The role of PPAR activation during the systemic response to brain injury

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

Pre-treatment with fenofibrate significantly reduces total infarct volume in MCAO mice compared to standard diet regimes. (a) Photomicrographs of representative cresyl-violet-stained coronal sections through the territory of the MCA reveal infarcts in the (i) control diet and (ii) fenofibrate treated animals and absence of infarct in a (iii) sham surgery animal. (b) Total, cortical and subcortical infarct volumes in the fenofibrate-treated and control animal group. Statistical significance denoted by asterisks where P < 0.05. Bars are mean ± SD.

Figure 2

Representative photomicrographs of hepatic MBS1-stained neutrophils (brown stain) 24 h after (a, c) transient MCAO or (b, d) sham surgery. The liver of animals fed with the fenofibrate diet, (c, d), contained fewer neutrophils compared to standard diet animals and were not, in appearance, different from naive controls. The livers are counterstained with haematoxylin (blue). Photomicrographs of neutrophils in infarcted cortical tissue of animals at 24 h in animals fed (e) standard diet or (f) the fenofibrate diet.

Figure 3

Neutrophil recruitment after 24 h. The number of neutrophils present after 24 h in the (a) liver or (b) brain of naive, sham-operated or transient MCAO rats which have been either fed a standard or fenofibrate-enhanced diet. Note that pre-treatment with fenofibrate significantly reduced the number of hepatic neutrophils present at 24 h following MCAO and the number of neutrophil in the brain. Bars represent mean ± SD. Statistical significance denoted by asterisks where P < 0.05.

Figuret 4

Effect of fenofibrate pretreatment on the acute phase response at 6 h following surgery. (a) The expression of hepatic CXCL10 (mRNA copies/ng of total RNA input corrected to GAPDH), (b) the expression of hepatic CXCL1 and (c) hepatic expression of SAA-1. Note that sham surgery alone induces the induction of all transcripts, which are sensitive to fenofibrate pre-treatment. Bars are mean ± SD. *P < 0.05, ***P < 0.0001.