title: The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice.
abstract: Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage.
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Akshata
authors.initials: A
authors.lastname: Almad
authors.forename: A Todd
authors.initials: AT
authors.lastname: Lash
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology; D015248:Gemfibrozil / Q000494:pharmacology* / Q000633:toxicity; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000633:toxicity; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009187:Myelitis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology; D017211:Treatment Failure
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D015248:Gemfibrozil; D011345:Fenofibrate