Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
Exp Neurol. 2011 Dec;232(2):309-17. doi: 10.1016/j.expneurol.2011.09.023. Epub 2011 Sep 21.
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.
过氧化物酶体增殖物激活受体（PPAR）-α 是脂质代谢的关键调节剂，最近的研究表明它还可以调节几种不同疾病模型中的炎症。吉非贝齐（PPAR-α 的激动剂）是一种 FDA 批准用于治疗高脂血症的药物，已被证明可抑制多发性硬化症啮齿动物模型中的临床症状。由于许多研究表明抗炎和神经保护剂可改善脊髓损伤（SCI）的预后，我们测试了在 SCI 前或后给予口服吉非贝齐对促进小鼠脊髓挫伤损伤后的组织保存和行为恢复的疗效。不幸的是，结果与我们的假设相反；在我们的第一次尝试中，吉非贝齐治疗使 SCI 后的运动功能缺陷恶化，并增加了组织病理学变化。在随后的实验中，未复制行为效应，但组织学结果再次更差。我们还测试了另一种 PPAR-α 激动剂非诺贝特的疗效，非诺贝特也可调节免疫反应，并且在几种神经退行性疾病模型中有益。非诺贝特治疗并未改善恢复，尽管在组织学上有轻微趋势表明适度增加组织保留。基于我们的结果，我们得出结论，PPAR-α 激动剂要么没有效果，要么使脊髓损伤的恢复恶化，至少在我们在此处测试的剂量和药物给药时间点上是如此。此外，正在服用吉非贝齐的脊髓损伤患者可能容易发生组织损伤加重。
