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. 2020 May 29;11(1):173-181.
doi: 10.1515/tnsci-2020-0119. eCollection 2020.

EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats

Jianjun Wang  1   2 , Ying Chen  3 , Long Chen  2 , Yanzhi Duan  2 , Xuejun Kuang  1 , Zhao Peng  1 , Conghui Li  1 , Yuanhao Li  2 , Yang Xiao  2 , Hao Jin  2 , Quandan Tan  2 , Shaofeng Zhang  2 , Bopei Zhu  2 , Yinjuan Tang  4
Affiliations

EGCG modulates PKD1 and ferroptosis to promote recovery in ST rats

Jianjun Wang et al. Transl Neurosci. .

Abstract

Background: Spinal cord injury (SCI) causes devastating loss of function and neuronal death without effective treatment. (-)-Epigallocatechin-3-gallate (EGCG) has antioxidant properties and plays an essential role in the nervous system. However, the underlying mechanism by which EGCG promotes neuronal survival and functional recovery in complete spinal cord transection (ST) remains unclear.

Methods: In the present study, we established primary cerebellar granule neurons (CGNs) and a T10 ST rat model to investigate the antioxidant effects of EGCG via its modulation of protein kinase D1 (PKD1) phosphorylation and inhibition of ferroptosis.

Results: We revealed that EGCG significantly increased the cell survival rate of CGNs and PKD1 phosphorylation levels in comparison to the vehicle control, with a maximal effect observed at 50 µM. EGCG upregulated PKD1 phosphorylation levels and inhibited ferroptosis to reduce the cell death of CGNs under oxidative stress and to promote functional recovery and ERK phosphorylation in rats following complete ST.

Conclusion: Together, these results lay the foundation for EGCG as a novel strategy for the treatment of SCI related to PKD1 phosphorylation and ferroptosis.

Keywords: (−)-epigallocatechin-3-gallate; cerebellar granule neurons; ferroptosis; oxidative stress; spinal cord injury.

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Conflict of interest statement

Conflict of interest: The authors state no conflict of interest.

Figures

Figure 1
Figure 1
Effect of EGCG on cell viability and PKD1 phosphorylation in CGNs in vitro. (a) EGCG increased the peak levels of CGN survival and PKD1 phosphorylation at a concentration of 50 µM (a and b). (*p < 0.05, **p < 0.01, ***p < 0.0001, five independent experiments.)
Figure 2
Figure 2
Effect of EGCG on CGN survival under oxidative stress in vitro. (a) EGCG protected against the cell death of CGNs induced by H2O2 by modulating PKD1 and ferroptosis. (b) PKD1 phosphorylation levels were increased in response to EGCG treatment in CGNs under oxidative stress. (c–h) Ferroptosis was inhibited in response to EGCG treatment in CGNs under oxidative stress, as indicated by the downregulation of ACSL4, COX2, NOX1, and PTGS2 and the upregulation of FTH1 and GPX4. (*p < 0.05, **p < 0.01, ***p < 0.0001, five independent experiments.)
Figure 3
Figure 3
Effect of EGCG on CGNs and functional recovery in rats after complete ST. EGCG increased PKD1 phosphorylation and inhibited ferroptosis to promote functional recovery in rats, as indicated by (a) increased BBB score, (b) knee joint angle, (c) speed in the rotarod test, and (d) biceps femoris muscle weight. (*p < 0.05, **p < 0.01, ***p < 0.0001, n = 8.)
Figure 4
Figure 4
Effect of EGCG on neuronal survival in the spinal cord in rats after complete ST. (a–f) Ferroptosis was inhibited in response to EGCG treatment in the spinal cord, as indicated by the downregulation of ACSL4, COX2, NOX1, and PTGS2 and upregulation of FTH1 and GPX4. (g) PKD1 phosphorylation levels were increased in response to EGCG treatment. (h and i) ERK phosphorylation levels were increased in response to EGCG treatment. (*p < 0.05, **p < 0.01, ***p < 0.0001, n = 5.)
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