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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

Cortical expression of α-synuclein (2A), 14-3-3 Zeta (B) and TUC-4 (2C) in Control and treated rats. Western blot and quantification of α-synuclein and 14-3-3 Zeta (KCIP-1) and TUC-4 expression in the brain cortex. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicate a p value <0.05 vs. control group.
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Figure 2: Cortical expression of α-synuclein (2A), 14-3-3 Zeta (B) and TUC-4 (2C) in Control and treated rats. Western blot and quantification of α-synuclein and 14-3-3 Zeta (KCIP-1) and TUC-4 expression in the brain cortex. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicate a p value <0.05 vs. control group.

Mentions: Referred to figure 2A, we observed a statistically significant decrease of the cortical expression of α-synuclein of atorvastatin-treated rats when compared to the control group. (OD ratio: Control group: 0.12 ± 0.01, Atorvastatin-treated group: 0.08 ± 0.02, p < 0.05). α-synuclein expression in I/R group was reduced (OD ratio: 0.07 ± 0.05) but not significantly when compared to control. With regards to fenofibrate-treated I/R rats and atorvastatin-treated I/R rats, we observed a similar tendency to a reduced expression of brain cortical α-synuclein expression. But the observed decrease in both fenofibrate-treated or atorvastatin group was not statistically significant (OD ratio respectively: 0.09 ± 0.01; 0.10 ± 0.01). α-synuclein can form intracellular aggregates when it is produce in excess leading to the formation of the Lewy bodies in the neuronal cytoplasm [31]. Accumulation of aggregated α-synuclein is one of the major causes of neuronal death in Parkinson disease and the loss of α-synuclein have been described in a model of perinatal hypoxia/ischemia [29] suggesting a sensitivity of dopaminergic neurons to hypoxia. Interestingly, atorvastatin showed its ability, for the first time, to lower α-synuclein expression. The mechanisms of the decrease are still elusive and several hypotheses are possible, including the interaction with other proteins or regulation of lipid metabolism. However, lowering α-synuclein could be protective toward the potential toxicity of α-synuclein in neurological disorders remains to be considered as a potential long-term treatment in Parkinson’s disease [32].


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)

Cortical expression of α-synuclein (2A), 14-3-3 Zeta (B) and TUC-4 (2C) in Control and treated rats. Western blot and quantification of α-synuclein and 14-3-3 Zeta (KCIP-1) and TUC-4 expression in the brain cortex. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicate a p value <0.05 vs. control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Cortical expression of α-synuclein (2A), 14-3-3 Zeta (B) and TUC-4 (2C) in Control and treated rats. Western blot and quantification of α-synuclein and 14-3-3 Zeta (KCIP-1) and TUC-4 expression in the brain cortex. Results are expressed as mean ± sem (n = 6 in each group). Statistical analysis using ANOVA followed by Fisher’s LSD test: ★ indicate a p value <0.05 vs. control group.
Mentions: Referred to figure 2A, we observed a statistically significant decrease of the cortical expression of α-synuclein of atorvastatin-treated rats when compared to the control group. (OD ratio: Control group: 0.12 ± 0.01, Atorvastatin-treated group: 0.08 ± 0.02, p < 0.05). α-synuclein expression in I/R group was reduced (OD ratio: 0.07 ± 0.05) but not significantly when compared to control. With regards to fenofibrate-treated I/R rats and atorvastatin-treated I/R rats, we observed a similar tendency to a reduced expression of brain cortical α-synuclein expression. But the observed decrease in both fenofibrate-treated or atorvastatin group was not statistically significant (OD ratio respectively: 0.09 ± 0.01; 0.10 ± 0.01). α-synuclein can form intracellular aggregates when it is produce in excess leading to the formation of the Lewy bodies in the neuronal cytoplasm [31]. Accumulation of aggregated α-synuclein is one of the major causes of neuronal death in Parkinson disease and the loss of α-synuclein have been described in a model of perinatal hypoxia/ischemia [29] suggesting a sensitivity of dopaminergic neurons to hypoxia. Interestingly, atorvastatin showed its ability, for the first time, to lower α-synuclein expression. The mechanisms of the decrease are still elusive and several hypotheses are possible, including the interaction with other proteins or regulation of lipid metabolism. However, lowering α-synuclein could be protective toward the potential toxicity of α-synuclein in neurological disorders remains to be considered as a potential long-term treatment in Parkinson’s disease [32].

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