Important Role of Reverse Na⁺-Ca²⁺Exchange in Spinal Cord White Matter Injury at Physiological Temperature

Abstract

Spinal cord injury is a devastating condition in which most of the clinical disability results from dysfunction of white matter tracts. Excessive cellular Ca(2+) accumulation is a common phenomenon after anoxia/ischemia or mechanical trauma to white matter, leading to irreversible injury because of overactivation of multiple Ca(2+)-dependent biochemical pathways. In the present study, we examined the role of Na(+)-Ca(2+) exchange, a ubiquitous Ca(2+) transport mechanism, in anoxic and traumatic injury to rat spinal dorsal columns in vitro. Excised tissue was maintained in a recording chamber at 37 degrees C and injured by exposure to an anoxic atmosphere for 60 min or locally compressed with a force of 2 g for 15 s. Mean compound action potential amplitude recovered to approximately 25% of control after anoxia and to approximately 30% after trauma. Inhibitors of Na(+)-Ca(2+) exchange (50 microM bepridil or 10 microM KB-R7943) improved functional recovery to approximately 60% after anoxia and approximately 70% after traumatic compression. These inhibitors also prevented the increase in calpain-mediated spectrin breakdown products induced by anoxia. We conclude that, at physiological temperature, reverse Na(+)-Ca(2+) exchange plays an important role in cellular Ca(2+) overload and irreversible damage after anoxic and traumatic injury to dorsal column white matter tracts.

Silencing or knocking out the Na+/Ca2+ exchanger-3 (NCX3) impairs oligodendrocyte differentiation

“…8,9 Furthermore, NCX is involved in regulating intracellular Ca 2 þ concentration under pathological conditions and has been proposed as a potential therapeutic target in different disorders of the nervous system, including de-myelinating conditions such as MS, 10,11 ischemia-reperfusion injury, [12][13][14] and spinal cord injury. 15,16 Three different ncx1, ncx2, and ncx3 genes have been identified in mammals. [17][18][19] Although the expression of the different NCX mRNAs in oligodendrocytes has been described, 20 their role during oligodendrocyte development has never been investigated.…”

Ameliorative Potential of Pralidoxime in Tibial and Sural Nerve Transection-Induced Neuropathic Pain in Rats

“…The activation of Na ϩ /Ca 2ϩ in reverse mode has been noted to play an important role in cellular Ca 2ϩ overload and irreversible damage after anoxic and traumatic injury to dorsal column white matter tracts. 44,45) Na ϩ /Ca 2ϩ exchange inhibitor, KB-R7943, has been reported to attenuate ischemia-induced injury in dorsal horn neurons of spinal cord. 46) Therefore, it may be possible that inhibitory actions of pralidoxime on Na ϩ /Ca 2ϩ exchanger located on dorsal horn of spinal cord is responsible for its observed beneficial effect in neuropathic pain.…”

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].…”