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PPARγ upregulation induced by vagus nerve stimulation exerts anti-inflammatory effect in cerebral ischemia/reperfusion rats.

Jiang Y, Li L, Liu B, Zhang Y, Chen Q, Li C - Med. Sci. Monit. (2015)

Bottom Line: The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining.Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).

ABSTRACT

Background: It is well known that peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, plays a protective role in anti-inflammatory responses in both acute and chronic central nerve system (CNS) insults. Emerging evidence in rats suggests that vagus nerve stimulation (VNS), while restraining inflammatory cytokine production in the peripheral nervous system, also exerts a significant CNS neuroprotective function against ischemic stroke injury. The aim of this study was to explore the role of PPARγ in VNS-mediated anti-inflammatory protection against ischemic stroke damage.

Material/methods: Adult male Sprague-Dawley rats (total n=160) preconditioned through transfection with either PPARγ small interfering RNA (siRNA) or lentiviral vector without siRNA and surgically subjected to middle cerebral artery occlusion and reperfusion subsequently received VNS treatment at 30 min post-occlusion. The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining. Subsequently, the neurological deficits scores, the infarct volume, and the brain histopathology were all evaluated. Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.

Results: We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05). However, rats with PPARγ silencing failed to manifest significant neuroprotection and anti-inflammatory effect induced by VNS treatment (p>0.05).

Conclusions: PPARγ may participate in the process by which VNS modulates the neuro-inflammatory response following ischemia/reperfusion in rats.

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Related in: MedlinePlus

Upregulation of PPARγ expression induced by VNS at 24 h post-reperfusion in the cerebral ischemic cortex. (A) PPARγ gene expression induced by VNS in rat brain measured by RT-PCR. Data are presented as mean ±SEM. (*p<0.05 compared with I/R group and #p<0.05 compared with I/R+SS group.) (B) PPARγ protein level after VNS assessed by Western blot at 24 h post-MCAO. Data are presented as mean ±SEM. A: I/R group B: I/R+SS group C: I/R+VNS group. (*p<0.05 vs. I/R group, #p<0.05 vs. I/R+SS group). (C) Immunofluorescence staining showing peri-nuclear PPARγ expression in the ischemic penumbra, and VNS treatment leading to an increase in PPARγ protein expression, A: I/R group; B: I/R+SS group; C: I/R+VNS group. Scale bar=75 μm.
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f1-medscimonit-21-268: Upregulation of PPARγ expression induced by VNS at 24 h post-reperfusion in the cerebral ischemic cortex. (A) PPARγ gene expression induced by VNS in rat brain measured by RT-PCR. Data are presented as mean ±SEM. (*p<0.05 compared with I/R group and #p<0.05 compared with I/R+SS group.) (B) PPARγ protein level after VNS assessed by Western blot at 24 h post-MCAO. Data are presented as mean ±SEM. A: I/R group B: I/R+SS group C: I/R+VNS group. (*p<0.05 vs. I/R group, #p<0.05 vs. I/R+SS group). (C) Immunofluorescence staining showing peri-nuclear PPARγ expression in the ischemic penumbra, and VNS treatment leading to an increase in PPARγ protein expression, A: I/R group; B: I/R+SS group; C: I/R+VNS group. Scale bar=75 μm.

Mentions: To explore the possible relationship between the protective mechanisms of VNS and PPARγ, we detected PPARγ expression in the cortical ischemic penumbra at 24 h post-I/R in rats treated with VNS compared with untreated animals. As shown in Figure 1, PPARγ mRNA levels were significantly upregulated in the I/R+VNS group as compared to the I/R and I/R+SS groups (p<0.05). Correspondingly, stimulation also enhanced PPARγprotein expression around the ischemic boundary in the I/R+VNS group but not in the I/R and I/R+SS group. Thus, it seemed that a dramatic increase of PPARγ expression in the brain was due to a brief and repeated VNS. To confirm the localization of PPARγ expression, immunofluorescence staining was also performed. As shown in Figure 1, PPARγ was expressed in a perinuclear location in neurons in the cerebral cortex and its expression was elevated after subjected to VNS. These results indicate that at least a portion of the PPARγ expression up-regulation after ischemic insult in the rat brain is induced by VNS.


PPARγ upregulation induced by vagus nerve stimulation exerts anti-inflammatory effect in cerebral ischemia/reperfusion rats.

Jiang Y, Li L, Liu B, Zhang Y, Chen Q, Li C - Med. Sci. Monit. (2015)

Upregulation of PPARγ expression induced by VNS at 24 h post-reperfusion in the cerebral ischemic cortex. (A) PPARγ gene expression induced by VNS in rat brain measured by RT-PCR. Data are presented as mean ±SEM. (*p<0.05 compared with I/R group and #p<0.05 compared with I/R+SS group.) (B) PPARγ protein level after VNS assessed by Western blot at 24 h post-MCAO. Data are presented as mean ±SEM. A: I/R group B: I/R+SS group C: I/R+VNS group. (*p<0.05 vs. I/R group, #p<0.05 vs. I/R+SS group). (C) Immunofluorescence staining showing peri-nuclear PPARγ expression in the ischemic penumbra, and VNS treatment leading to an increase in PPARγ protein expression, A: I/R group; B: I/R+SS group; C: I/R+VNS group. Scale bar=75 μm.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4310716&req=5

f1-medscimonit-21-268: Upregulation of PPARγ expression induced by VNS at 24 h post-reperfusion in the cerebral ischemic cortex. (A) PPARγ gene expression induced by VNS in rat brain measured by RT-PCR. Data are presented as mean ±SEM. (*p<0.05 compared with I/R group and #p<0.05 compared with I/R+SS group.) (B) PPARγ protein level after VNS assessed by Western blot at 24 h post-MCAO. Data are presented as mean ±SEM. A: I/R group B: I/R+SS group C: I/R+VNS group. (*p<0.05 vs. I/R group, #p<0.05 vs. I/R+SS group). (C) Immunofluorescence staining showing peri-nuclear PPARγ expression in the ischemic penumbra, and VNS treatment leading to an increase in PPARγ protein expression, A: I/R group; B: I/R+SS group; C: I/R+VNS group. Scale bar=75 μm.
Mentions: To explore the possible relationship between the protective mechanisms of VNS and PPARγ, we detected PPARγ expression in the cortical ischemic penumbra at 24 h post-I/R in rats treated with VNS compared with untreated animals. As shown in Figure 1, PPARγ mRNA levels were significantly upregulated in the I/R+VNS group as compared to the I/R and I/R+SS groups (p<0.05). Correspondingly, stimulation also enhanced PPARγprotein expression around the ischemic boundary in the I/R+VNS group but not in the I/R and I/R+SS group. Thus, it seemed that a dramatic increase of PPARγ expression in the brain was due to a brief and repeated VNS. To confirm the localization of PPARγ expression, immunofluorescence staining was also performed. As shown in Figure 1, PPARγ was expressed in a perinuclear location in neurons in the cerebral cortex and its expression was elevated after subjected to VNS. These results indicate that at least a portion of the PPARγ expression up-regulation after ischemic insult in the rat brain is induced by VNS.

Bottom Line: The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining.Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05).

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China (mainland).

ABSTRACT

Background: It is well known that peroxisome proliferator-activated receptor gamma (PPARγ), a ligand-activated transcription factor, plays a protective role in anti-inflammatory responses in both acute and chronic central nerve system (CNS) insults. Emerging evidence in rats suggests that vagus nerve stimulation (VNS), while restraining inflammatory cytokine production in the peripheral nervous system, also exerts a significant CNS neuroprotective function against ischemic stroke injury. The aim of this study was to explore the role of PPARγ in VNS-mediated anti-inflammatory protection against ischemic stroke damage.

Material/methods: Adult male Sprague-Dawley rats (total n=160) preconditioned through transfection with either PPARγ small interfering RNA (siRNA) or lentiviral vector without siRNA and surgically subjected to middle cerebral artery occlusion and reperfusion subsequently received VNS treatment at 30 min post-occlusion. The expression of PPARγ after VNS treatment was measured by real-time PCR and Western blotting, also supported by immunofluorescence staining. Subsequently, the neurological deficits scores, the infarct volume, and the brain histopathology were all evaluated. Additionally, the influence on the pro-inflammatory cytokines expression and neuro-immune cells activation was determined by ELISA and immunofluorescence staining.

Results: We found that VNS upregulated expression of PPARγ in ischemia penumbra, diminished the extent of ischemic infarct, alleviated neuronal injury, and suppressed pro-inflammatory cytokine expression and immune cell activation (P<0.05). However, rats with PPARγ silencing failed to manifest significant neuroprotection and anti-inflammatory effect induced by VNS treatment (p>0.05).

Conclusions: PPARγ may participate in the process by which VNS modulates the neuro-inflammatory response following ischemia/reperfusion in rats.

Show MeSH
Related in: MedlinePlus