Anoxie Injury in the Rat Spinal Cord: Pharmacological Evidence for Multiple Steps in Ca²⁺-Dependent Injury of the Dorsal Columns

Abstract

To examine anoxic injury in spinal cord white matter, we studied axonal conduction in the dorsal columns during and following a standard 60 min anoxic insult at 36 degrees C. Perfusion of the spinal cord in 0-Ca2+ Ringer solution resulted in significantly improved recovery of the compound action potential. Similarly, removal of Na+ from the perfusate resulted in significantly improved recovery of conduction in dorsal column axons. Exposure of the anoxic spinal cord to the Na+ channel blocker tetrodotoxin (TTX), the Na-Ca exchange blockers benzamil and bepridil, Na(+)-H+ exchange blockers amiloride and harmaline, and perfusion in Ringer solution with pH adjusted to 6.4, all resulted in improved recovery. The tertiary anesthetics procaine and lidocaine, as well as phenytoin and carbamazepine, also resulted in improved recovery of compound action potential amplitude after 60 min of anoxia. These results demonstrate that a significant component of irreversible loss of conduction, following anoxic injury of the dorsal columns, is Ca(2+)-dependent. Moreover, these results demonstrate that TTX-inhibitable Na+ channels participate in the pathophysiology of anoxic injury in spinal cord white matter, and indicate that reverse Na-Ca exchange provides a route for at least part of the damaging influx of Ca2+ into an intracellular compartment in anoxic spinal cord white matter. Our results also suggest that extracellular acidosis may have a protective effect on anoxic spinal cord white matter, and support the hypothesis that anoxic injury of spinal cord white matter may involve the Na(+)-H+ exchanger.

Experimental Model of Lacunar Infarction in the Gyrencephalic Brain of the Miniature Pig

“…23 Loss of electrical excitability as a result of the collapse of the Na ϩ and K ϩ gradients will not necessarily induce irreversible damage, because the axons can fully recover with reoxygenation after anoxia of less than 15 minutes, 24 but longer periods result in irreversible functional damage resulting from the excessive accumulation of intracellular Ca 2ϩ . 25 In our study, AchAO for approximately 6 minutes induced functional impairment of the corticospinal tract.…”

Effects of the Sodium Channel Blocker Tetrodotoxin on Acute White Matter Pathology After Experimental Contusive Spinal Cord Injury

“…The loss of axonal conductivity has also been linked to Na ϩ /H ϩ antiporter dysf unction. Pharmacological blockade of this exchanger prevented the loss of compound action potentials after an anoxic (Imaizumi et al, 1997) or mechanical insult (Agrawal and Fehlings, 1996) to W M in vitro. These findings suggest that WM injury either involves multiple mechanisms or different mechanistic pathways are activated by specific components of injury, i.e., anoxia, mechanical stretch, etc.…”

“…The development of in vitro models of W M injury has given rise to the concept that W M injury results from elevations of intraaxonal C a 2ϩ brought about through an injury-mediated increase in intraaxonal Na ϩ Stys et al, 1990Stys et al, , 1993Waxman et al, 1994;Imaizumi et al, 1997;Stys, 1998). There is strong evidence that under pathological conditions, Na ϩ enters the axon not only through voltage-gated Na ϩ channels but also through "leak" channels that do not inactivate (Stys et al, 1993).…”

Disruption of ionic and cell volume homeostasis in cerebral ischemia: The perfect storm

“…Of special interest is the involvement of NCX in white matter injury (reviewed in [14]). Rat optic nerve and spinal cord white matter tracks are functionally protected against anoxic injury by removal of extracellular Ca 2+ or by NCX inhibitors benzamil, bepridil, DCB, and KN-R7943 [117][118][119]. These data are of particular importance, as ischemic white matter injury is less understood and may contribute substantially to neurological deficits in human stroke [120].…”