3-Nitropropionic acid toxicity in hippocampus: protection through N-methyl-D-aspartate receptor antagonism.

The over-activation of glutamate receptors can lead to excitotoxic cell death and is believed to be involved in the progression of neurodegenerative events in the vulnerable hippocampus. Here, we used an in vitro slice model to study toxicity produced in the hippocampus by the mitochondrial toxin 3-nitropropionic acid (3-NP). The organotypic slice cultures exhibit native cellular organization as well as dense arborization of neuronal processes and synaptic contacts. The hippocampal slices were exposed to 3-NP for 2-20 days, causing calpain-mediated breakdown of the spectrin cytoskeleton, a loss of pre- and postsynaptic markers, and neuronal atrophy. The N-methyl-D-aspartate (NMDA) receptor antagonist memantine reduced both the cytoskeletal damage and synaptic decline in a dose-dependent manner. 3-NP-induced cytotoxicity, as determined by the release of lactate dehydrogenase, was also reduced by memantine with EC50 values from 1.7 to 2.3 microM. Propidium iodide fluorescence and phase contrast microscopy confirmed memantine neuroprotection against the chronic toxin exposure. In addition, the protected tissue exhibited normal neuronal morphology in the major hippocampal subfields. These results indicate that antagonists of NMDA-type glutamate receptors are protective during the toxic outcome associated with mitochondrial dysfunction. They also provide further evidence of memantine's therapeutic potential against neurodegenerative diseases.

Karanian DA ，Baude AS ，Brown QB ，Parsons CG ，Bahr BA ... -  《HIPPOCAMPUS》

Resistance to kynurenic acid of the NMDA receptor-dependent toxicity of 3-nitropropionic acid and cyanide in cerebellar granule neurons.

Fatokun AA ，Smith RA ，Stone TW 《BRAIN RESEARCH》

GMP prevents excitotoxicity mediated by NMDA receptor activation but not by reversal activity of glutamate transporters in rat hippocampal slices.

Molz S ，Tharine DC ，Decker H ，Tasca CI ... -  《BRAIN RESEARCH》

Stretch-induced injury in organotypic hippocampal slice cultures reproduces in vivo post-traumatic neurodegeneration: role of glutamate receptors and voltage-dependent calcium channels.

Cater HL ，Gitterman D ，Davis SM ，Benham CD ，Morrison B 3rd ，Sundstrom LE ... -  《JOURNAL OF NEUROCHEMISTRY》

Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity.

Volbracht C ，van Beek J ，Zhu C ，Blomgren K ，Leist M ... -  《EUROPEAN JOURNAL OF NEUROSCIENCE》