Mn (III) Tetrakis (4-Benzoic Acid) Porphyrin Administered into the Intrathecal Space Reduces Oxidative Damage and Neuron Death after Spinal Cord Injury: A Comparison with Methylprednisolone

Abstract

The metalloporphyrin Mn (III) tetrakis (4–benzoic acid) porphyrin (MnTBAP) is a cell-permeable superoxide dismutase mimetic and a broad-spectrum scavenger of reactive species. Since MnTBAP may not cross the blood–brain barrier, this study evaluated the therapeutic potential of MnTBAP to treat spinal cord injury (SCI; 25 g · cm) by directly administering it into the intrathecal space of the rat spinal cord. The cells in spinal sections removed at 24 h post-SCI were immunohistochemically stained with anti-4-hydroxynonenal (HNE), a marker of membrane lipid peroxidation (MLP); anti-nitrotyrosine (Ntyr), a marker of protein nitration; and anti–neuron-specific enolase (NSE) antibodies. Immunostained neurons were counted for quantitative evaluation. Pre-treatment 30 min before SCI with 1 mg/kg MnTBAP or 4-h post-SCI treatment with 2.5 mg/kg MnTBAP administered into the intrathecal space significantly reduced MLP and protein nitration, and increased the number of surviving neurons compared to vehicle controls. However, post-SCI treatment with a standard regimen of methylprednisolone sodium succinate (MPSS; 30 mg/kg followed by 5.4 mg/kg for maintenance, iv administration), the only drug used for clinical treatment of SCI, not only did not reduce MLP and neuron loss, it increased protein nitration compared with vehicle controls (two-way analysis of variance [ANOVA] followed by the Tukey test). These results demonstrate that pre- and post-intrathecal treatments with the low doses of MnTBAP provide sustained neuroprotection by preventing oxidative stress and that post-treatment with MnTBAP is superior to post-treatment with MPSS in preventing oxidative stress and resulting neuron loss.