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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

Histopathological changes at 24 h post-reperfusion after VNS treatment in rat with PPARr silencing or vehicle control. Brain slices were examined at a magnification of 400×. A: I/R+ LV-control group, B: I/R+VNS+LV-control group, C: I/R+LV-shPPARr group, D: I/R+VNS+ LV-shPPARr group. Black arrows represent perinuclear vacuolization and blue arrows represent pyknotic nuclei.
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f3-medscimonit-21-268: Histopathological changes at 24 h post-reperfusion after VNS treatment in rat with PPARr silencing or vehicle control. Brain slices were examined at a magnification of 400×. A: I/R+ LV-control group, B: I/R+VNS+LV-control group, C: I/R+LV-shPPARr group, D: I/R+VNS+ LV-shPPARr group. Black arrows represent perinuclear vacuolization and blue arrows represent pyknotic nuclei.

Mentions: At 24 h post-reperfusion, brain histopathology was evaluated in HE-stained sections. In normal, untreated animals (data not shown), neuron morphology exhibits regular cellular and organelle structure with a regular neuronal arrangement. As shown in Figure 3, in the I/R group neurons were sparse (presumably the outcome of widespread necrosis) and these neurons that did survive exhibited vacuolization, disordered structure, swelling, interstitial edema, and severe cell deformation, with karyopyknotic nuclei; additionally, the neuropil exhibited a loosening compared to the normally tightly packed nerve fibers, indicating disintegration due to necrosis. Compared with the I/R+LV-control group, the scope of brain damage after VNS treatment (I/R+VNS+LV-control group) appeared to be diminished, with denser neuropil and a greater density of surviving neurons, with relatively distinct cell outlines and relatively intact internal structure. After PPARr silencing, there were no significant differences in brain histopathology between I/R+LV-shPPARr and I/R+VNS+LV-shPPARr group. These results show that PPARr has an important role in the neuroprotective effect of VNS in mediating cerebral ischemia injury.


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)

Histopathological changes at 24 h post-reperfusion after VNS treatment in rat with PPARr silencing or vehicle control. Brain slices were examined at a magnification of 400×. A: I/R+ LV-control group, B: I/R+VNS+LV-control group, C: I/R+LV-shPPARr group, D: I/R+VNS+ LV-shPPARr group. Black arrows represent perinuclear vacuolization and blue arrows represent pyknotic nuclei.
© Copyright Policy
Related In: Results  -  Collection

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

f3-medscimonit-21-268: Histopathological changes at 24 h post-reperfusion after VNS treatment in rat with PPARr silencing or vehicle control. Brain slices were examined at a magnification of 400×. A: I/R+ LV-control group, B: I/R+VNS+LV-control group, C: I/R+LV-shPPARr group, D: I/R+VNS+ LV-shPPARr group. Black arrows represent perinuclear vacuolization and blue arrows represent pyknotic nuclei.
Mentions: At 24 h post-reperfusion, brain histopathology was evaluated in HE-stained sections. In normal, untreated animals (data not shown), neuron morphology exhibits regular cellular and organelle structure with a regular neuronal arrangement. As shown in Figure 3, in the I/R group neurons were sparse (presumably the outcome of widespread necrosis) and these neurons that did survive exhibited vacuolization, disordered structure, swelling, interstitial edema, and severe cell deformation, with karyopyknotic nuclei; additionally, the neuropil exhibited a loosening compared to the normally tightly packed nerve fibers, indicating disintegration due to necrosis. Compared with the I/R+LV-control group, the scope of brain damage after VNS treatment (I/R+VNS+LV-control group) appeared to be diminished, with denser neuropil and a greater density of surviving neurons, with relatively distinct cell outlines and relatively intact internal structure. After PPARr silencing, there were no significant differences in brain histopathology between I/R+LV-shPPARr and I/R+VNS+LV-shPPARr group. These results show that PPARr has an important role in the neuroprotective effect of VNS in mediating cerebral ischemia injury.

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