Abstract
BackgroundFenofibrate, 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.
Highlights
Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects
Infarct volume was reduced by the fenofibrate diet from 50 to 28 mm3, which was mostly attributable to a reduction in cortical infarct (Figure 1a,b)
Brain neutrophil recruitment following focal cerebral ischaemia is attenuated by 14-day fenofibrate pre-treatment In the same animals, immunohistochemistry was used to assess the effects of experimental stroke on hepatic and brain neutrophil recruitment
Summary
Fenofibrate, a PPAR-α activator, has shown promising results as a neuroprotective therapy, with proposed anti-inflammatory and anti-oxidant effects. It displays poor blood-brain barrier permeability leading to some ambiguity over its mechanism of action. We sought to discover whether one effect of fenofibrate might include the suppression of the acute phase response (APR) following brain injury. More than 85% of strokes are primarily ischaemic, with the remaining minority being haemorrhagic in origin. Both produce an ischaemic core surrounded by a threatened penumbra [4] which, whilst hypoxic and functionally impaired, initially manages to preserve its metabolic status [5]. One possibility involves highlighting high-risk individuals and prophylactically deploying
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