Potent inhibition of anoxic depolarization by the sodium channel blocker dibucaine

Heather A. Douglas, Jennifer K. Callaway, Jeremy Sword, Sergei A. Kirov, R. David Andrew

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Recurring waves of peri-infarct depolarizations (PIDs) propagate across gray matter in the hours and days following stroke, expanding the primary site of injury. Ischemic epolarization (termed anoxic depolarization or AD in live brain slices) is PID-like but immediately arises in the more metabolically compromised ischemic core. This causes dramatic neuronal and astrocyte swelling and dendritic beading with spine loss within minutes, resulting in acute cell death. AD is evoked in rodent neocortical slices by suppressing the Na +/K + -ATPase pump with either oxygen/glucose deprivation (OGD) or exposure to ouabain. The process driving AD and PIDs remains poorly understood. Here we show that dibucaine is a potent drug inhibiting AD because of its high binding affinity to the Na + channel. Field recording reveals that, when superfused with ouabain (5 min), neocortical slices pretreated with 1 μM dibucaine for 45 min display either no AD or delayed AD onset compared with untreated controls. If ouabain exposure is extended to 10 min, 1 μM dibucaine is still able to delay AD onset by ~60%. Likewise, it delays OGD-evoked AD onset by ~54% but does not depress action potentials (APs) or evoked orthodromic field potentials. Increasing dibucaine to 10 M inhibits AP firing, gradually putting the slice into a stasis that inhibits AD onset but also renders the slice functionally quiescent. Two-photon microscopy reveals that 10 μM dibucaine pretreatment prevents or helps reverse ouabain-induced structural neuronal damage. Although the therapeutic range of dibucaine is quite narrow, dibucaine-like drugs could prove therapeutically useful in inhibiting PIDs and their resultant neuronal damage.

Original languageEnglish (US)
Pages (from-to)1482-1494
Number of pages13
JournalJournal of Neurophysiology
Volume105
Issue number4
DOIs
StatePublished - Apr 1 2011

    Fingerprint

Keywords

  • Caine
  • Cortical spreading depression
  • Oxygen/glucose deprivation
  • Peri-infarct depolarization

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

Cite this