Prostaglandin release by spinal cord injury mediates production of hydroxyl radical, malondialdehyde and cell death: A site of the neuroprotective action of methylprednisolone

The present study explores in viva whether and how prostaglandin F_2α (PGF_2α), a membrane phospholipid hydrolysis product, causes neuronal death. The concentration of PGF_2α measured by microdialysis sampling increased three-fold immediately following impact injury to the rat spinal cord. Administration of PGF_2α into the cord through a dialysis fiber caused significant cell loss, increased extracellular levels of hydroxyl radicals and malondialdehyde - an end product of membrane lipid peroxidation - to 3.3 and 2.3 times basal levels, respectively. This suggests that PGF_2α-induced cell death is partly due to hydroxyl radical-triggered peroxidation. Generating hydroxyl radical by administering Fenton's reagents into the cord through the fibers significantly increased malondialdehyde production - the first direct in viva evidence that hydroxyl radical triggers membrane lipid peroxidation. Methylprednisolone significantly reduced the release of PGF_2α upon spinal cord injury and blocked PGF_2α-induced hydroxyl radical and malondialdehyde production, but did not significantly reduce Fenton's reagent-induced malondialdehyde production, despite the production of more malondialdehyde by PGF_2α. This suggests that methylprednisolone may not directly scavenge hydroxyl radical, and that its 'antioxidant' effect is a consequence of blocking the pathways for producing toxic PGF_2α and for PGF_2α-induced hydroxyl radical formation, thereby reducing membrane lipid peroxidation.