Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration.
Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain-Barré syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na(+) and Ca(2+) ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na(+) channel blockers, or an inhibitor of Na(+)/Ca(2+) exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders.
Kapoor
Raju
R
The Neuroinflammation Research Group, Guy's, King's St. Thomas' School of Medicine, London, United Kingdom.
Davies
Meirion
M
Blaker
Paul A
PA
Hall
Susan M
SM
Smith
Kenneth J
KJ
D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology*; D015764:Bepridil / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004594:Electrophysiology; D005424:Flecainide / Q000494:pharmacology; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors; D013126:Spinal Nerve Roots / Q000378:metabolism / Q000473:pathology
D000779:Anesthetics, Local; D002121:Calcium Channel Blockers; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D009569:Nitric Oxide; D015764:Bepridil; D008012:Lidocaine; D012964:Sodium; D005424:Flecainide; D002118:Calcium