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. 2021 Jul;11(7):e02143.
doi: 10.1002/brb3.2143. Epub 2021 Jun 8.

Isorhapontigenin ameliorates cerebral ischemia/reperfusion injury via modulating Kinase Cε/Nrf2/HO-1 signaling pathway

Zhe Xue  1   2 , Kai Zhao  1   2 , Zhenghui Sun  1   2 , Chen Wu  1   2 , Bowen Yu  1   2 , Dongsheng Kong  1   2 , Bainan Xu  1   2
Affiliations

Isorhapontigenin ameliorates cerebral ischemia/reperfusion injury via modulating Kinase Cε/Nrf2/HO-1 signaling pathway

Zhe Xue et al. Brain Behav. 2021 Jul.

Abstract

Background: Isorhapontigenin (ISO) has been shown to have antioxidant activity. This study aimed to investigate the antioxidant effects of ISO on cerebral ischemia/reperfusion (I/R) injury and its possible molecular mechanisms.

Methods: Focal cerebral ischemia-reperfusion injury (MCAO/R) model and primary cortical neurons were established an oxygen-glucose deprivation (OGD / R) injury model. After 24 hr of reperfusion, the neurological deficits of the rats were analyzed and HE staining was performed, and the infarct volume was calculated by TTC staining. In addition, the reactive oxygen species (ROS) in rat brain tissue, the content of 4-Hydroxynonenal (4-HNE), and 8-hydroxy2deoxyguanosine (8-OHdG) were detected. Neuronal cell viability was determined by MTT assay. Western blot analysis was determined for protein expression.

Results: ISO treatment significantly improved neurological scores, reduced infarct volume, necrotic neurons, ROS production, 4-HNE, and 8-OHdG levels. At the same time, ISO significantly increased the expression of Nrf2 and HO-1. The neuroprotective effects of ISO can be eliminated by knocking down Nrf2 and HO-1. In addition, knockdown of the PKCε blocked ISO-induced nuclear Nfr2, HO-1 expression.

Conclusion: ISO protected against oxidative damage induced by brain I/R, and its neuroprotective mechanism may be related to the PKCε/Nrf2/HO-1 pathway.

Keywords: HO-1; Nrf2; PKCε; cerebral ischemia; isorhapontigenin; oxidative stress; reperfusion.

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Conflict of interest statement

The authors declare no competing interests.

Figures

FIGURE 1
FIGURE 1
ISO protected the brain from I/R damage. (a) The chemical structure of ISO. (b) Neurological deficit score. (c) Cerebral infarction in rat brain. (d) Percentage of infarct volume in the brain. (e) Nissl staining to assess rat neuronal damage. (f) H&E staining to assess rat neuronal damage. (g) PKCε and phosphorylated PKCε levels in the brain. Scale bar =100 μm (×200 times). n = 6. ## p < .01 versus the sham group; *p < .05 and **p < .01 versus the I/R group
FIGURE 2
FIGURE 2
ISO reduced oxidative damage. (a) ROS levels. (b) 4‐HNE content. (c) 8‐OHdG content. n = 6. ## p < .01 versus the sham group; *p < .05 and **p < .01 versus the I/R group
FIGURE 3
FIGURE 3
Protein expression levels of Nrf2 (a) and HO‐1 (b). n = 6. ** p < .01 versus the sham group
FIGURE 4
FIGURE 4
Cell viability determined. n = 6. ## p < .01 versus the sham group; *p < .05 and **p < .01 versus the OGD/R group
FIGURE 5
FIGURE 5
ISO’s effects on protein expression of Nrf2 (a) and HO‐1 (b) in SH‐SY5Y cells. n = 6. * p < .05 and **p < .01 versus the OGD/R group
FIGURE 6
FIGURE 6
ISO produced neuroprotection via the Nrf2/HO‐1 signaling pathway. (a, b) Protein expression levels of HO‐1 and Nrf2. n = 6. ## p < .01 versus the control group. && p < .01 versus the 80 μM+ si‐Con group. (C, D) Cell viability. n = 6. ## p < .01 versus the control group; ** p < .01 versus the OGD/R group; & p < .05 versus the 80 μM group
FIGURE 7
FIGURE 7
PKCε knockdown eliminated ISO‐induced neuroprotection. (a) PKCε and phosphorylated PKCε (p‐PKCε) levels, (b) Nrf2 expression, and (c) HO‐1 expression under different treatment conditions. n = 6. ## p < .01 versus the control group; & p < .05, && p < .01 versus the 80 μM + si‐Con group. (d) PKCε knockdown abolished ISO‐induced neuroprotection against OGD/R injury. n = 6. ## p < .01 versus the control group; ** p < .01 versus the OGD/R group; & p < .05 versus the 80 μM group
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References

    1. Abiko, Y. , Mizokawa, M. , & Kumagai, Y. J. (2014). Activation of the Kelch‐like ECH‐associated protein 1 (Keap1)/NF‐E2‐related factor 2 (Nrf2) pathway through covalent modification of the 2‐Alkenal group of aliphatic electrophiles in Coriandrum sativum L. Journal of Agricultural and Food Chemistry, 62(45), 10936‐10944. - PubMed
    1. Carden, D. L. (2015). Pathophysiology of ischaemia‐reperfusion injury. The Journal of Pathology, 190(3), 255–266. - PubMed
    1. Che, F. , Du, H. , Zhang, W. , Cheng, Z. , & Tong, Y. (2017). MicroRNA‐132 modifies angiogenesis in patients with ischemic cerebrovascular disease by suppressing the NF‑κB and VEGF pathway. Molecular Medicine Reports, 17(2), 2724–2730. 10.3892/mmr.2017.8138 - DOI - PubMed
    1. Chopra, R. , Wasserman, A. H. , Pulst, S. M. , & De Zeeuw, C. I. (2018). Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia. Human Molecular Genetics, 27(8), 1396–1410. 10.1093/hmg/ddy050 - DOI - PMC - PubMed
    1. Dai, Y. U. , Yeo, S. C. M. , Barnes, P. J. , Donnelly, L. E. , Loo, L. C. , & Lin, H.‐S. (2018). Pre‐clinical pharmacokinetic and metabolomic analyses of isorhapontigenin, a dietary resveratrol derivative. Frontiers in Pharmacology, 9, 753. 10.3389/fphar.2018.00753 - DOI - PMC - PubMed

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