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Pyruvate kinase M2 (PKM2) improve symptoms of post-ischemic stroke depression by activating VEGF to mediate the MAPK/ERK pathway - PubMed

Pyruvate kinase M2 (PKM2) improve symptoms of post-ischemic stroke depression by activating VEGF to mediate the MAPK/ERK pathway

Yun Feng et al. Brain Behav. 2022 Jan.

Abstract

Purpose: To evaluate and identify the effects and explore the mechanisms of pyruvate kinase M2 (PKM2) on stroke-induced post stroke depression (PSD).

Methods: Rats were separated into six different groups, including sham + saline, Stroke + saline, PSD + saline, PSD + recombinant pyruvate kinase M2 (rPKM2) (112 ng/kg), PSD + rPKM2 (224 ng/kg), and PSD + rPKM2 (224 ng/kg) + bevacizumab. Then, the body weight, sucrose preference rate, immobility time, horizontal movement, and vertical movement were determined to evaluate the effect of PKM2 on improving the depressive behavior of PSD rats. Subsequently, the proliferation of oligodendrocytes in subventricular zone (SVZ) of rats in each group was examined by western blot and immunofluorescent staining. Furthermore, the mRNA and protein expression levels of TNF-α, IL-6, and IL-1β were also detected by qPCR and ELISA to verify the anti-inflammatory effects of PKM2 on PSD rats. In addition, the protein expression levels of MDA, LDH, and NO were tested to reveal that PKM2 can reduce oxidative stress in PSD rats. The western blot and IHC assays were employed to examine the protein expression levels of VEGF, PKM2, and ERK in PSD rats.

Results: In this study, the results showed that PKM2 can improve the depressive behavior and proliferation of oligodendrocytes in PSD rats. In addition, PKM2 has anti-inflammatory and anti-oxidative stress effects on PSD rats. Meanwhile, PKM2 activated the expression level of VEGF/MAPK/ERK pathway.

Conclusion: PKM2 improves symptoms of post-ischemic stroke depression by activating VEGF-mediated MAPK/ERK pathway.

Keywords: ERK; MAPK; PKM2; PSD; VEGF.

© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

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Conflict of interest statement

The authors state that there are no conflicts of interest to disclose.

Figures

FIGURE 1
FIGURE 1

PKM2 can improve the depressive behavior of PSD rats. (a) The body weight. (b) The sucrose preference rate in SPT. (c) The immobility time in FST. (d,e) The horizontal movement and vertical movement in OFT of sham, stroke, or PSD rats at indicated time points in response to intranasal administration of saline or PKM2. Data were presented as the mean ± SD with three independent experiments. *p < .05, **p < .01 versus sham group, and ## p < .01 versus PSD group

FIGURE 2
FIGURE 2

PKM2 can promote the proliferation of oligodendrocytes in PSD rats. (a) The protein expression levels of MBP and Olig‐2 of rats in each group. (b) The number of MBP and Olig‐2 positive oligodendrocytes in PSD rats. Data were presented as the mean ± SD with three independent experiments. **p < .01 versus sham group and ## p < .01 versus PSD group

FIGURE 3
FIGURE 3

PKM2 can reduce the inflammatory response in PSD rats. (a) The mRNA expression levels of TNF‐α, IL‐6, and IL‐1β of rats in each group. (b) The protein expression levels of TNF‐α, IL‐6, and IL‐1β of rats in each group. Data were presented as the mean ± SD with three independent experiments. **p < .01 versus sham group and ## p < .01 versus PSD group

FIGURE 4
FIGURE 4

PKM2 can reduce oxidative stress in PSD rats. The protein expression levels of MDA, LDH, and NO of rats in each group. Data were presented as the mean ± SD with three independent experiments. **p < .01 versus sham group and ## p < .01 versus PSD group

FIGURE 5
FIGURE 5

PKM2 promotes activation of the MAPK/ERK pathway by activating VEGF expression. (a) The protein levels of PKM2, ERK, and VEGF in PSD rat, as determined using western blotting. Relatively quantitative results were determined by Image J and shown as histogram. (b) IHC assay was applied to examine the protein levels of PKM2, ERK, and VEGF in PSD rat. Data were presented as the mean ± SD with three independent experiments. **p < .01 versus sham group, ## p < .01 versus PSD group, and @@ p < .01 versus PSD + rPKM2 (224 ng/kg) group

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