Recovery of brain biomarkers following peroxisome proliferator-activated receptor agonist neuroprotective treatment before ischemic stroke

Abstract

BackgroundLipid lowering agent such as agonists of peroxisome proliferator-activated receptors (PPAR) are suggested as neuroprotective agents and may protect from the sequelae of brain ischemic stroke. Although the demonstration is not clearly established in human, the underlying molecular mechanism may be of interest for future therapeutic purposes. To this end, we have used our well established rodent model of ischemia-reperfusion pre-treated or not with fenofibrate or atorvastatin and performed a differential proteomics analyses of the brain and analysed the protein markers which levels returned to “normal” following pre-treatments with PPARα agonists.ResultsIn order to identify potential therapeutic targets positively modulated by pre-treatment with the PPARα agonists, two-dimensional gel electrophoresis proteome profiles between control, ischemia-reperfusion and pre-treated or not, were compared. The polypeptide which expression was altered following ischemia – reperfusion but whose levels remain unchanged after pre-treatment were characterized by mass spectrometry and further investigated by Western-blotting and immunohistochemistry. A series of 28 polypeptides were characterized among which the protein disulfide isomerase reduction – a protein instrumental to the unfolded protein response system - was shown to be reduced following PPARα agonists treatment while it was strongly increased in ischemia-reperfusion.ConclusionsPre-treatment with PPARα agonist or atorvastatin show potential neuroprotective effects by inhibiting the PDI overexpression in conjunction with the preservation of other neuronal markers, several of which are associated with the regulation of protein homeostasis, signal transduction and maintenance of synaptic plasticity. This proteomic study therefore suggests that neuroprotective effect of PPARα agonists supposes the preservation of the expression of several proteins essential for the maintenance of protein homeostasis not necessarily directly linked to PPARα known-regulated targets.

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

“…Forty-two rats were fed a control diet (standard chow for Harlan), and 42 were fed a diet containing 0.2 % fenofibrate (roughly equal to around 200 mg/kg) for 14 days prior to the induction of ischaemia. This dose was selected following previous studies that have been found to be neuroprotective and able to normalise the ischaemic proteome [ 37 ].…”

Protective effects of fenofibrate against acute lung injury induced by intestinal ischemia/reperfusion in mice

“…As a nuclear receptor activator, fenofibrate up-regulates or down-regulates genes that are involved in many pathophysiological processes, such as oxidative stress, inflammation, and leukocyte endothelium interactions 8 9 . Recent studies have demonstrated an anti-oxidant, anti-inflammatory, and anti-ischemic role of fenofibrate to attenuate I/R injury in kidney 10 11 , liver 12 , brain 13 14 and heart 15 . But to date there are no literatures reporting the protective effects of fenofibrate in I/R injury in the organ of intestine.…”

Protein disulfide isomerase in cardiovascular disease

“…Consistently, studies using a rat model of ischemia/reperfusion-induced stroke suggested that upregulation of PDI exhibits the cytoprotective effect of p-hydroxybenzyl alcohol and tanshinone IIA in the brain 108,109 . In contrast, proteomic analysis revealed that lipid-lowering agents such as atorvastatin protect from the sequelae of brain ischemic stroke by inhibiting the overexpression of PDI 110 . Our recent study demonstrated that specific deletion of platelet PDI decreases the infarct volume by mitigating thromboinflammatory conditions and improves neurological deficits in a mouse model of middle cerebral artery occlusion/reperfusion-induced stroke.…”