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

Gelé P, Vingtdeux V, Potey C, Drobecq H, Ghestem A, Melnyk P, Buée L, Sergeant N, Bordet R - Proteome Sci (2014)

Bottom Line: 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.Pre-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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Investigation center, IMPRT, University of Lille II, Cardiologic Hospital, Lille, France ; Inserm UMR 837, JPARC, Place de Verdun, Lille 59045, France ; PRES University Lille Nord de France, University of Lille II, Jean-Pierre Aubert Research Center, Institute of Predictive Medicine and Therapeutic Research, Lille IFR114, France ; EA1046 - Department de Pharmacology - University of Lille 2, University Hospital Centre Place de Verdun, Lille, France.

ABSTRACT

Background: Lipid 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.

Results: In 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.

Conclusions: Pre-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.

No MeSH data available.


Related in: MedlinePlus

Expression of Protein Disulfide Isomerase in the rat brain. 3A Cortical expression of Protein Disulfide Isomerase (PDI, Erp 60) in the different groups. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicates a p value < 0.05 vs Control group. 3B Expression of PDI in the cortex and striatum 24 hours after reperfusion. PDI is expressed under basal condition (contra) and only found in pycnotic cell of the penombra under ischemia-reperfusion injury. Striatum cells had a lower level of expression when compared to cortical cell. 3C The PDI expressing cell were identified as neuron using immunofluorescent double labelling with an NSE antibody.
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Figure 3: Expression of Protein Disulfide Isomerase in the rat brain. 3A Cortical expression of Protein Disulfide Isomerase (PDI, Erp 60) in the different groups. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicates a p value < 0.05 vs Control group. 3B Expression of PDI in the cortex and striatum 24 hours after reperfusion. PDI is expressed under basal condition (contra) and only found in pycnotic cell of the penombra under ischemia-reperfusion injury. Striatum cells had a lower level of expression when compared to cortical cell. 3C The PDI expressing cell were identified as neuron using immunofluorescent double labelling with an NSE antibody.

Mentions: Found during the proteome exploration, the expression variation of Protein Disulfide Isomerase A3 (58 kDa isoform, Erp60) (PDI) was studied by western blot (Figure 3A). The PDI is expressed in the cortex of the rat at a basal level. A 14 days fenofibrate treatment induced a slight but not statistically significant decrease expression of PDI (OD ratio: Control group: 1.57 ± 0.22; fenofibrate: 1.05 ± 0.16). A 14 days Atorvastatin treatment was more effective and induced a dramatic decrease of expression of PDI when compared to control (OD ratio: 0.78 ± 0.08, p < 0.05). Following Ischemia-Reperfusion injury, the PDI expression was enhanced in the cortex even if the statistical significance threshold was not reached (OD ratio: 2.18 ± 0.03). This elevation of PDI expression is reported to be lowered by anti-inflammatory treatment [40]. The hypolipidemic drug treatment before ischemia-reperfusion injury had a lowering effect on the ischemia-reperfusion injury induced PDI surged expression. Both fenofibrate and atorvastatin pre-treatments maintained a PDI expression comparable to that observed in control condition but statistically different from the ischemia-reperfusion group (OD ratio of fenofibrate and atorvastatin of 1.48 ± 0.5 and 1.32 ± 0.04, respectively; p < 0.05).


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

Gelé P, Vingtdeux V, Potey C, Drobecq H, Ghestem A, Melnyk P, Buée L, Sergeant N, Bordet R - Proteome Sci (2014)

Expression of Protein Disulfide Isomerase in the rat brain. 3A Cortical expression of Protein Disulfide Isomerase (PDI, Erp 60) in the different groups. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicates a p value < 0.05 vs Control group. 3B Expression of PDI in the cortex and striatum 24 hours after reperfusion. PDI is expressed under basal condition (contra) and only found in pycnotic cell of the penombra under ischemia-reperfusion injury. Striatum cells had a lower level of expression when compared to cortical cell. 3C The PDI expressing cell were identified as neuron using immunofluorescent double labelling with an NSE antibody.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4061923&req=5

Figure 3: Expression of Protein Disulfide Isomerase in the rat brain. 3A Cortical expression of Protein Disulfide Isomerase (PDI, Erp 60) in the different groups. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicates a p value < 0.05 vs Control group. 3B Expression of PDI in the cortex and striatum 24 hours after reperfusion. PDI is expressed under basal condition (contra) and only found in pycnotic cell of the penombra under ischemia-reperfusion injury. Striatum cells had a lower level of expression when compared to cortical cell. 3C The PDI expressing cell were identified as neuron using immunofluorescent double labelling with an NSE antibody.
Mentions: Found during the proteome exploration, the expression variation of Protein Disulfide Isomerase A3 (58 kDa isoform, Erp60) (PDI) was studied by western blot (Figure 3A). The PDI is expressed in the cortex of the rat at a basal level. A 14 days fenofibrate treatment induced a slight but not statistically significant decrease expression of PDI (OD ratio: Control group: 1.57 ± 0.22; fenofibrate: 1.05 ± 0.16). A 14 days Atorvastatin treatment was more effective and induced a dramatic decrease of expression of PDI when compared to control (OD ratio: 0.78 ± 0.08, p < 0.05). Following Ischemia-Reperfusion injury, the PDI expression was enhanced in the cortex even if the statistical significance threshold was not reached (OD ratio: 2.18 ± 0.03). This elevation of PDI expression is reported to be lowered by anti-inflammatory treatment [40]. The hypolipidemic drug treatment before ischemia-reperfusion injury had a lowering effect on the ischemia-reperfusion injury induced PDI surged expression. Both fenofibrate and atorvastatin pre-treatments maintained a PDI expression comparable to that observed in control condition but statistically different from the ischemia-reperfusion group (OD ratio of fenofibrate and atorvastatin of 1.48 ± 0.5 and 1.32 ± 0.04, respectively; p < 0.05).

Bottom Line: 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.Pre-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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Clinical Investigation center, IMPRT, University of Lille II, Cardiologic Hospital, Lille, France ; Inserm UMR 837, JPARC, Place de Verdun, Lille 59045, France ; PRES University Lille Nord de France, University of Lille II, Jean-Pierre Aubert Research Center, Institute of Predictive Medicine and Therapeutic Research, Lille IFR114, France ; EA1046 - Department de Pharmacology - University of Lille 2, University Hospital Centre Place de Verdun, Lille, France.

ABSTRACT

Background: Lipid 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.

Results: In 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.

Conclusions: Pre-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.

No MeSH data available.


Related in: MedlinePlus