Axonal protection achieved by blockade of sodium/calcium exchange in a new model of ischemia in vivo

Abstract

Ischemic white matter injury has been relatively little studied despite its importance to the outcome of stroke. To aid such research a new rat model has been developed in vivo and used to assess whether blockade of the sodium/calcium exchanger is effective in protecting central axons from ischemic injury. Vasoconstrictive agent endothelin-1 was injected into the rat spinal cord to induce ischemia. KB-R7943 or SEA0400 was administered systemically to block the operation of the sodium/calcium exchanger. Endothelin-1 caused profound reduction of local blood perfusion and resulted in a prompt loss of axonal conduction. Whereas recovery of conduction following vehicle administration was only to 10.5 ± 9% of baseline ( n = 8) 4.5 h after endothelin-1 injection, recovery following KB-R7943 (30 mg/kg, i.a.) administration was increased to 35 ± 9% of baseline ( n = 6; P < 0.001). SEA0400 (30 mg/kg, i.a.) was also protective (33.2 ± 6% of baseline, n = 4; P < 0.001). Neither drug improved conduction by diminishing the severity of the ischemia. The protective effect of KB-R7943 persisted for at least 3 days after ischemia, as it improved axonal conduction (76.3 ± 11% for KB-R7943 vs. 51.0 ± 19% for vehicle; P < 0.01) and reduced lesion area (55.6 ± 15% for KB-R7943 vs. 77.9 ± 9% for vehicle; P < 0.01) at this time. In conclusion, a new model of white matter ischemia has been introduced suitable for both structural and functional studies in vivo. Blocking the sodium/calcium exchanger protects central axons from ischemic injury in vivo.

Highlights

► A new in vivo model in the rat for studying ischemic injury of the white matter. ► The model permits direct, serial functional examination of the axons. ► Protection of axons against ischemia by blocking the sodium/calcium exchanger.