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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.
Eur J Neurosci. 2006 May; 23(10):2686-94.EJ

Abstract

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 thionine 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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/KA glutamate receptor subtypes, calpain proteases and L-type Ca2+-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 Ca2+-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.

Authors+Show Affiliations

Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16817871

Citation

Lopez-Picon, Francisco R., et al. "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." The European Journal of Neuroscience, vol. 23, no. 10, 2006, pp. 2686-94.
Lopez-Picon FR, Kukko-Lukjanov TK, Holopainen IE. 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. Eur J Neurosci. 2006;23(10):2686-94.
Lopez-Picon, F. R., Kukko-Lukjanov, T. K., & Holopainen, I. E. (2006). 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. The European Journal of Neuroscience, 23(10), 2686-94.
Lopez-Picon FR, Kukko-Lukjanov TK, Holopainen IE. 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. Eur J Neurosci. 2006;23(10):2686-94. PubMed PMID: 16817871.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Lopez-Picon,Francisco R, AU - Kukko-Lukjanov,Tiina-Kaisa, AU - Holopainen,Irma E, PY - 2006/7/5/pubmed PY - 2006/8/5/medline PY - 2006/7/5/entrez SP - 2686 EP - 94 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 23 IS - 10 N2 - 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 thionine 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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/KA glutamate receptor subtypes, calpain proteases and L-type Ca2+-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 Ca2+-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. SN - 0953-816X UR - https://www.unboundmedicine.com/medline/citation/16817871/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_ L2 - https://doi.org/10.1111/j.1460-9568.2006.04793.x DB - PRIME DP - Unbound Medicine ER -