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
Ischemic stroke is a major cause of permanent, severe neurological deficits (Stroke Therapy Academic Industry Roundtable, 1999; Lo et al, 2003b)
Both of the NCX inhibitors KBR7943 and SEA0400 were found significantly to improve the number of functional axons in the dorsal columns following ischemia, as assessed by the magnitude of the conducted compound action potentials (CAPs)
For example the function of the affected axons in the dorsal columns can be monitored electrophysiologically, serially over days, to assess the time course of axonal damage and recovery, and the efficacy of strategies for axonal protection. This ability to assess axonal function serially is of particular interest, since no such assessment of axonal function after ischemia has been reported in vivo to our knowledge
Summary
Ischemic stroke is a major cause of permanent, severe neurological deficits (Stroke Therapy Academic Industry Roundtable, 1999; Lo et al, 2003b). The raised intra-axonal Naþ concentration is believed to result in the detrimental influx of Ca2þ via reverse operation of the axolemmal sodium/calcium exchanger (NCX) (see below). In support of this scheme, axonal protection has been achieved by inhibiting Naþ entry in a number of models believed to involve energy insufficiency, including spinal cord injury (Agrawal and Fehlings, 1996; Hains et al, 2004) and models of multiple sclerosis (Kapoor et al, 2003; Lo et al, 2003a; Bechtold et al, 2004). We have developed and employed a new model of ischemia to test the efficacy in axonal protection in vivo of two selective inhibitors of reverse-mode operation of the NCX, KB-R7943 (2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea methane-sulfonate) and SEA0400 (2-[4[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline)
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