Skip to main content
SpringerLink
Log in

An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier–TNF-α–BBB–HMGB1–Caspase-1 inflammasome–pyroptosis–M1 microglia pathway is a novel mechanism of POCD related to the gut–brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Graphical Abstract

According to our findings, AAD injection, which is based on the ERAS concept, alleviates POCD by decreasing the activity of the gut barrier–TNF‐α–BBB–HMGB1–Caspase-1 inflammasome–pyroptosis–M1 microglial axis

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The authors declare that all the data supporting the findings of this study are available within the article.

Abbreviations

POCD:

Postoperative cognitive dysfunction

ERAS:

Enhan

ced recovery after surgery

BBB:

Blood–brain barrier

AAD:

Amino acid and dipeptide

HMGB1:

High mobility group box-1

HE:

Hematoxylin–eosin

IHC:

Immunohistochemistry

IF:

Immu

nofluorescence

CCK-8:

Cell counting kit-8

MMP:

Mitochondrial membrane potential

DCFH-DA:

Dichlorodihydrofluorescein diacetate

References

  1. Liu B, Huang D, Guo Y, Sun X, Chen C, Zhai X et al (2022) Recent advances and perspectives of postoperative neurological disorders in the elderly surgical patients. CNS Neurosci Ther 28(4):470–483

    Article  PubMed  Google Scholar 

  2. Suraarunsumrit P, Pathonsmith C, Srinonprasert V, Sangarunakul N, Jiraphorncharas C, Siriussawakul A (2022) Postoperative cognitive dysfunction in older surgical patients associated with increased healthcare utilization: a prospective study from an upper-middle-income country. BMC Geriatr 22(1):213

    Article  PubMed  PubMed Central  Google Scholar 

  3. Luo A, Yan J, Tang X, Zhao Y, Zhou B, Li S (2019) Postoperative cognitive dysfunction in the aged: the collision of neuroinflammaging with perioperative neuroinflammation. Inflammopharmacology 27(1):27–37

    Article  CAS  PubMed  Google Scholar 

  4. Cryan JF, Mazmanian SK (2022) Microbiota-brain axis: Context and causality. Science 376(6596):938–939

    Article  CAS  PubMed  Google Scholar 

  5. Wilmore DW, Smith RJ, O’Dwyer ST, Jacobs DO, Ziegler TR, Wang XD (1988) The gut: a central organ after surgical stress. Surgery 104(5):917–923

    CAS  PubMed  Google Scholar 

  6. Tan S, Zhou F, Zhang Z, Wang J, Xu J, Zhuang Q et al (2021) Beta-1 blocker reduces inflammation and preserves intestinal barrier function after open abdominal surgery. Surgery 169(4):885–893

    Article  PubMed  Google Scholar 

  7. Ralls MW, Demehri FR, Feng Y, Woods Ignatoski KM, Teitelbaum DH (2015) Enteral nutrient deprivation in patients leads to a loss of intestinal epithelial barrier function. Surgery 157(4):732–742

    Article  PubMed  Google Scholar 

  8. Tan S, Yu W, Lin Z, Chen Q, Shi J, Dong Y et al (2015) Berberine ameliorates intestinal mucosal barrier damage induced by peritoneal air exposure. Biol Pharm Bull 38(1):122–126

    Article  CAS  PubMed  Google Scholar 

  9. Keita AV, Söderholm JD (2010) The intestinal barrier and its regulation by neuroimmune factors. Neurogastroenterol Motil: Off J Eur Gastrointest Motil Soc 22(7):718–733

    Article  CAS  Google Scholar 

  10. Terrando N, Monaco C, Ma D, Foxwell BM, Feldmann M, Maze M (2010) Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc Natl Acad Sci USA 107(47):20518–20522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen L, Dong R, Lu Y, Zhou Y, Li K, Zhang Z, Peng M (2019) MicroRNA-146a protects against cognitive decline induced by surgical trauma by suppressing hippocampal neuroinflammation in mice. Brain Behav Immun 78:188–201

    Article  CAS  PubMed  Google Scholar 

  12. Chen X, He WT, Hu L, Li J, Fang Y, Wang X et al (2016) Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res 26(9):1007–1020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gu L, Sun M, Li R, Tao Y, Luo X, Xu J et al (2022) Activation of RKIP binding ASC attenuates neuronal pyroptosis and brain injury via caspase-1/GSDMD signaling pathway after intracerebral hemorrhage in mice. Transl Stroke Res13(6):1037–1054

  14. Feng X, Valdearcos M, Uchida Y, Lutrin D, Maze M, Koliwad SK (2017) Microglia mediate postoperative hippocampal inflammation and cognitive decline in mice. JCI Insight 2(7):e91229

    Article  PubMed  PubMed Central  Google Scholar 

  15. Kwon HS, Koh SH (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9(1):42

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liao S, Wu J, Liu R, Wang S, Luo J, Yang Y et al (2020) A novel compound DBZ ameliorates neuroinflammation in LPS-stimulated microglia and ischemic stroke rats: role of akt(Ser473)/GSK3β(Ser9)-mediated Nrf2 activation. Redox Biol 36:101644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ljungqvist O, Scott M, Fearon KC (2017) Enhanced recovery after surgery: a review. JAMA Surg 152(3):292–298

    Article  PubMed  Google Scholar 

  18. Wang Y, Zhao X, Ma Y, Yang Y, Ge S (2023) The effects of vitamin B6 on the nutritional support of BCAAs-enriched amino acids formula in rats with partial gastrectomy. Clin Nutr (Edinburgh Scotland) 42(6):954–961

    Article  CAS  Google Scholar 

  19. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J et al (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science (New York NY) 285(5425):248–251

    Article  CAS  Google Scholar 

  20. He HJ, Wang Y, Le Y, Duan KM, Yan XB, Liao Q et al (2012) Surgery upregulates high mobility group box-1 and disrupts the blood-brain barrier causing cognitive dysfunction in aged rats. CNS Neurosci Ther 18(12):994–1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yan W, Chang Y, Liang X, Cardinal JS, Huang H, Thorne SH et al (2012) High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology (Baltimore MD) 55(6):1863–1875

    Article  CAS  PubMed  Google Scholar 

  22. Buijs J, Dofferhoff AS, Mouton JW, van der Meer JW (2007) Continuous administration of PBP-2- and PBP-3-specific beta-lactams causes higher cytokine responses in murine Pseudomonas aeruginosa and Escherichia coli sepsis. J Antimicrob Chemother 59(5):926–933

    Article  CAS  PubMed  Google Scholar 

  23. Diehl KH, Hull R, Morton D, Pfister R, Rabemampianina Y, Smith D et al (2001) A good practice guide to the administration of substances and removal of blood, including routes and volumes. J Appl Toxicol: JAT 21(1):15–23

    Article  CAS  PubMed  Google Scholar 

  24. Chen D, Chen C, Xiao X, Huang Z, Huang X, Yao W (2021) TNF-α induces Neutrophil apoptosis Delay and promotes Intestinal Ischemia-Reperfusion-Induced Lung Injury through activating JNK/FoxO3a pathway. Oxidative Med Cell Longev 2021:8302831

    Article  Google Scholar 

  25. Tajik N, Frech M, Schulz O, Schälter F, Lucas S, Azizov V et al (2020) Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun 11(1):1995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Abdullah Z, Bayraktutan U (2014) NADPH oxidase mediates TNF-α-evoked in vitro brain barrier dysfunction: roles of apoptosis and time. Mol Cell Neurosci 61:72–84

    Article  CAS  PubMed  Google Scholar 

  27. Sun X, Zeng H, Wang Q, Yu Q, Wu J, Feng Y et al (2018) Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation-mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway. Exp Cell Res 369(1):112–119

    Article  CAS  PubMed  Google Scholar 

  28. Tian DD, Wang M, Liu A, Gao MR, Qiu C, Yu W et al (2021) Antidepressant effect of paeoniflorin is through inhibiting pyroptosis CASP-11/GSDMD pathway. Mol Neurobiol 58(2):761–776

    Article  CAS  PubMed  Google Scholar 

  29. Zhao Z, Yao M, Wei L, Ge S (2020) Obesity caused by a high-fat diet regulates the Sirt1/PGC-1α/FNDC5/BDNF pathway to exacerbate isoflurane-induced postoperative cognitive dysfunction in older mice. Nutr Neurosci 23(12):971–982

    Article  CAS  PubMed  Google Scholar 

  30. Yao M, Zhao Z, Wei L, Zhou D, Xue Z, Ge S (2019) HSF1/HSP pathway in the hippocampus is involved in SIRT1-mediated caloric restriction-induced neuroprotection after surgery in aged mice. Exp Gerontol 119:184–192

    Article  CAS  PubMed  Google Scholar 

  31. Ji Y, Teng L, Zhang R, Sun J, Guo Y (2017) NRG-1β exerts neuroprotective effects against ischemia reperfusion-induced injury in rats through the JNK signaling pathway. Neuroscience 362:13–24

    Article  CAS  PubMed  Google Scholar 

  32. Qin X, Wang J, Chen S, Liu G, Wu C, Lv Q et al (2022) Astrocytic p75(NTR) expression provoked by ischemic stroke exacerbates the blood-brain barrier disruption. Glia 70(5):892–912

    Article  CAS  PubMed  Google Scholar 

  33. Wehner S, Behrendt FF, Lyutenski BN, Lysson M, Bauer AJ, Hirner A, Kalff JC (2007) Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents. Gut 56(2):176–185

    Article  CAS  PubMed  Google Scholar 

  34. Tsuchiya T, Kurihara S (2021) Cystine and theanine as stress-reducing amino acids-perioperative use for early recovery after surgical stress. Nutrients 14(1):129

  35. Yoshizaki S, Tamaru T, Hara M, Kijima K, Tanaka M, Konno DJ et al (2021) Microglial inflammation after chronic spinal cord injury is enhanced by reactive astrocytes via the fibronectin/β1 integrin pathway. J Neuroinflamm 18(1):12

    Article  CAS  Google Scholar 

  36. Yang Y, Liu Y, Zhu J, Song S, Huang Y, Zhang W et al (2022) Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction. Free Radic Biol Med 178:134–146

    Article  CAS  PubMed  Google Scholar 

  37. Sido B, Teklote JR, Hartel M, Friess H, Büchler MW (2004) Inflammatory response after abdominal surgery. Best Pract Res Clin Anaesthesiol 18(3):439–454

    Article  CAS  PubMed  Google Scholar 

  38. Lobo DN, Gianotti L, Adiamah A, Barazzoni R, Deutz NEP, Dhatariya K et al (2020) Perioperative nutrition: recommendations from the ESPEN expert group. Clin Nutr 39(11):3211–3227

    Article  CAS  PubMed  Google Scholar 

  39. Hu J, Deng F, Zhao B, Lin Z, Sun Q, Yang X et al (2022) Lactobacillus murinus alleviate intestinal ischemia/reperfusion injury through promoting the release of interleukin-10 from M2 macrophages via toll-like receptor 2 signaling. Microbiome 10(1):38

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Agirman G, Yu KB, Hsiao EY (2021) Signaling inflammation across the gut-brain axis. Science 374(6571):1087–1092

    Article  CAS  PubMed  Google Scholar 

  41. Zhou Y, Ju H, Hu Y, Li T, Chen Z, Si Y et al (2023) Tregs dysfunction aggravates postoperative cognitive impairment in aged mice. J Neuroinflammation 20(1):75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Osburg B, Peiser C, Dömling D, Schomburg L, Ko YT, Voigt K, Bickel U (2002) Effect of endotoxin on expression of TNF receptors and transport of TNF-alpha at the blood-brain barrier of the rat. Am J Physiol Endocrinol Metab 283(5):E899-908

    Article  CAS  PubMed  Google Scholar 

  43. Wang P, Ba ZF, Cioffi WG, Bland KI, Chaudry IH (1998) Is gut the motor for producing hepatocellular dysfunction after trauma and hemorrhagic shock? J Surg Res 74(2):141–148

    Article  CAS  PubMed  Google Scholar 

  44. Ruan J, Wang S, Wang J (2020) Mechanism and regulation of pyroptosis-mediated in cancer cell death. Chem-Biol Interact 323:109052

    Article  CAS  PubMed  Google Scholar 

  45. Cai Y, Chai Y, Fu Y, Wang Y, Zhang Y, Zhang X et al (2021) Salidroside ameliorates Alzheimer’s disease by targeting NLRP3 inflammasome-mediated pyroptosis. Front Aging Neurosci 13:809433

    Article  CAS  PubMed  Google Scholar 

  46. Tang H, Li J, Zhou Q, Li S, Xie C, Niu L et al (2022) Vagus nerve stimulation alleviated cerebral ischemia and reperfusion injury in rats by inhibiting pyroptosis via α7 nicotinic acetylcholine receptor. Cell Death Disc 8(1):54

    Article  CAS  Google Scholar 

  47. Zhang T, Wu KY, Ma N, Wei LL, Garstka M, Zhou W, Li K (2020) The C5a/C5aR2 axis promotes renal inflammation and tissue damage. JCI Insight 5(7):e134081

  48. Bock FJ, Tait SWG (2020) Mitochondria as multifaceted regulators of cell death. Nat Rev Mol Cell Biol 21(2):85–100

    Article  CAS  PubMed  Google Scholar 

  49. Cornell J, Salinas S, Huang HY, Zhou M (2022) Microglia regulation of synaptic plasticity and learning and memory. Neural Regen Res 17(4):705–716

    Article  CAS  PubMed  Google Scholar 

  50. Guo S, Wang H, Yin Y (2022) Microglia polarization from M1 to M2 in neurodegenerative diseases. Front Aging Neurosci 14:815347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Colonna M, Butovsky O (2017) Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 35:441–468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Long Y, Li XQ, Deng J, Ye QB, Li D, Ma Y et al (2024) Modulating the polarization phenotype of microglia - a valuable strategy for central nervous system diseases. Ageing Res Rev 93:102160

    Article  PubMed  Google Scholar 

  53. Ruganzu JB, Zheng Q, Wu X, He Y, Peng X, Jin H et al (2021) TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway. Exp Neurol 336:113506

    Article  CAS  PubMed  Google Scholar 

  54. Tian Q, Tang HL, Tang YY, Zhang P, Kang X, Zou W, Tang XQ (2022) Hydrogen sulfide attenuates the cognitive dysfunction in parkinson’s disease rats via promoting hippocampal microglia M2 polarization by enhancement of hippocampal warburg effect. Oxidative Med Cell Longev 2022:2792348

  55. Loveless R, Bloomquist R, Teng Y (2021) Pyroptosis at the forefront of anticancer immunity. J Exp Clin Cancer Res: CR 40(1):264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang Z, Meng S, Cao L, Chen Y, Zuo Z, Peng S (2018) Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment. J Neuroinflammation 15(1):109

    Article  PubMed  PubMed Central  Google Scholar 

  57. Dong R, Han Y, Jiang L, Liu S, Zhang F, Peng L et al (2022) Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice. J Neuroinflammation 19(1):64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the laboratory at Zhongshan Hospital, Fudan University, for their support of our study.

Funding

This study was supported by grants from the Shanghai Municipal Key Clinical Specialty (shslczdzk03603) and the Research Program of Zhongshan Hospital, Fudan University (2021ZSCX27).

Author information

Author notes

  1. Yelong Ji and Yuanyuan Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Anaesthesia, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China

    Yelong Ji, Yuanyuan Ma, Yimei Ma, Ying Wang, Xining Zhao, Li Xu & Shengjin Ge

Authors
  1. Yelong Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuanyuan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yimei Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xining Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shengjin Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Shengjin Ge designed the overall project and supervised the study; Shengjin Ge, Yelong Ji and Yuanyuan Ma designed the experiments; Yelong Ji, Li Xu and Yimei Ma performed the in vivo experiments; Yelong Ji and Xining Zhao performed the in vitro experiments; Yelong Ji and Ying Wang performed the formal analysis; and Yelong Ji and Yuanyuan Ma wrote the paper with input from the other authors; Shengjin Ge reviewed and supervised the paper. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Shengjin Ge.

Ethics declarations

Ethics Approval and Consent to Participate

All animal procedures were conducted in accordance with the Guidelines for Care and Use of Laboratory Animals of Fudan University, and all efforts were made to minimize animal suffering. The study protocol was approved by the Ethics Committee of the Affiliated Zhongshan Hospital, Fudan University (approval: 202106021 S).

Consent for Publication

Not applicable.

Competing Interests

The authors declare that there are no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

ESM 1

(DOCX 1.34 MB)

ESM 2

(DOCX 76.0 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, Y., Ma, Y., Ma, Y. et al. An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04209-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04209-1

Keywords

Search

Navigation