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Journal of Neuroscience, Vol 16, 545-552, Copyright © 1996 by Society for Neuroscience
Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger
SK Agrawal and MG Fehlings
Spinal Cord Injury Neurophysiology Laboratory, Playfair Neuroscience Unit, Toronto Hospital Research Institute, University of Toronto, Ontario, Canada.
There is evidence that intracellular Na+ entry potentiates hypoxic-
ischemic cell death by causing cytotoxic cell edema, intracellular
acidosis, and gating of Ca2+ entry by reverse activation of the Na(+)- Ca2+
exchanger. In this study, we examined the role of Na+ in mediating
traumatic injury to spinal cord axons. Dorsal column segments from adult
rats (n = 87) were isolated and maintained in an in vitro recording chamber
while being superfused with oxygenated Ringer's solution (95% O2/5% CO2, 25
degrees C). Selected experiments (n = 10) also were done at 33 degrees C.
Compound action potentials (CAP) were recorded from microelectrodes. Injury
was performed by compression of the dorsal column segment for 15 sec with a
modified aneurysm clip exerting a closing force of 2 gm. With injury, the
CAP decreased to 72.1 +/- 9.6% of baseline values. Removal of extracellular
Na+ and replacement with the impermeant cation N-methyl-D-glucamine
enhanced recovery of the CAP to 98.3 +/- 18.3% (p < 0.05) of baseline.
The Na+ channel blockers tetrodotoxin and procaine also improved recovery
of the CAP to 96.3 +/- 23.7% (p < 0.05) and 82.8 +/- 4.6% (p < 0.05)
of baseline values, respectively. In contrast, increasing Na+ permeability
with veratridine resulted in greater attenuation of CAP amplitude after 1
hr of trauma (60.1 +/- 8.4%, p < 0.05). Similarly, prevention of
extrusion of Na+ from the intracellular compartment by inhibiting the
Na(+)-K(+)-ATPase pump with ouabain resulted in greater attenuation of CAP
amplitude at 1 hr after trauma (56.7 +/- 3.6%, p < 0.05). The Na(+)- H+
exchange blockers amiloride (100 microM) and harmaline (100 microM)
significantly improved recovery after injury to 89.6 +/- 17.0% (p <
0.05) and 85.7 +/- 7.2% (p < 0.05) of baseline, respectively. However,
administration of the Na(+)-Ca2+ exchange blockers benzamil (100 or 500
microM) and bepridil (50 microM) was ineffective. In summary, reduction of
extracellular Na+ confers neuroprotection after spinal cord injury in
vitro. Intracellular sodium rises appear to be mediated by voltage- gated
Na+ channels. Blockade of the Na(+)-H+ exchanger also is neuroprotective,
possibly by reducing intracellular acidosis. Furthermore, prevention of
extrusion of intracellular Na+ by the Na(+)- K(+)-ATPase pump exacerbates
the effects of compression trauma. However, reverse operation of the
Na(+)-Ca2+ exchanger does not explain the injurious effects of Na+ in
traumatically injured CNS white matter.
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