Methylprednisolone (MP), a synthetic glucocorticoid (GC), is the only proven therapeutic agent for acute spinal cord injury (SCI). The therapeutic action of MP in SCI has been previously attributed to its antioxidant action. Tirilazad, a GC analog with more potent antioxidant action than MP but little GC activity, is less effective than MP in recent clinical SCI trials. This finding suggests that the therapeutic efficacy of MP in SCI may be more related to its GC activity than antioxidant action. An inflammatory reaction has been extensively documented after SCI. GCs including MP are among the most potent anti-inflammatory agents ever developed. The anti-inflammatory action of GC is mediated by a receptor mechanism involving a nuclear receptor, glucocorticoid receptor (GR). GC (ligand) binds to GR (receptor) forming an activated GR (aGR). aGR is a transcription factor serving dual and complimentary roles to confer a broad spectrum of anti-inflammatory actions: (1) binding to the nuclear glucocorticoid response element (GRE) to transactivate anti-inflammatory genes; and (2) inhibiting 2 key pro-inflammatory transcription factors, NF-B and AP-1, to transrepress pro-inflammatory genes. In contrast to the anti-inflammatory effects of GCs, the antioxidant action of MP or tirilazad does NOT involve a receptor mechanisms. This project is designed to explore the molecular mechanisms of MP action in SCI focusing on receptor-mediated events. We will test a central hypothesis that the therapeutic effect of MP in SCI is mediated at least in part by a receptor mechanism involving aGR. First, we will study anti-inflammatory effects of MP in SCI involving aGR mediated events. Second, we will examine whether anti-inflammatory actions of MP in SCI can be blocked by a potent GR antagonist, RU486. Third, GR agonists with variable potencies will be tested for their effects on the post-traumatic inflammatory reaction. Fourth, the therapeutic significance of GR in SCI will be assessed by comparing MP effects with selected GR agonists and antagonists in functional and morphological outcome studies. The overall objective of this project is to establish that a receptor mechanism involving aGR contributes to the therapeutic effects of MP in SCI. The ultimate goal is to develop more effective therapeutic strategies for SCI based on a better understanding of the mechanism of MP action.
