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The calpain inhibitor MDL‐28170 and the AMPA/KA receptor antagonist CNQX inhibit neurofilament degradation and enhance neuronal survival in kainic acid‐treated hippocampal slice cultures
Author(s) -
LopezPicon Francisco R.,
KukkoLukjanov TiinaKaisa,
Holopainen Irma E.
Publication year - 2006
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2006.04793.x
Subject(s) - ampa receptor , cnqx , calpain , kainic acid , excitotoxicity , glutamate receptor , biology , microbiology and biotechnology , nmda receptor , neuroscience , channel blocker , chemistry , receptor , biochemistry , calcium , enzyme , organic chemistry
The cytoskeleton controls the architecture and survival of the central nervous system neurons by maintaining the stability of axons, dendrites and cellular architecture, and any disturbance in this genuine structure could compromise cell survival. The developmentally regulated intracellular intermediate filament protein neurofilament (NF), composed of the light (NF‐L), medium (NF‐M) and high (NF‐H) molecular weight isoforms, is expressed abundantly in nerve cells but its significance in nerve cell survival in stress situations in the brain is unknown. We have used Western blotting, immunocytochemistry, and Fluoro‐Jade B and thionin stainings to clarify the effect of kainic acid (KA) treatment on NF protein stability, and its importance for neuronal survival in hippocampal slice cultures. The contribution of N ‐methyl‐ D ‐aspartate (NMDA) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA)/KA glutamate receptor subtypes, calpain proteases and l ‐type Ca 2+ ‐channels to these processes were also assessed. Our results indicated that KA‐induced degradation of NF was a fast process, similarly affecting all three NF proteins. It was effectively inhibited by the AMPA/KA receptor antagonist CNQX and the calpain inhibitor MDL‐28170, whereas the Ca 2+ ‐channel blocker nifedipine and the NMDA receptor antagonist MK‐801 had no significant effect. Moreover, KA‐induced neuronal damage was effectively decreased in cultures treated with CNQX and MDL‐28170. Our results suggest that the stability of NF proteins is an important factor contributing to neuronal survival after excitotoxic injury, and that both AMPA/KA receptor antagonists and calpain inhibitors might serve as neuroprotectants against this type of insult in the immature hippocampus.