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Planta Med 2023; 89(15): 1468-1482
DOI: 10.1055/a-2148-7427
Biological and Pharmacological Activity
Original Papers

Acetyl-11-Keto-Beta-Boswellic Acid Activates the Nrf2/HO-1 Signaling Pathway in Schwann Cells to Reduce Oxidative Stress and Promote Sciatic Nerve Injury Repair

Chong Zhou
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Yao Wang
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Qiyuan Zhang
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Guanghu Zhou
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Xianglin Ma
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Xiaowen Jiang
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
,
Wenhui Yu
1   Department of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
2   Key Laboratory of Heilongjiang Education Department for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, Heilongjiang Province, China
3   Institute of Chinese Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang Province, China
› Author AffiliationsThis work was supported by the National Natural Science Foundation of China [No. 31 972 725 (to W. H. Y.)].
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Abstract

Boswellia is a traditional medicine for bruises and injuries. Its main active ingredient, acetyl-11-keto-beta-boswellic acid, has antioxidant and antiapoptotic effects. In this experiment, we used Sprague-Dawley rats to make a sciatic nerve injury model to detect the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway and apoptosis, combined with clinical indicators, for testing whether acetyl-11-keto-beta-boswellic acid can reduce oxidative stress and promote sciatic nerve repair. Our results showed that acetyl-11-keto-beta-boswellic acid administration promoted myelin regeneration and functional recovery in the rat sciatic nerve, reduced lipid peroxidation levels, upregulated the expression of various antioxidant enzymes and enhanced enzyme activity, decreased the expression levels of apoptosis-related proteins, and promoted nuclear translocation of the transcription factor NF-E2-related factor 2 protein. In vitro studies revealed that acetyl-11-keto-beta-boswellic acid reduced H2O2-induced reactive oxygen species production, restored mitochondrial membrane potential, upregulated the expression of various antioxidant enzymes, and downregulated apoptosis-related indicators in Schwann cells, and these therapeutic effects of acetyl-11-keto-beta-boswellic acid were reversed after ML385 treatment in Schwann cells. In summary, acetyl-11-keto-beta-boswellic acid alleviates oxidative stress and apoptosis caused by sciatic nerve injury in rats by activating the transcription factor NF-E2-related factor 2/heme oxygenase 1 signaling pathway, promotes the recovery of sciatic nerve function in rats, and is a promising therapeutic agent to promote sciatic nerve repair by alleviating excessive oxidative stress.

Key words

Boswellia serrata Roxb - Burseraceae - acetyl-11-keto-beta-boswellic acid - sciatic nerve injury - oxidative stress


Publication History

Received: 28 March 2023

Accepted after revision: 04 August 2023

Accepted Manuscript online:
04 August 2023

Article published online:
23 August 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
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  • References

  • 1 Gaudet A, Popovich P, Ramer M. Wallerian degeneration: Gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 2011; 8: 110
    CrossrefPubMedGoogle Scholar
  • 2 Arthur-Farraj P, Latouche M, Wilton D, Quintes S, Chabrol E, Banerjee A, Woodhoo A, Jenkins B, Rahman M, Turmaine M, Wicher G, Mitter R, Greensmith L, Behrens A, Raivich G, Mirsky R, Jessen K. c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration. Neuron 2012; 75: 633-647
    CrossrefPubMedGoogle Scholar
  • 3 Büttner R, Schulz A, Reuter M, Akula A, Mindos T, Carlstedt A, Riecken L, Baader S, Bauer R, Morrison H. Inflammaging impairs peripheral nerve maintenance and regeneration. Aging Cell 2018; 17: e12833
    CrossrefPubMedGoogle Scholar
  • 4 Faroni A, Mobasseri S, Kingham P, Reid A. Peripheral nerve regeneration: Experimental strategies and future perspectives. Adv Drug Deliv Rev 2015; 82 – 83: 160-167
    CrossrefPubMedGoogle Scholar
  • 5 Kong L, Gao X, Qian Y, Sun W, You Z, Fan C. Biomechanical microenvironment in peripheral nerve regeneration: From pathophysiological understanding to tissue engineering development. Theranostics 2022; 12: 4993-5014
    CrossrefPubMedGoogle Scholar
  • 6 Li W, Ren L, Zheng X, Liu J, Wang J, Ji T, Du G. 3-O-Acetyl-11-keto- β -boswellic acid ameliorated aberrant metabolic landscape and inhibited autophagy in glioblastoma. Acta Pharm Sin B 2020; 10: 301-312
    CrossrefPubMedGoogle Scholar
  • 7 Gong Y, Jiang X, Yang S, Huang Y, Hong J, Ma Y, Fang X, Fang Y, Wu J. The biological activity of 3-O-Acetyl-11-keto-β-boswellic acid in nervous system diseases. Neuromolecular Med 2022; 24: 374-384
    CrossrefPubMedGoogle Scholar
  • 8 Wei C, Fan J, Sun X, Yao J, Guo Y, Zhou B, Shang Y. Acetyl-11-keto-β-boswellic acid ameliorates cognitive deficits and reduces amyloid-β levels in APPswe/PS1dE9 mice through antioxidant and anti-inflammatory pathways. Free Radic Biol Med 2020; 150: 96-108
    CrossrefPubMedGoogle Scholar
  • 9 Banji D, Banji OJF, Rashida S, Alshahrani S, Alqahtani SS. Bioavailability, anti-inflammatory and anti-arthritic effect of Acetyl Keto Boswellic acid and its combination with methotrexate in an arthritic animal model. J Ethnopharmacol 2022; 292: 115200
    CrossrefPubMedGoogle Scholar
  • 10 Barakat BM, Ahmed HI, Bahr HI, Elbahaie AM. Protective effect of Boswellic Acids against doxorubicin-induced hepatotoxicity: Impact on Nrf2/HO-1 defense pathway. Oxid Med Cell Longev 2018; 2018: 8296451
    CrossrefPubMedGoogle Scholar
  • 11 Wagstaff LJ, Gomez-Sanchez JA, Fazal SV, Otto GW, Kilpatrick AM, Michael K, Wong LYN, Ma KH, Turmaine M, Svaren J, Gordon T, Arthur-Farraj P, Velasco-Aviles S, Cabedo H, Benito C, Mirsky R, Jessen KR. Failures of nerve regeneration caused by aging or chronic denervation are rescued by restoring Schwann cell c-Jun. Elife 2021; 10: e62232
    CrossrefPubMedGoogle Scholar
  • 12 Dong L, Li R, Li D, Wang B, Lu Y, Li P, Yu F, Jin Y, Ni X, Wu Y, Yang S, Lv G, Li X, Xiao J, Wang J. FGF10 enhances peripheral nerve regeneration via the preactivation of the PI3K/Akt signaling-mediated antioxidant response. Front Pharmacol 2019; 10: 1224
    CrossrefPubMedGoogle Scholar
  • 13 Cattin A, Burden J, Van Emmenis L, Mackenzie F, Hoving J, Garcia Calavia N, Guo Y, McLaughlin M, Rosenberg L, Quereda V, Jamecna D, Napoli I, Parrinello S, Enver T, Ruhrberg C, Lloyd A. Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves. Cell 2015; 162: 1127-1139
    CrossrefPubMedGoogle Scholar
  • 14 Ma J, Liu J, Wang Q, Yu H, Chen Y, Xiang L. The beneficial effect of ginsenoside Rg1 on Schwann cells subjected to hydrogen peroxide induced oxidative injury. Int J Biol Sci 2013; 9: 624-636
    CrossrefPubMedGoogle Scholar
  • 15 Martin L, Kaiser A, Price A. Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. J Neurobiol 1999; 40: 185-201
    CrossrefPubMedGoogle Scholar
  • 16 Caillaud M, Chantemargue B, Richard L, Vignaud L, Favreau F, Faye PA, Vignoles P, Sturtz F, Trouillas P, Vallat JM, Desmoulière A, Billet F. Local low dose curcumin treatment improves functional recovery and remyelination in a rat model of sciatic nerve crush through inhibition of oxidative stress. Neuropharmacology 2018; 139: 98-116
    CrossrefPubMedGoogle Scholar
  • 17 Areti A, Komirishetty P, Akuthota M, Malik RA, Kumar A. Melatonin prevents mitochondrial dysfunction and promotes neuroprotection by inducing autophagy during oxaliplatin-evoked peripheral neuropathy. J Pineal Res 2017; DOI: 10.1111/jpi.12393.
    CrossrefPubMedGoogle Scholar
  • 18 Bao Q, Shi Y. Apoptosome: A platform for the activation of initiator caspases. Cell Death Differ 2007; 14: 56-65
    CrossrefPubMedGoogle Scholar
  • 19 Ow YP, Green DR, Hao Z, Mak TW. Cytochrome C: Functions beyond respiration. Nat Rev Mol Cell Biol 2008; 9: 532-542
    CrossrefPubMedGoogle Scholar
  • 20 Crisman E, Duarte P, Dauden E, Cuadrado A, Rodríguez-Franco MI, López MG, León R. KEAP1-NRF2 protein-protein interaction inhibitors: Design, pharmacological properties and therapeutic potential. Med Res Rev 2023; 43: 237-287
    CrossrefPubMedGoogle Scholar
  • 21 Lee DH, Park JS, Lee YS, Han J, Lee DK, Kwon SW, Han DH, Lee YH, Bae SH. SQSTM1/p 62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity. Autophagy 2020; 16: 1949-1973
    CrossrefPubMedGoogle Scholar
  • 22 Huang W, Yu L, Cai W, Ma C. Resveratrol protects BEAS-2B cells against Erastin-Induced Ferroptosis through the Nrf2/Keap1 pathway. Planta Med 2022; 89: 408-415
    PubMedGoogle Scholar
  • 23 Dai C, Xiao X, Zhang Y, Xiang B, Hoyer D, Shen J, Velkov T, Tang S. Curcumin attenuates colistin-induced peripheral neurotoxicity in mice. ACS Infect Dis 2020; 6: 715-724
    CrossrefPubMedGoogle Scholar
  • 24 Li J, Yao Y, Wang Y, Xu J, Zhao D, Liu M, Shi S, Lin Y. Modulation of the crosstalk between Schwann cells and macrophages for nerve regeneration: A therapeutic strategy based on a multifunctional tetrahedral framework nucleic acids system. Adv Mater 2022; 34: e2202513
    CrossrefPubMedGoogle Scholar
  • 25 Jiang XW, Zhang BQ, Qiao L, Liu L, Wang XW, Yu WH. Acetyl-11-keto-β-boswellic acid extracted from Boswellia serrata promotes Schwann cell proliferation and sciatic nerve function recovery. Neural Regen Res 2018; 13: 484-491
    CrossrefPubMedGoogle Scholar
  • 26 Wang Y, Xiong Z, Ma X, Zhou C, Huo M, Jiang X, Yu WH. Acetyl-11-keto-beta-boswellic acid promotes sciatic nerve repair after injury: Molecular mechanism. Neural Regen Res 2022; 17: 2778-2784
    CrossrefPubMedGoogle Scholar
  • 27 Hichor M, Sundaram V, Eid S, Abdel-Rassoul R, Petit P, Borderie D, Bastin J, Eid A, Manuel M, Grenier J, Massaad C. Liver X Receptor exerts a protective effect against the oxidative stress in the peripheral nerve. Sci Rep 2018; 8: 2524
    CrossrefPubMedGoogle Scholar
  • 28 Fischer L, Li Y, Asress S, Jones D, Glass J. Absence of SOD1 leads to oxidative stress in peripheral nerve and causes a progressive distal motor axonopathy. Exp Neurol 2012; 233: 163-171
    CrossrefPubMedGoogle Scholar
  • 29 Flynn JM, Melov S. SOD2 in mitochondrial dysfunction and neurodegeneration. Free Radic Biol Med 2013; 62: 4-12
    CrossrefPubMedGoogle Scholar
  • 30 Sarutipaiboon I, Settasatian N, Komanasin N, Kukongwiriyapan U, Sawanyawisuth K, Intharaphet P, Senthong V, Settasatian C. Association of genetic variations in NRF2, NQO1, HMOX1, and MT with severity of coronary artery disease and related risk factors. Cardiovasc Toxicol 2020; 20: 176-189
    CrossrefPubMedGoogle Scholar