Protection of ischemic rat spinal cord white matter: Dual action of KB-R7943 on Na+/Ca2+ exchange and L-type Ca2+ channels

Neuropharmacology. 2005 Mar;48(4):566-75. doi: 10.1016/j.neuropharm.2004.12.007.

Abstract

The effect of the Na+/Ca(2+)-exchange inhibitor KB-R7943 was investigated in spinal cord dorsal column ischemia in vitro. Oxygen/glucose deprivation at 37 degrees C for 1 h causes severe injury even in the absence of external Ca2+. KB-R7943 was very protective in the presence and absence of external Ca2+ implicating mechanisms in addition to extracellular Ca2+ influx through Na+/Ca(2+)-exchange, such as activation of ryanodine receptors by L-type Ca2+ channels. Indeed, blockade of L-type Ca2+ by nimodipine confers a certain degree of protection of dorsal column against ischemia; combined application of nimodipine and KB-R7943 was not additive suggesting that KB-R7943 may also act on Ca2+ channels. KB-R7943 reduced inward Ba2+ current with IC50 = 7 microM in tsA-201 cells expressing Ca(v)1.2. Moreover, nifedipine and KB-R7943 both reduced depolarization-induced [Ca2+]i increases in forebrain neurons and effects were not additive. Nimodipine or KB-R7943 also reduced ischemic axoplasmic Ca2+ increase, which persisted in 0Ca2+/EGTA perfusate in dorsal column during ischemia. While KB-R7943 cannot be considered to be a specific Na+/Ca2+ exchange inhibitor, its profile makes it a very useful neuroprotectant in dorsal columns by: reducing Ca2+ import through reverse Na+/Ca2+ exchange; reducing influx through L-type Ca2+ channels, and indirectly inhibiting Ca2+ release from the ER through activation of ryanodine receptors.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Calcium Channel Blockers / pharmacology
  • Calcium Channel Blockers / therapeutic use
  • Calcium Channels, L-Type / metabolism*
  • Dose-Response Relationship, Drug
  • Male
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Long-Evans
  • Sodium-Calcium Exchanger / antagonists & inhibitors*
  • Sodium-Calcium Exchanger / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord Ischemia / metabolism
  • Spinal Cord Ischemia / prevention & control*
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology
  • Thiourea / therapeutic use*

Substances

  • 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Neuroprotective Agents
  • Sodium-Calcium Exchanger
  • Thiourea