Peroxynitrite generated in the rat spinal cord induces neuron death and neurological deficits

F Bao, D Liu
Neuroscience 2002, 115 (3): 839-49
We previously demonstrated that the concentration of peroxynitrite significantly increases following impact spinal cord injury (SCI). The aim of this study was to test whether the SCI-induced elevation of peroxynitrite induces neuronal death and consequent neurological deficits. Peroxynitrite was generated by administering 5 mM S-morpholinosydnonimine, a donor of peroxynitrite, through a microdialysis fiber into the gray matter of the rat spinal cord for 5 h. This mimics the concentration and duration of peroxynitrite elevation after SCI. Neuron death was assessed by counting the neurons along the fiber track in Cresyl Violet-stained sections removed at different times post-peroxynitrite exposure. Peroxynitrite induced significantly more neuron death than did the artificial cerebrospinal fluid (ACSF) control, with the percentage of neuronal loss being 17+/-2%, 28+/-2%, 39+/-3%, and 43+/-4% at 6, 12, 24 and 48 h post-peroxynitrite exposure (P=0.01-<0.001). The losses of total neurons or motoneurons immuno-stained with anti-neuron-specific enolase or anti-choline acetyltransferase antibodies was significantly higher in the peroxynitrate-exposed group than in ACSF controls at 24 h post-exposure, further confirming peroxynitrate damage to neurons. The susceptibility to oxidative damage in motoneurons was similar to that of other neurons characterized at 24 h post-peroxynitrite exposure. Peroxynitrite-induced neurological deficits were examined by the Basso-Beattie-Bresnahan test (BBB test), the inclined-plane test and footprint analysis. Peroxynitrite significantly (P<0.001) reduced the locomotor rating score (BBB test) and the maximum angle of inclined plane compared to sham and ACSF-exposed animals (repeated measures analysis of variance). The footprint analysis revealed that peroxynitrite significantly increased the distance between the feet and the angle of hindlimb rotation compared to sham (P=0.01 and P<0.001) or ACSF controls (P=0.01 and P=0.005) and significantly shortened the stride length compared to sham (P<0.001) and ACSF control (P=0.005) treatments. Therefore the SCI-produced level of peroxynitrite induced neuron loss and neurological dysfunction, strong evidence that peroxynitrite is a secondary damage agent in SCI.

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