Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Spine (Phila Pa 1976). 2012 Jan 15;37(2):E73-8. doi: 10.1097/BRS.0b013e3182276d88.
Experimental study of spinal cord injury (SCI) using an organotypic slice culture.
To clarify the protective mechanism of PPAR-δ agonist GW0742 in the injured spinal cord using an in vitro model.
In vivo data suggest that ligands of the δ isoform have activity in a number of disease models that are partly driven by the inflammatory response. Moreover, reports from in vivo studies using models of ischemia reperfusion and Parkinson disease also have shown neuroprotection conferred by PPAR-δ. The biological role and function of PPAR-δ remains relatively unclear.
Spinal cord from 6-week-old mice was cut into transverse slices of 400-μm thickness to generate the organotypic slice cultures. The slices were injured using a weight dropped onto the center of the slice. PPAR-δ agonist was applied at 10 μM at 1 hour before injury.
Our study shows that GW0742 incubation (10 μM) at 1 hour before transverse lesion significantly reduced (1) p38 mitogen-activated protein kinase (MAPK), (2) c-Jun N-terminal kinase (JNK/SAP kinase), (3) NF-κB activation, (4) loss of neurotrophic factors (BDNF, GDNF), (5) COX-2 expression, and (6) cell death.
GW0742 reduces the cellular and molecular changes occurring in SCI by targeting different downstream pathways modulating PPAR-δ receptors.
采用器官型切片培养的方法对脊髓损伤（SCI）进行实验研究。
利用体外模型阐明过氧化物酶体增殖物激活受体-δ（PPAR-δ）激动剂 GW0742 在损伤脊髓中的保护机制。
体内数据表明，δ 亚型配体在多种疾病模型中具有活性，这些模型部分受炎症反应驱动。此外，使用缺血再灌注和帕金森病模型的体内研究报告也表明，PPAR-δ 可提供神经保护作用。PPAR-δ 的生物学作用和功能仍相对不明确。
取 6 周龄小鼠的脊髓，切成 400-μm 厚的横切片，以生成器官型切片培养物。使用重物撞击切片中心的方法对切片进行损伤。在损伤前 1 小时用 10 μM 的 PPAR-δ 激动剂进行处理。
我们的研究表明，GW0742（10 μM）孵育 1 小时可显著减少（1）p38 丝裂原活化蛋白激酶（MAPK）、（2）c-Jun N 末端激酶（JNK/SAP 激酶）、（3）NF-κB 激活、（4）神经营养因子（BDNF、GDNF）的丢失、（5）COX-2 表达和（6）细胞死亡。
GW0742 通过靶向不同的下游通路调节 PPAR-δ 受体，减少 SCI 中发生的细胞和分子变化。
