Losey Patrick, Ladds Emma, Laprais Maud, Guevel Borna, Burns Laura, Bordet Regis, Anthony Daniel C
Department of Pharmacology, Experimental Neuropathology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
EA 1046, Pharmacology, Faculty of Medicine, Research Branch, IMPRT, University of Lille North of France, Place de Verdun, Lille, Cedex, 59045, France.
J Neuroinflammation. 2015 May 22;12:99. doi: 10.1186/s12974-015-0295-7.
Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. However, it displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. Experimentally induced brain injury has been shown to elicit a hepatic acute phase response that modulates leukocyte recruitment to the injured brain. Here, we sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury.
A 1-h intraluminal thread middle cerebral artery occlusion (MCAO) model followed by a 6-h reperfusion was performed in C57/BL6 mice. Quantitative reverse transcriptase-polymerase chain reaction was then used to measure hepatic expression of chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine ligand 10 (CXCL10) and serum amyloid A-1 (SAA-1), and immunohistochemical analysis was used to quantify brain and hepatic neutrophil infiltration following stroke.
The MCAO and sham surgery induced the expression of all three acute phase reactants. A 14-day fenofibrate pre-treatment decreased reactant production, infarct volume, and neutrophil recruitment to the brain and liver, which is a hallmark of the APR.
The data highlight a novel mechanism of action for fenofibrate and lend further evidence towards the promotion of its use as a prophylactic therapy in patients at risk of cerebral ischaemia. Further research is required to elucidate the mechanistic explanation underlying its actions.
非诺贝特是一种过氧化物酶体增殖物激活受体-α（PPAR-α）激动剂，作为一种神经保护疗法已显示出有前景的结果，具有抗炎和抗氧化作用。然而，它的血脑屏障通透性较差，导致其作用机制存在一些不明确之处。实验性诱导的脑损伤已被证明会引发肝脏急性期反应，从而调节白细胞向损伤脑区的募集。在此，我们试图探究非诺贝特的一种作用是否可能包括抑制脑损伤后的急性期反应（APR）。
在C57/BL6小鼠中进行1小时的管腔内丝线大脑中动脉闭塞（MCAO）模型，随后再灌注6小时。然后使用定量逆转录聚合酶链反应来测量趋化因子（C-X-C基序）配体1（CXCL1）、趋化因子配体10（CXCL10）和血清淀粉样蛋白A-1（SAA-1）的肝脏表达，并使用免疫组织化学分析来量化中风后脑和肝脏中的中性粒细胞浸润。
MCAO和假手术均诱导了所有三种急性期反应物的表达。非诺贝特预处理14天可降低反应物产生、梗死体积以及中性粒细胞向脑和肝脏的募集，而中性粒细胞募集是APR的一个标志。
这些数据突出了非诺贝特一种新的作用机制，并进一步证明了促进其在有脑缺血风险患者中作为预防性治疗药物使用的合理性。需要进一步研究以阐明其作用背后的机制解释。
