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Chronic exposure of kainate and NBQX changes AMPA toxicity in hippocampal slice cultures
1Neuroscience PharmaBiotec, Anatomy and Neurobiology, Institute of Medical Biology, SDU-Odense University, Winsloewparken 21, DK-5000 Odense C, Denmark.
Abstract:
Receptor agonist/antagonist mediated modulation of the excitotoxic effect of AMPA was studied in organotypic hippocampal slice cultures. Treatment of developing cultures for 2 weeks with a subtoxic dose of 2 microM kainate reduced the toxicity of 3 microM AMPA, applied for 48 h with 24 h of recovery, as measured by cellular uptake of the fluorescent dye propidium iodide. In contrast long-term treatment with 0.3 microM of the AMPA/KA antagonist NBQX increased the susceptibility of the cultures to an even lower dose of 2 microM AMPA. The modulatory effects of long-term application of low doses of kainate and NBQX, have implications for the development and use of related drugs that aim to protect against glutamate receptor-mediated disturbances.
Insights
Long-term exposure to low-dose kainate protects against AMPA excitotoxicity, while NBQX, an AMPA/kainate antagonist, increases susceptibility. These findings impact glutamate receptor drug development.
Area of Science:
- Neuroscience
- Neuropharmacology
Background:
- Excitotoxicity, mediated by glutamate receptors like AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), is implicated in neurological disorders.
- Understanding receptor modulation is crucial for developing neuroprotective strategies.
Purpose of the Study:
- To investigate how chronic low-dose agonist (kainate) and antagonist (NBQX) treatments modulate AMPA-induced excitotoxicity in hippocampal slice cultures.
Main Methods:
- Organotypic hippocampal slice cultures were chronically treated with kainate or NBQX.
- Excitotoxicity was assessed by measuring propidium iodide uptake after AMPA exposure.
Main Results:
- Subtoxic kainate treatment reduced AMPA excitotoxicity.
- Chronic NBQX treatment enhanced AMPA excitotoxicity, even at lower AMPA concentrations.
Conclusions:
- Long-term modulation of AMPA receptor activity by low-dose agonists or antagonists can significantly alter neuronal susceptibility to excitotoxicity.
- These findings have implications for the therapeutic use of drugs targeting glutamate receptors.
