Genovese Tiziana, Mazzon Emanuela, Di Paola Rosanna, Cannavò Giuseppe, Muià Carmelo, Bramanti Placido, Cuzzocrea Salvatore
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica-Policlinico Universitario Via C. Valeria-Gazzi, 98100 Messina, Italy.
Exp Neurol. 2005 Jul;194(1):267-78. doi: 10.1016/j.expneurol.2005.03.003.
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous PPAR-alpha ligand in an experimental model of spinal cord trauma. Spinal cord injury was induced in PPAR-alpha wild-type (WT) mice and PPAR-alpha knock out mice (PPAR-alpha KO) mice by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, neutrophil infiltration (measured as an increase in myeloperoxidase activity) and apoptosis (measured by Annexin 5 staining). An increase of immunoreactivity to TNF-alpha was observed in the spinal cord of spinal cord-injured PPAR-alpha WT mice. Absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of all the above described parameters. In a separate set of experiments, we have also demonstrated that the absence of PPAR-alpha gene in PPAR-alphaKO mice significantly worsened the recovery of limb function (evaluated by motor recovery score). Thus, endogenous PPAR-alpha ligands reduce the degree of development of inflammation and tissue injury events associated with spinal cord trauma in the mice.
过氧化物酶体增殖物激活受体α（PPAR-α）是核受体超家族的成员，属于与视黄酸、类固醇和甲状腺激素受体相关的配体依赖性转录因子。本研究的目的是在脊髓损伤实验模型中检测内源性PPAR-α配体的作用。通过四级T5-T8椎板切除术对硬脑膜施加血管夹（24克力），在PPAR-α野生型（WT）小鼠和PPAR-α基因敲除小鼠（PPAR-α KO）中诱导脊髓损伤。小鼠脊髓损伤导致严重创伤，其特征为水肿、中性粒细胞浸润（以髓过氧化物酶活性增加衡量）和细胞凋亡（通过膜联蛋白5染色测量）。在脊髓损伤的PPAR-α WT小鼠的脊髓中观察到对肿瘤坏死因子-α的免疫反应性增加。PPAR-α KO小鼠中功能性PPAR-α基因的缺失导致上述所有参数显著增加。在另一组实验中，我们还证明PPAR-α KO小鼠中PPAR-α基因的缺失显著恶化了肢体功能的恢复（通过运动恢复评分评估）。因此，内源性PPAR-α配体降低了小鼠脊髓损伤相关的炎症和组织损伤事件的发展程度。
