Skip to main content
SpringerLink
Log in

Temporin-GHaR Peptide Alleviates LPS-Induced Cognitive Impairment and Microglial Activation by Modulating Endoplasmic Reticulum Stress

  • Research
  • Published:
Probiotics and Antimicrobial Proteins Aims and scope Submit manuscript

Abstract

Neuroinflammation is considered an important factor that leads to cognitive impairment. Microglia play a crucial role in neuroinflammation, which leads to cognitive impairment. This study aimed at determining whether temporin-GHaR peptide (GHaR) could improve cognitive function and at uncovering the underlying mechanisms. We found that GHaR treatment alleviated LPS-induced cognitive impairment and inhibited activation of microglia in LPS-induced mice. Furthermore, GHaR inhibited activation of endoplasmic reticulum stress (ERS) and the NF-κB signaling pathway in LPS-induced mice. In vitro, GHaR inhibited M1 polarization of BV2 cells and suppressed TNF-α and IL-6 secretion. Additionally, GHaR neuronal cell viability and apoptosis were induced by LPS-activated microglia-conditioned medium. Moreover, in LPS-induced BV2 cells, GHaR inhibited activation of ERS and the NF-κB signaling pathway. In summary, GHaR improved LPS-induced cognitive and attenuated inflammatory responses via microglial activation reversal. In conclusion, the neuroprotective effects of GHaR were mediated via the ERS signaling pathway.

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

Data will be made available on request.

References

  1. Leng F, Edison P (2021) Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here? Nat Rev Neurol 17(3):157–172. https://doi.org/10.1038/s41582-020-00435-y

    Article  PubMed  Google Scholar 

  2. Wang T, Shi C, Luo H, Zheng H, Fan L, Tang M, Su Y, Yang J, Mao C, Xu Y (2022) Neuroinflammation in Parkinson’s Disease: Triggers, Mechanisms, and Immunotherapies. Neuroscientist 28(4):364–381. https://doi.org/10.1177/1073858421991066

    Article  CAS  PubMed  Google Scholar 

  3. Krukowski K, Nolan A, Becker M, Picard K, Vernoux N, Frias ES, Feng X, Tremblay ME, Rosi S (2021) Novel microglia-mediated mechanisms underlying synaptic loss and cognitive impairment after traumatic brain injury. Brain Behav Immun 98:122–135. https://doi.org/10.1016/j.bbi.2021.08.210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C, Godbout JP (2021) Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. J Neurosci 41(7):1597–1616. https://doi.org/10.1523/JNEUROSCI.2469-20.2020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Woodburn SC, Bollinger JL, Wohleb ES (2021) The semantics of microglia activation: neuroinflammation, homeostasis, and stress. J Neuroinflammation 18(1):258. https://doi.org/10.1186/s12974-021-02309-6

    Article  PubMed  PubMed Central  Google Scholar 

  6. Inta D, Lang UE, Borgwardt S, Meyer-Lindenberg A, Gass P (2017) Microglia Activation and Schizophrenia: Lessons From the Effects of Minocycline on Postnatal Neurogenesis, Neuronal Survival and Synaptic Pruning. Schizophr Bull 43(3):493–496. https://doi.org/10.1093/schbul/sbw088

    Article  PubMed  Google Scholar 

  7. Kwon HS, Koh SH (2020) Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener 9(1):42. https://doi.org/10.1186/s40035-020-00221-2

    Article  PubMed  PubMed Central  Google Scholar 

  8. He Y, Gao Y, Zhang Q, Zhou G, Cao F, Yao S (2020) IL-4 Switches Microglia/macrophage M1/M2 Polarization and Alleviates Neurological Damage by Modulating the JAK1/STAT6 Pathway Following ICH. Neuroscience 437:161–171. https://doi.org/10.1016/j.neuroscience.2020.03.008

    Article  CAS  PubMed  Google Scholar 

  9. Li L, Gan H, Jin H, Fang Y, Yang Y, Zhang J, Hu X, Chu L (2021) Astragaloside IV promotes microglia/macrophages M2 polarization and enhances neurogenesis and angiogenesis through PPARγ pathway after cerebral ischemia/reperfusion injury in rats. Int Immunopharmacol 92:107335. https://doi.org/10.1016/j.intimp.2020.107335

    Article  CAS  PubMed  Google Scholar 

  10. Kardani K, Bolhassani A (2021) Antimicrobial/anticancer peptides: bioactive molecules and therapeutic agents. Immunotherapy 13(8):669–684. https://doi.org/10.2217/imt-2020-0312

    Article  CAS  PubMed  Google Scholar 

  11. Zeng ZZ, Huang SH, Alezra V, Wan Y (2021) Antimicrobial peptides: triumphs and challenges. Future Med Chem 13(16):1313–1315. https://doi.org/10.4155/fmc-2021-0134

    Article  CAS  PubMed  Google Scholar 

  12. He X, Yang S, Wei L, Liu R, Lai R, Rong M (2013) Antimicrobial peptide diversity in the skin of the torrent frog. Amolops jingdongensis Amino Acids 44(2):481–487. https://doi.org/10.1007/s00726-012-1358-z

    Article  CAS  PubMed  Google Scholar 

  13. Kaneider NC, Djanani A, Wiedermann CJ (2007) Heparan sulfate proteoglycan-involving immunomodulation by cathelicidin antimicrobial peptides LL-37 and PR-39. ScientificWorldJournal 7:1832–1838. https://doi.org/10.1100/tsw.2007.285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mohammed ESI, Radey R (2021) Immunomodulation of Antimicrobial Peptides Expression in the Gastrointestinal Tract by Probiotics in Response to Stimulation by Salmonella minnesota Lipopolysaccharides. Probiotics Antimicrob Proteins 13(4):1157–1172. https://doi.org/10.1007/s12602-021-09746-y

    Article  CAS  PubMed  Google Scholar 

  15. Dong Z, Luo W, Zhong H, Wang M, Song Y, Deng S, Zhang Y (2017) Molecular cloning and characterization of antimicrobial peptides from skin of Hylarana guentheri. Acta Biochim Biophys Sin (Shanghai) 49(5):450–457. https://doi.org/10.1093/abbs/gmx023

    Article  CAS  PubMed  Google Scholar 

  16. Wei H, Xie Z, Tan X, Guo R, Song Y, Xie X, Wang R, Li L, Wang M, Zhang Y (2020) Temporin-Like Peptides Show Antimicrobial and Anti-Biofilm Activities against Streptococcus mutans with Reduced Hemolysis. Molecules. https://doi.org/10.3390/molecules25235724

    Article  PubMed  PubMed Central  Google Scholar 

  17. Zhang F, Zhang JG, Yang W, Xu P, Xiao YL, Zhang HT (2018) 6-Gingerol attenuates LPS-induced neuroinflammation and cognitive impairment partially via suppressing astrocyte overactivation. Biomed Pharmacother 107:1523–1529. https://doi.org/10.1016/j.biopha.2018.08.136

    Article  CAS  PubMed  Google Scholar 

  18. Kim J, Lee HJ, Park JH, Cha BY, Hoe HS (2022) Nilotinib modulates LPS-induced cognitive impairment and neuroinflammatory responses by regulating P38/STAT3 signaling. J Neuroinflammation 19(1):187. https://doi.org/10.1186/s12974-022-02549-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Heinbockel L, Weindl G, Martinez-de-Tejada G, Correa W, Sanchez-Gomez S, Bárcena-Varela S, Goldmann T, Garidel P, Gutsmann T, Brandenburg K (2018) Inhibition of Lipopolysaccharide- and Lipoprotein-Induced Inflammation by Antitoxin Peptide Pep19–2.5. Front Immunol 9:1704. https://doi.org/10.3389/fimmu.2018.01704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Sousa NA, Oliveira GAL, de Oliveira AP, Lopes ALF, Iles B, Nogueira KM, Araújo TSL, Souza LKM, Araújo AR, Ramos-Jesus J, Plácido A, Amaral C, Campelo YDM, Barbosa EA, Portugal CC, Socodato R, Lobo A, Relvas J, Bemquerer M, Eaton P, Leite J, Medeiros JVR (2020) Novel Ocellatin Peptides Mitigate LPS-induced ROS Formation and NF-kB Activation in Microglia and Hippocampal Neurons. Sci Rep 10(1):2696. https://doi.org/10.1038/s41598-020-59665-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shang D, Liang H, Wei S, Yan X, Yang Q, Sun Y (2014) Effects of antimicrobial peptide L-K6, a temporin-1CEb analog on oral pathogen growth, Streptococcus mutans biofilm formation, and anti-inflammatory activity. Appl Microbiol Biotechnol 98(20):8685–8695. https://doi.org/10.1007/s00253-014-5927-9

    Article  CAS  PubMed  Google Scholar 

  22. Qin C, Fan WH, Liu Q, Shang K, Murugan M, Wu LJ, Wang W, Tian DS (2017) Fingolimod Protects Against Ischemic White Matter Damage by Modulating Microglia Toward M2 Polarization via STAT3 Pathway. Stroke 48(12):3336–3346. https://doi.org/10.1161/STROKEAHA.117.018505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Luo G, Wang X, Cui Y, Cao Y, Zhao Z, Zhang J (2021) Metabolic reprogramming mediates hippocampal microglial M1 polarization in response to surgical trauma causing perioperative neurocognitive disorders. J Neuroinflammation 18(1):267. https://doi.org/10.1186/s12974-021-02318-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13(8):477–491. https://doi.org/10.1038/nrneurol.2017.99

    Article  CAS  PubMed  Google Scholar 

  25. Haile Y, Deng X, Ortiz-Sandoval C, Tahbaz N, Janowicz A, Lu JQ, Kerr BJ, Gutowski NJ, Holley JE, Eggleton P, Giuliani F, Simmen T (2017) Rab32 connects ER stress to mitochondrial defects in multiple sclerosis. J Neuroinflammation 14(1):19. https://doi.org/10.1186/s12974-016-0788-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Markovinovic A, Greig J, Martín-Guerrero SM, Salam S, Paillusson S (2022) Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases. J Cell Sci. https://doi.org/10.1242/jcs.248534

    Article  PubMed  Google Scholar 

  27. Di Conza G, Ho PC (2020) ER Stress Responses: An Emerging Modulator for Innate Immunity. Cells. https://doi.org/10.3390/cells9030695

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wu Chuang A, Kepp O, Kroemer G, Bezu L (2020) Endoplasmic reticulum stress in the cellular release of damage-associated molecular patterns. Int Rev Cell Mol Biol 350:1–28. https://doi.org/10.1016/bs.ircmb.2019.11.006

    Article  CAS  PubMed  Google Scholar 

  29. Wang YW, Zhou Q, Zhang X, Qian QQ, Xu JW, Ni PF, Qian YN (2020) Correction to: Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. J Neuroinflammation 17(1):353. https://doi.org/10.1186/s12974-020-01990-3

    Article  PubMed  PubMed Central  Google Scholar 

  30. Ismael S, Wajidunnisa SK, McDonald MP, Liao FF, Ishrat T (2021) ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer’s disease. Neurochem Int 148:105104. https://doi.org/10.1016/j.neuint.2021.105104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hosoi T, Ozawa K (2012) Molecular approaches to the treatment, prophylaxis, and diagnosis of Alzheimer’s disease: endoplasmic reticulum stress and immunological stress in pathogenesis of Alzheimer’s disease. J Pharmacol Sci 118(3):319–324. https://doi.org/10.1254/jphs.11r09fm

    Article  CAS  PubMed  Google Scholar 

  32. Wang J, Ding Y, Zhuang L, Wang Z, Xiao W, Zhu J (2021) Ginkgolide B-induced AMPK pathway activation protects astrocytes by regulating endoplasmic reticulum stress, oxidative stress and energy metabolism induced by Aβ1-42. Mol Med Rep. https://doi.org/10.3892/mmr.2021.12096

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by grants from the National Natural Science Foundation of China (82104129 to R.W. and 82260250 to DQ.Z.), the Hainan provincial natural science foundation of China (322RC584 to R.W., 820MS140 to DQ.Z.), the Hainan Province Science and Technology Special Fund, Key Research and Development Project of Hainan Province (ZDYF2022SHFZ294 to DQ.Z. and ZDYF2021SHFZ042 to YX.Z.), the Project supported by Hainan Province Clinical Medical Center, and the Foundation of Collaborative Innovation Center of One Health of Hainan University (XTCX2022JKB05 to YX.Z.).

Author information

Authors and Affiliations

  1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Collaborative Innovation Center of One Health, Hainan University, Haikou, 570228, China

    Da-Qi Zhang, Xiaoqian Dong, Simin Su, Linlin Zhang, Jiayu Zhang, Wenjing Yang, Wenting Hu, Lushuang Li, Yanting Song, Xi Xie, Rong Wang & Yingxia Zhang

  2. Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, China

    Da-Qi Zhang & Qifu Li

  3. Key Laboratory of Brain Science Research &Transformation in Tropical Environment of Hainan Province, Haikou, 571199, China

    Da-Qi Zhang & Qifu Li

Authors
  1. Da-Qi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoqian Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simin Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Linlin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiayu Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenjing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wenting Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lushuang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanting Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xi Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qifu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yingxia Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Da-Qi Zhang: Performed the experiments; Analyzed and interpreted the data; Wrote the paper. Xiaoqian Dong, Simin Su, Linlin Zhang，Jiayu Zhang and Wenjing Yang: Performed the experiments; Analyzed and interpreted the data. Wenting Hu, Lushuang Li , Yanting Song, Xi Xie and Qifu Li: Analyzed and interpreted the data ; review & editing the paper. Rong Wang, Yingxia Zhang: Conceived and designed the experiments.All authors reviewed the manuscript.

Corresponding authors

Correspondence to Rong Wang or Yingxia Zhang.

Ethics declarations

Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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.

Supplementary file1 (TIF 898 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

Zhang, DQ., Dong, X., Su, S. et al. Temporin-GHaR Peptide Alleviates LPS-Induced Cognitive Impairment and Microglial Activation by Modulating Endoplasmic Reticulum Stress. Probiotics & Antimicro. Prot. (2024). https://doi.org/10.1007/s12602-024-10277-5

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12602-024-10277-5

Keywords

Search

Navigation