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      Platelet-rich plasma improves chronic inflammatory pain by inhibiting PKM2-mediated aerobic glycolysis in astrocytes

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          Abstract

          Background

          Astrocytes are highly glycolytic cells that play a crucial role in chronic pain. Recently it has been found that inflammation and metabolism are related to the inflammatory stimuli closely that cause cellular metabolic changes. Pyruvate kinase M2 (PKM2) is a critical metabolic kinase in aerobic glycolysis or the Warburg effect. Besides, it also plays a crucial role in cell proliferation and signal transduction, but its role in astrocytes is still unclear.

          Methods

          The chronic inflammatory pain model was set up by intraplantar injection of complete Freund’s adjuvant (CFA) in Sprague Dawley (SD) rats as well as the cell model was constructed by lipopolysaccharide-treated primary astrocytes. Von Frey filament stimulation was used to continuously observe the changes of pain behavior in rats after modeling. Then, immunofluorescence staining and Western blot tests were used to observe the expression levels of glial fibrillary acidic protein (GFAP), pyruvate kinase (PKM2), signal transducers and activators of transcription 3 (STAT3) and high mobility group box-1 protein (HMGB1). After that, specific kits measured lactate contents. Finally, we observed the platelet-rich plasma’s (PRP) effect on mechanical hyperalgesia in rats with inflammatory pain induced by CFA and its effect on related signal molecules.

          Results

          We found that in the CFA-induced inflammatory pain model, astrocytes were significantly activated, GFAP was increased, PKM2 was significantly up-regulated, and the glycolytic product lactate was increased. Also, intrathecal injection of PRP increased the pain threshold, inhibited the activation of astrocytes, and decreased the expression of PKM2 and aerobic glycolysis; in LPS-activated primary astrocytes as an in vitro model, we found PKM2 translocation activationSTAT3 signaling resulted in sustained activation of astrocyte marker GFAP, and the expression level and localization of p-STAT3 were correlated with PKM2. PRP could inhibit the activation of astrocytes, reduce the expression of PKM2 and the expression levels of glycolysis and GFAP, GLUT1, and p-STAT3 in astrocytes.

          Conclusions

          Our findings suggest PKM2 not only plays a glycolytic role in astrocytes, but also plays a crucial role in astrocyte-activated signaling pathways, and PRP attenuates CFA induced inflammatory pain by inhibiting aerobic glycolysis in astrocytes, providing a new therapeutic target for the treatment of inflammatory pain.

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          Author and article information

          Journal
          Ann Transl Med
          Ann Transl Med
          ATM
          Annals of Translational Medicine
          AME Publishing Company
          2305-5839
          2305-5847
          November 2020
          November 2020
          : 8
          : 21
          Affiliations
          Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University , Suzhou, China
          Author notes

          Contributions: (I) Conception and design: LN Wang; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: X Wei, XH Jin, XW Meng; (V) Data analysis and interpretation: X Wei, XH Jin, XW Meng, J Hua, FH Ji, JP Yang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

          [#]

          These authors contributed equally to this work.

          Correspondence to: Jian-Ping Yang; Li-Na Wang. Department of Anesthesiology and Pain Management, the First Affiliated Hospital of Soochow University, Suzhou, China. Email: szyangjp@ 123456126.com ; Wangln@ 123456suda.edu.cn .
          Article
          PMC7723564 PMC7723564 7723564 atm-08-21-1456
          10.21037/atm-20-6502
          7723564
          33313201
          2020 Annals of Translational Medicine. All rights reserved.
          Categories
          Original Article

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