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.

Palmitoylethanolamide Is a Disease-Modifying Agent in Peripheral Neuropathy: Pain Relief and Neuroprotection Share a PPAR-Alpha-Mediated Mechanism

“…Using a spinal cord injury model, Genovese et al [37] demonstrated that dexamethasone utilizes PPAR- α to reduce inflammation and tissue injury in a rat model of spinal cord trauma. On the contrary, the PPAR- α agonist gemfibrozil does not promote tissue preservation and behavioral recovery after spinal contusion injury in mice [38]. Our study shows the obligatory role of PPAR- α for the neuroprotective effect of PEA in peripheral neuropathy.…”

Satellite glial cells promote regenerative growth in sensory neurons

“…Our findings suggest that fenofibrate may be used to activate SGC and enhance axon regeneration in circumstances with poor sensory axon growth, such as after injury to dorsally projecting sensory axons in the spinal cord or peripheral nerve repair. Although fenofibrate treatment did not improve locomotor recovery following spinal contusion injury in mice (Almad et al, 2011), a slight trend for increased tissue sparing was observed. Whether fenofibrate can improve centrally projecting sensory axon growth will need to be rigorously tested.…”

Neuroprotective Effect of Ginsenoside Rd in Spinal Cord Injury Rats

“…All procedures conformed to the guidelines of the ethics committee of China Medical University. Spinal cord contusions were performed using the protocols as previously described . Briefly, a total of 108 adult female Sprague Dawley rats (250–300 g, purchased from the Animal Laboratory of China Medical University, Shenyang, China) were randomly divided into sham, SCI, SCI+GS Rd 12.5 mg/kg (GS Rd‐L), SCI+GS Rd 25 mg/kg (GS Rd‐M), SCI+GS Rd 50 mg/kg (GS Rd‐H), and dexamethasone 1 mg/kg (DEX) groups (n = 18 for each group).…”