Lack of Effect of Postinjury Treatment with Methylprednisolone or Tirilazad Mesylate on the Increase in Eicosanoid Levels in the Acutely Injured Cat Spinal Cord

Abstract

Methylprednisolone (MP) improves motor recovery in spinal cord-injured patients when administered in a 24 h intensive high dose regimen beginning within 8 h after spinal cord injury (SCI). The rationale for this regimen has been based upon the need for high doses (i.e., 30 mg/kg initial IV dose) to inhibit posttraumatic lipid peroxidation (LP) in the injured spinal segment. However, injury also triggers the immediate calcium-mediated activation of phospholipase A2 (PLA2), the release of arachidonic acid, and the enzymatic formation of potentially deleterious prostaglandins (PGE2 alpha, PGE2), thromboxane A2 (TXA2), and leukotrienes (LTs). Thus, in view of the glucocorticoid receptor-mediated inhibition of PLA2 that underlies much of MP's antiinflammatory actions, an additional neuroprotective mechanism may relate to an inhibition of eicosanoid formation. Using the cat spinal cord compression model (180g x 5 min at L3; Na pentobarbitol anesthesia), we examined whether 30 min postinjury dosing with MP (30 mg/kg IV) could attenuate spinal tissue eicosanoid levels measured by enzyme immunoassay at 1 h (Experiment 1). Pial blood flow was measured over the dorsal columns at the injury site using laser doppler flowmetry to monitor posttraumatic hyperperfusion as an index of the microvascular pathophysiology of acute SCI. In vehicle treated animals at 1 h postinjury, there was a significant increase in the tissue levels of PGF2 alpha (+290%), PGE2 (+260%), TXB2 (stable analog of TXA2, +126%), and LTB4 (+73%) in comparison to sham, uninjured animals. However, 6-keto-PGF1 alpha (stable analog of prostacyclin or PGI2) and LTC4 did not increase. Methylprednisolone did not reduce the increase in eicosanoid production. In the case of LTB4 and LTC4, MP actually increased the levels further. In addition, we examined the effects of a double dose MP regimen (30 mg/kg IV at 30 min plus 15 mg/kg IV at 2.5 h postinjury) on spinal cord eicosanoid levels at 4 h postinjury (Experiment 2). At 4 h postinjury, significant increases in PGF2 alpha, PGE2, TXB2, and 6-keto-PGF1 alpha were observed, and with the exception of PGE2, no MP attenuation of the increased eicosanoids was seen. These results fail to provide evidence that postinjury administration of high dose MP exerts a significant anti-PLA2 action. On the other hand, MP effectively inhibited secondary spinal cord pial hyperperfusion, which is believed to be largely mediated by free radical-lipid peroxidative mechanisms. Thus, it seems likely that the protective action of MP on the acute microvascular pathophysiology of SCI is mediated by its well-documented effects on posttraumatic LP.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of postinjury intravenous or intrathecal methylprednisolone on spinal cord excitatory amino-acid release, nitric oxide generation, PGE2 synthesis, and myeloperoxidase content in a pig model of acute spinal cord injury

“…In contrast, and in keeping with our findings, Hall et al 25 reported that methylprednisolone (30 mg/kg) administered 30 min after injury had no effect on eicosanoid (PGE 2 , PGF 2 , 6-keto-PGF 2a , thromboxane B 2 ) concentrations in cat spinal tissue when measured at a single time point 1 h after injury. Thus, the data would suggest that methylprednisolone can reduce generation of PGE 2 after spinal cord injury, but only if given before or immediately after injury occurs.…”

Preventive Effects of Lecithinized Superoxide Dismutase and Methylprednisolone on Spinal Cord Injury in Rats: Transcriptional Regulation of Inflammatory and Neurotrophic Genes

“…Hall and his co-workers stated that the doses of MP required for neuroprotection were closer to those needed to inhibit lipid peroxidation and greatly exceeded those required to activate GR (Hall, 1992;Hall, 1993;Hall and Braughler, 1993). MP or 21-aminosteroid is regarded to be effective chiefly as an antioxidant (Hall et al, 1995). On the other hand, the glucocorticoid effects have been recently demonstrated which are independent of the antioxidant effect such as suppressing tumor necrosis factor a (TNFa) expression and NF-kB activation (Hall, 1993;Xu et al, 1998).…”

Review : Apoptosis and Spinal Cord Injury

“…Secondary injuries may be triggered during ischemia or trauma by a variety of stimuli, including the formation of reactive oxygen species, lipid peroxidation, excitatory amino acids (25), and a variety of Ca2+-mediated intracellular processes activated by increased Ca +2 influx (26,27). The immune response has also been suggested to be a major contributor to long-term secondary changes.…”