Riluzole protects against glutamate-induced slowing of neurofilament axonal transport.
Riluzole is the only drug approved for the treatment of amyotrophic lateral sclerosis (ALS) but its precise mode of action is not properly understood. Damage to axonal transport of neurofilaments is believed to be part of the pathogenic mechanism in ALS and this has been linked to defective glutamate handling and increased phosphorylation of neurofilament side-arm domains. Here, we show that riluzole protects against glutamate-induced slowing of neurofilament transport. Protection is associated with decreased neurofilament side-arm phosphorylation and inhibition of the activities of two neurofilament kinases, ERK and p38 that are activated in ALS. Thus, the anti-glutamatergic properties of riluzole include protection against glutamate-induced changes to neurofilament phosphorylation and transport.
MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College, London, UK.
Alison
A
Stevenson
Darran M
DM
Yates
Catherine
C
Manser
Kurt J
KJ
De Vos
Alessio
A
Vagnoni
P Nigel
PN
Leigh
Declan M
DM
McLoughlin
Christopher C J
CC
Miller
D000704:Analysis of Variance; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects*; D001369:Axons / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D007150:Immunohistochemistry; D016900:Neurofilament Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D019782:Riluzole / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; D018698:Glutamic Acid; D019782:Riluzole; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases