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Neuroprotection against excitotoxicity by N-alkylglycines in rat hippocampal neurons
- Source :
- Neuromolecular medicine. 2(3)
- Publication Year :
- 2003
-
Abstract
- Excessive activation of glutamate receptors of the N-methyl-D-aspartate (NMDA) subtype is considered a relevant initial step underlying different neurodegenerative diseases. Recently, with the approval of memantine to treat Alzheimer dementia, NMDA receptors have regained clinical interest. Accordingly, the development and validation of NMDA receptor antagonists is being reconsidered. We recently identified a family of trialkylglycines that act as channel blockers of the NMDAreceptor. Their neuroprotective activity against excitotoxic insults remains elusive. To address this issue, we first characterized the contribution of glutamate receptor subtypes to hippocampal death in culture as a function of days in culture in vitro (DIV). Whereas at 7 DIV neither NMDA nor glutamate produced a significant neuronal death, at 14 and 21 DIV, NMDA produced the death of 40% of the neurons exposed to this receptor agonist that was fully protected by MK-801. Similar results were obtained for L-glutamate at 14 DIV. In contrast, when neurons at 21 DIV were used, glutamate killed 51.1 +/- 4.9% of the neuronal population. This neuronal death was only partially prevented by MK-801, and fully abrogated by a combination of MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Glucose deprivation injured 37.1 +/- 9.2% of the neurons through a mechanism sensitive to MK-801. The family of recently identified N-alkylglycines tested protected neurons against NMDA and glucosedeprivation toxicity, but not against glutamate toxicity. Noteworthy, N-alkylglicines with a moderate protection against NMDA-induced toxicity strongly protected from beta-amyloid toxicity. Collectively, these findings imply both NMDA and non-NMDA receptors in excitotoxicity of hippocampal neurons, and suggest that blockade of NMDA receptors alone may not suffice to efficiently abrogate neurodegeneration.
- Subjects :
- Neurotoxins
Excitotoxicity
Glycine
Glutamic Acid
AMPA receptor
Pharmacology
Biology
medicine.disease_cause
Neuroprotection
Hippocampus
Receptors, N-Methyl-D-Aspartate
Cellular and Molecular Neuroscience
Fetus
medicine
Animals
Long-term depression
Cells, Cultured
Neurons
Amyloid beta-Peptides
Neurodegeneration
Glutamate receptor
Memantine
Neurodegenerative Diseases
medicine.disease
Rats
Neuroprotective Agents
nervous system
Neurology
Molecular Medicine
NMDA receptor
Neuroscience
Excitatory Amino Acid Antagonists
medicine.drug
Subjects
Details
- ISSN :
- 15351084
- Volume :
- 2
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Neuromolecular medicine
- Accession number :
- edsair.doi.dedup.....fe3e6a6d93972528b0e3b76ba8bc697b