits induced by chronic intraventricular infusion of quinolinic acid — protection by MK-801 and memantine

Misztal, Marcin; Frankiewicz, Tadeusz; Parsons, Chris G.; Danysz, Wojciech

doi:10.1016/0014-2999(95)00682-6

Cited by 91 publications

(46 citation statements)

References 37 publications

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“…Indeed, there is ample evidence that relatively low doses of many uncompetitive NMDA receptor antagonists block LTP in vivo and cause memory deficits in rats at similar doses (see Danysz & Archer, 1994;Danysz et al, 1995a, b for review). As such, the fact that chronic treatment with therapeutically-relevant doses of memantine has no negative effects on LTP in the rat dentate gyrus in vivo or in area CAl of hippocampal slices ex vivo (Barnes et al, 1995;Misztal et al, 1995) can be taken as providing further support for the results of the present study.…”

Section: Discussionsupporting

confidence: 63%

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

Frankiewicz

Potier

Bashir

et al. 1996

British J Pharmacology

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124

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Section: Discussionsupporting

confidence: 63%

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

Frankiewicz

Potier

Bashir

et al. 1996

British J Pharmacology

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124

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“…The human data rely on one case report [67] in which the concentration of memantine in brain was measured at autopsy in a single individual who died while receiving a daily dose (20 mg) of memantine. In this individual, the brain level measured was 1.3 μM, but in rats a dose of 20 mg/kg produces brain levels ranging from 35-40 μM (not 1-10μM as mentioned above) [39,64,66]. Thus, although a measurement in one person does not establish, with any degree of confidence, what concentrations of memantine are produced in the human brain by the dosing regimen currently being administered to AD patients, it may be as little as one fortieth the concentration required for neuroprotection in rat brain.…”

Section: Discussionmentioning

confidence: 63%

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Creeley

Wozniak

Nardi

et al. 2008

Neurobiology of Aging

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The NMDA antagonist, memantine (Namenda), and the cholinesterase inhibitor, donepezil (Aricept), are currently being used widely, either individually or in combination, for treatment of Alzheimer's disease (AD). NMDA antagonists have both neuroprotective and neurotoxic properties; the latter is augmented by drugs, such as pilocarpine, that increase cholinergic activity. Whether donepezil, by increasing cholinergic activity, might augment memantine's neurotoxic potential has not been investigated. In the present study, we determined that a dose of memantine (20 mg/kg ip), considered to be in the therapeutic (neuroprotective) range for rats, causes a mild neurotoxic reaction in the adult rat brain. Co-administration of memantine (20 or 30 mg/kg) with donepezil (2.5 to 10mg/kg) markedly potentiated this neurotoxic reaction, causing neuronal injury at lower doses of memantine, and causing the toxic reaction to become disseminated and lethal to neurons throughout many brain regions. These findings raise questions about using this drug combination in AD, especially in the absence of evidence that the combination is beneficial, or that either drug arrests or reverses the disease process.

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“…Treatment with low concentrations of memantine protects against NMDA-induced toxicity in vitro Papadia et al, 2008;Gouix et al, 2009;Bordji et al, 2010), as well as neurotoxicity and learning deficits in chemical lesion models (Misztal et al, 1996;Lee et al, 2006) and neurodegenerative disease models (Okamoto et al, 2009;Martinez-Coria et al, 2010;. However, higher doses of memantine produce deleterious effects (Chen et al, 1998;Chen and Lipton, 2006;Okamoto et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

Kaufman

Milnerwood²,

Sepers³

et al. 2012

J. Neurosci.

115

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The NMDAR plays a unique and vital role in subcellular signaling. Calcium influx initiates signaling cascades important for both synaptic plasticity and survival; however, overactivation of the receptor leads to toxicity and cell death. This dichotomy is partially explained by the subcellular location of the receptor. NMDARs located at the synapse stimulate cell survival pathways, while extrasynaptic receptors signal for cell death. Thus far, this interplay between synaptic and extrasynaptic NMDARs has been studied exclusively in cortical (CTX) and hippocampal neurons. It was unknown whether other cell types, such as GABAergic medium-sized spiny projection neurons of the striatum (MSNs), which bear the brunt of neurodegeneration in Huntington's disease, follow the same pattern. Here we report synaptic versus extrasynaptic NMDAR signaling in striatal MSNs and resultant activation of cAMP response element binding protein (CREB), in rat primary corticostriatal cocultures. Similarly to CTX, we found in striatal MSNs that synaptic NMDARs activate CREB, whereas extrasynaptic NMDARs dominantly oppose CREB activation. However, MSNs are much less susceptible to NMDA-mediated toxicity than CTX cells and show differences in subcellular GluN2B distribution. Blocking NMDARs with memantine (30 M) or GluN2B-containing receptors with ifenprodil (3 M) prevents CREB shutoff effectively in CTX and MSNs, and also rescues both neuronal types from NMDA-mediated toxicity. This work may provide cell and NMDAR subtype-specific targets for treatment of diseases with putative NMDAR involvement, including neurodegenerative disorders and ischemia.

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Learning deficits induced by chronic intraventricular infusion of quinolinic acid — protection by MK-801 and memantine

Cited by 91 publications

References 37 publications

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

Effects of memantine and MK‐801 on NMDA‐induced currents in cultured neurones and on synaptic transmission and LTP in area CA1 of rat hippocampal slices

Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain

Opposing Roles of Synaptic and Extrasynaptic NMDA Receptor Signaling in Cocultured Striatal and Cortical Neurons

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