The use of organotypic hippocampal slice cultures to evaluate protection by non-competitive NMDA receptor antagonists against excitotoxicity

Avi Ring, Rita Tanso, Jens Noraberg

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

There is a wide interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of brain NMDA receptors.  As an alternative to in vivo testing in animal models we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the Alzheimer drug memantine, the Parkinson drug procyclidine and the novel neuroprotectant gacyclidine (GK11) against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open channel blockers that inhibit excitotoxic injury and their neuroprotective capacity have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in the hippocampal regions CA1, CA3 and DG showed that, after exposure to 10 µM NMDA for 24 hr, GK11 was the most potent with an IC50 of about 50 nM and complete protection at 250 nM. When applied at high doses GK11 was still the more potent neuroprotectant and also the least cytotoxic. These findings are consistent with in vivo tests in rodents . We conclude that the slice culture model provides valuable pre-clinical data and applying the model to screen neuroprotectants may significantly limit the use of in vivo tests in animals.
OriginalsprogEngelsk
TidsskriftATLA (Alternatives to Laboratory Animals)
Vol/bind38
Udgave nummer1
Sider (fra-til)71-82
ISSN0261-1929
StatusUdgivet - 2010

Fingeraftryk

Neuroprotective Agents
N-Methyl-D-Aspartate Receptors
N-Methylaspartate
Animals
Procyclidine
Hippocampal CA3 Region
Pharmaceutical Preparations
Toxicity
Organophosphate Poisoning
Memantine
Hippocampal CA1 Region
Propidium
Organophosphates
Inhibitory Concentration 50
Testing
Rodentia
Image analysis
Brain
Chemical activation
gacyclidine

Citer dette

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title = "The use of organotypic hippocampal slice cultures to evaluate protection by non-competitive NMDA receptor antagonists against excitotoxicity",
abstract = "There is a wide interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of brain NMDA receptors.  As an alternative to in vivo testing in animal models we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the Alzheimer drug memantine, the Parkinson drug procyclidine and the novel neuroprotectant gacyclidine (GK11) against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open channel blockers that inhibit excitotoxic injury and their neuroprotective capacity have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in the hippocampal regions CA1, CA3 and DG showed that, after exposure to 10 µM NMDA for 24 hr, GK11 was the most potent with an IC50 of about 50 nM and complete protection at 250 nM. When applied at high doses GK11 was still the more potent neuroprotectant and also the least cytotoxic. These findings are consistent with in vivo tests in rodents . We conclude that the slice culture model provides valuable pre-clinical data and applying the model to screen neuroprotectants may significantly limit the use of in vivo tests in animals.",
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The use of organotypic hippocampal slice cultures to evaluate protection by non-competitive NMDA receptor antagonists against excitotoxicity. / Ring, Avi; Tanso, Rita; Noraberg, Jens.

I: ATLA (Alternatives to Laboratory Animals), Bind 38, Nr. 1, 2010, s. 71-82.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The use of organotypic hippocampal slice cultures to evaluate protection by non-competitive NMDA receptor antagonists against excitotoxicity

AU - Ring, Avi

AU - Tanso, Rita

AU - Noraberg, Jens

N1 - Paper id:: 20377305

PY - 2010

Y1 - 2010

N2 - There is a wide interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of brain NMDA receptors.  As an alternative to in vivo testing in animal models we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the Alzheimer drug memantine, the Parkinson drug procyclidine and the novel neuroprotectant gacyclidine (GK11) against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open channel blockers that inhibit excitotoxic injury and their neuroprotective capacity have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in the hippocampal regions CA1, CA3 and DG showed that, after exposure to 10 µM NMDA for 24 hr, GK11 was the most potent with an IC50 of about 50 nM and complete protection at 250 nM. When applied at high doses GK11 was still the more potent neuroprotectant and also the least cytotoxic. These findings are consistent with in vivo tests in rodents . We conclude that the slice culture model provides valuable pre-clinical data and applying the model to screen neuroprotectants may significantly limit the use of in vivo tests in animals.

AB - There is a wide interest in testing neuroprotectants which inhibit the neurodegeneration that results from excessive activation of brain NMDA receptors.  As an alternative to in vivo testing in animal models we demonstrate here the use of a complex in vitro model to compare the efficacy and toxicity of NMDA receptor inhibitors. Organotypic hippocampal slice cultures were used to compare the Alzheimer drug memantine, the Parkinson drug procyclidine and the novel neuroprotectant gacyclidine (GK11) against NMDA-induced toxicity. All three drugs are non-competitive NMDA receptor open channel blockers that inhibit excitotoxic injury and their neuroprotective capacity have been extensively investigated in vivo in animal models. They have also been evaluated as potential countermeasure agents against organophosphate poisoning. Quantitative densitometric image analysis of propidium iodide uptake in the hippocampal regions CA1, CA3 and DG showed that, after exposure to 10 µM NMDA for 24 hr, GK11 was the most potent with an IC50 of about 50 nM and complete protection at 250 nM. When applied at high doses GK11 was still the more potent neuroprotectant and also the least cytotoxic. These findings are consistent with in vivo tests in rodents . We conclude that the slice culture model provides valuable pre-clinical data and applying the model to screen neuroprotectants may significantly limit the use of in vivo tests in animals.

KW - : in vitro models, NMDA receptor; toxicity assays; neuroprotection; brain slices; Alzheimer’s disease; Parkinson’s disease; organophosphate.

M3 - Journal article

VL - 38

SP - 71

EP - 82

JO - Alternatives to Laboratory Animals

JF - Alternatives to Laboratory Animals

SN - 0261-1929

IS - 1

ER -