Glutamate induces rapid loss of axonal neurofilament proteins from cortical neurons in vitro.
One of the primary hallmarks of glutamate excitotoxicity is degradation of the neuronal cytoskeleton. Using a tissue culture approach, we have investigated the relationship between excitotoxicity and cytoskeletal degradation within axons, with particular reference to the axon specific neurofilament proteins. Neurofilaments were rapidly lost from axons over a 24-h period in response to excitotoxic insult (as observed by immunocytochemistry and western blotting), while other axonal cytoskeletal markers (such as betaIII-tubulin) remained intact. Treatment with kainic acid and NMDA, or complementary experiments using the pharmacological glutamate receptors blockers CNQX (kainate/AMPA receptor antagonist) and MK-801 (NMDA receptor antagonist), demonstrated that neurofilament degeneration was mediated primarily by NMDA receptor activity. This work suggests that excitotoxicity triggers a progressive pathway of cytoskeletal degeneration within axons, initially characterised by the loss of neurofilament proteins.
Chung
Roger S
RS
NeuroRepair Group, School of Medicine, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia. rschung@utas.edu.au
McCormack
Graeme H
GH
King
Anna E
AE
West
Adrian K
AK
Vickers
James C
JC
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D016900:Neurofilament Proteins / Q000145:classification / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D016900:Neurofilament Proteins; D014404:Tubulin; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione