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image of Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury

Abstract

Background

Plasmalogens, the primary phospholipids in the brain, possess intrinsic antioxidant properties and are crucial components of the myelin sheath surrounding neuronal axons. While their neuroprotective effects have been demonstrated in Alzheimer's disease, their potential benefits in spinal cord injury remain unexplored. This study investigates the reparative effects of plasmalogens on spinal cord injury and the underlying mechanisms.

Methods

, we developed dorsal root ganglion (DRG) and RAW 264.7 cell models under high-reactive oxygen species (ROS) conditions to assess ROS levels, neuronal damage, and inflammatory microenvironment changes before and after plasmalogen application. , we used a complete mouse spinal cord transection model to evaluate changes in ROS levels, neuronal demyelination, and apoptosis following plasmalogen treatment. Additionally, we assessed sensory and motor function recovery and investigated the regulatory effects of plasmalogens on the AKT/mTOR signaling pathway.

Results

In high-ROS cell models, plasmalogens protected DRG neurons (TUJ-1) from axonal damage and modulated the proinflammatory/anti-inflammatory balance in RAW 264.7 cells. , plasmalogens significantly reduced ROS levels, improved the immune microenvironment, decreased the proinflammatory (iNOS)/anti-inflammatory (ARG-1) ratio, lowered neuronal (TUJ-1) apoptosis (Caspase-3, BAX), and reduced axonal degeneration while promoting myelin (MBP) regeneration, indicating a neuroprotective effect. These findings are linked to the activation of the AKT/mTOR signaling pathway.

Conclusion

Plasmalogens reduce ROS levels and regulate inflammation-induced damage, contributing to neuroprotection. This study reveals that plasmalogens promote remyelination, reduce axonal degeneration and neuronal apoptosis, and—used here for the first time in spinal cord injury repair—may protect neurons by reducing ROS levels and activating the AKT/mTOR signaling pathway.

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2025-01-20
2025-09-13

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References

  1. Assinck P. Duncan G.J. Hilton B.J. Plemel J.R. Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat. Neurosci. 2017 20 5 637 647 10.1038/nn.4541 28440805
    [Google Scholar]
  2. Hu X. Xu W. Ren Y. Wang Z. He X. Huang R. Ma B. Zhao J. Zhu R. Cheng L. Spinal cord injury: Molecular mechanisms and therapeutic interventions. Signal Transduct. Target. Ther. 2023 8 1 245 10.1038/s41392‑023‑01477‑6 37357239
    [Google Scholar]
  3. Yin Z. Wan B. Gong G. Yin J. ROS: Executioner of regulating cell death in spinal cord injury. Front. Immunol. 2024 15 1330678 10.3389/fimmu.2024.1330678 38322262
    [Google Scholar]
  4. Ying Y. Huang Z. Tu Y. Wu Q. Li Z. Zhang Y. Yu H. Zeng A. Huang H. Ye J. Ying W. Chen M. Feng Z. Xiang Z. Ye Q. Zhu S. Wang Z. A shear-thinning, ROS-scavenging hydrogel combined with dental pulp stem cells promotes spinal cord repair by inhibiting ferroptosis. Bioact. Mater. 2023 22 274 290 10.1016/j.bioactmat.2022.09.019 36263097
    [Google Scholar]
  5. Zhang Y. Yang X. Ge X. Zhang F. Puerarin attenuates neurological deficits via Bcl-2/Bax/cleaved caspase-3 and Sirt3/SOD2 apoptotic pathways in subarachnoid hemorrhage mice. Biomed. Pharmacother. 2019 109 726 733 10.1016/j.biopha.2018.10.161 30551525
    [Google Scholar]
  6. Liu C. Hu F. Jiao G. Guo Y. Zhou P. Zhang Y. Zhang Z. Yi J. You Y. Li Z. Wang H. Zhang X. Dental pulp stem cell-derived exosomes suppress M1 macrophage polarization through the ROS-MAPK-NFκB P65 signaling pathway after spinal cord injury. J. Nanobiotechnology 2022 20 1 65 10.1186/s12951‑022‑01273‑4 35109874
    [Google Scholar]
  7. Freyermuth-Trujillo X. Segura-Uribe J.J. Salgado-Ceballos H. Orozco-Barrios C.E. Coyoy-Salgado A. Inflammation: A target for treatment in spinal cord injury. Cells 2022 11 17 2692 10.3390/cells11172692 36078099
    [Google Scholar]
  8. Paul S. Lancaster G.I. Meikle P.J. Plasmalogens: A potential therapeutic target for neurodegenerative and cardiometabolic disease. Prog. Lipid Res. 2019 74 186 195 10.1016/j.plipres.2019.04.003 30974122
    [Google Scholar]
  9. Leßig J. Fuchs B. Plasmalogens in biological systems: Their role in oxidative processes in biological membranes, their contribution to pathological processes and aging and plasmalogen analysis. Curr. Med. Chem. 2009 16 16 2021 2041 10.2174/092986709788682164 19519379
    [Google Scholar]
  10. Hossain M.S. Mawatari S. Fujino T. Plasmalogens, the vinyl ether-linked glycerophospholipids, enhance learning and memory by regulating brain-derived neurotrophic factor. Front. Cell Dev. Biol. 2022 10 828282 10.3389/fcell.2022.828282 35223852
    [Google Scholar]
  11. Youssef M. Ibrahim A. Akashi K. Hossain M.S. PUFA-plasmalogens attenuate the lps-induced nitric oxide production by inhibiting the NF-kB, p38 MAPK and JNK pathways in microglial cells. Neuroscience 2019 397 18 30 10.1016/j.neuroscience.2018.11.030 30496826
    [Google Scholar]
  12. Che H. Zhang L. Ding L. Xie W. Jiang X. Xue C. Zhang T. Wang Y. EPA-enriched ethanolamine plasmalogen and EPA-enriched phosphatidylethanolamine enhance BDNF/TrkB/CREB signaling and inhibit neuronal apoptosis in vitro and in vivo. Food Funct. 2020 11 2 1729 1739 10.1039/C9FO02323B 32043504
    [Google Scholar]
  13. Fujino T. Yamada T. Asada T. Tsuboi Y. Wakana C. Mawatari S. Kono S. Efficacy and Blood plasmalogen changes by oral administration of plasmalogen in patients with mild alzheimer’s disease and mild cognitive impairment: A multicenter, randomized, double-blind, placebo-controlled trial. EBioMedicine 2017 17 199 205 10.1016/j.ebiom.2017.02.012 28259590
    [Google Scholar]
  14. Xu B. Yin M. Yang Y. Zou Y. Liu W. Qiao L. Zhang J. Wang Z. Wu Y. Shen H. Sun M. Liu W. Xue W. Fan Y. Zhang Q. Chen B. Wu X. Shi Y. Lu F. Zhao Y. Xiao Z. Dai J. Transplantation of neural stem progenitor cells from different sources for severe spinal cord injury repair in rat. Bioact. Mater. 2023 23 300 313 10.1016/j.bioactmat.2022.11.008 36439085
    [Google Scholar]
  15. Xiong X.Y. Liu L. Yang Q.W. Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog. Neurobiol. 2016 142 23 44 10.1016/j.pneurobio.2016.05.001 27166859
    [Google Scholar]
  16. Li L. Jiang W. Yu B. Liang H. Mao S. Hu X. Feng Y. Xu J. Chu L. Quercetin improves cerebral ischemia/reperfusion injury by promoting microglia/macrophages M2 polarization via regulating PI3K/Akt/NF-κB signaling pathway. Biomed. Pharmacother. 2023 168 115653 10.1016/j.biopha.2023.115653 37812891
    [Google Scholar]
  17. Wang D. Liu F. Zhu L. Lin P. Han F. Wang X. Tan X. Lin L. Xiong Y. FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages. J. Neuroinflammation 2020 17 1 257 10.1186/s12974‑020‑01921‑2 32867781
    [Google Scholar]
  18. Tremblay M.È. Almsherqi Z.A. Deng Y. Plasmalogens and platelet‐activating factor roles in chronic inflammatory diseases. Biofactors 2022 48 6 1203 1216 10.1002/biof.1916 36370412
    [Google Scholar]
  19. Deng S. Dai G. Chen S. Nie Z. Zhou J. Fang H. Peng H. Dexamethasone induces osteoblast apoptosis through ROS-PI3K/AKT/GSK3β signaling pathway. Biomed. Pharmacother. 2019 110 602 608 10.1016/j.biopha.2018.11.103 30537677
    [Google Scholar]
  20. Li K. Deng Y. Deng G. Chen P. Wang Y. Wu H. Ji Z. Yao Z. Zhang X. Yu B. Zhang K. High cholesterol induces apoptosis and autophagy through the ROS-activated AKT/FOXO1 pathway in tendon-derived stem cells. Stem Cell Res. Ther. 2020 11 1 131 10.1186/s13287‑020‑01643‑5 32197645
    [Google Scholar]
  21. Wu L.K. Agarwal S. Kuo C.H. Kung Y.L. Day C.H. Lin P.Y. Lin S.Z. Hsieh D.J.Y. Huang C.Y. Chiang C.Y. Artemisia Leaf Extract protects against neuron toxicity by TRPML1 activation and promoting autophagy/mitophagy clearance in both in vitro and in vivo models of MPP+/MPTP-induced Parkinson’s disease. Phytomedicine 2022 104 154250 10.1016/j.phymed.2022.154250 35752074
    [Google Scholar]
  22. da Silva T.F. Eira J. Lopes A.T. Malheiro A.R. Sousa V. Luoma A. Avila R.L. Wanders R.J.A. Just W.W. Kirschner D.A. Sousa M.M. Brites P. Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination. J. Clin. Invest. 2014 124 6 2560 2570 10.1172/JCI72063 24762439
    [Google Scholar]
  23. Ferreira da Silva T. Granadeiro L.S. Bessa-Neto D. Luz L.L. Safronov B.V. Brites P. Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment. Prog. Neurobiol. 2021 205 102123 10.1016/j.pneurobio.2021.102123 34302896
    [Google Scholar]
  24. Hossain M.S. Ifuku M. Take S. Kawamura J. Miake K. Katafuchi T. Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling. PLoS One 2013 8 12 e83508 10.1371/journal.pone.0083508 24376709
    [Google Scholar]
  25. Yu L. Wei J. Liu P. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer. Semin. Cancer Biol. 2022 85 69 94 10.1016/j.semcancer.2021.06.019 34175443
    [Google Scholar]
  26. Glaviano A. Foo A.S.C. Lam H.Y. Yap K.C.H. Jacot W. Jones R.H. Eng H. Nair M.G. Makvandi P. Geoerger B. Kulke M.H. Baird R.D. Prabhu J.S. Carbone D. Pecoraro C. Teh D.B.L. Sethi G. Cavalieri V. Lin K.H. Javidi-Sharifi N.R. Toska E. Davids M.S. Brown J.R. Diana P. Stebbing J. Fruman D.A. Kumar A.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer 2023 22 1 138 10.1186/s12943‑023‑01827‑6 37596643
    [Google Scholar]
  27. Huang Y. Zhou J. Luo S. Wang Y. He J. Luo P. Chen Z. Liu T. Tan X. Ou J. Miao H. Liang H. Shi C. Identification of a fluorescent small-molecule enhancer for therapeutic autophagy in colorectal cancer by targeting mitochondrial protein translocase TIM44. Gut 2018 67 2 307 319 10.1136/gutjnl‑2016‑311909 27849558
    [Google Scholar]
  28. Dorvash M. Farahmandnia M. Tavassoly I. A Systems biology roadmap to decode mTOR control system in cancer. Interdiscip. Sci. 2020 12 1 1 11 10.1007/s12539‑019‑00347‑6 31531812
    [Google Scholar]
  29. Marques-Ramos A. Cervantes R. Expression of mTOR in normal and pathological conditions. Mol. Cancer 2023 22 1 112 10.1186/s12943‑023‑01820‑z 37454139
    [Google Scholar]
  30. Ding Y. Chen Q. mTOR pathway: A potential therapeutic target for spinal cord injury. Biomed. Pharmacother. 2022 145 112430 10.1016/j.biopha.2021.112430 34800780
    [Google Scholar]
  31. Chen K Zheng Y Wei J Exercise training improves motor skill learning via selective activation of mTOR. Sci Adv 2019 5 7 10.1126/sciadv.aaw1888
    [Google Scholar]
  32. Zhi S-M. Fang G-X. Xie X-M. Liu L.H. Yan J. Liu D.B. Yu H.Y. Melatonin reduces OGD/R-induced neuron injury by regulating redox/inflammation/apoptosis signaling. Eur. Rev. Med. Pharmacol. Sci. 2020 24 3 1524 1536 32096202
    [Google Scholar]
  33. Walker C.L. Wu X. Liu N.K. Xu X.M. Bisperoxovanadium mediates neuronal protection through inhibition of PTEN and activation of PI3K/AKT-mTOR signaling after traumatic spinal injuries. J. Neurotrauma 2019 36 18 2676 2687 10.1089/neu.2018.6294 30672370
    [Google Scholar]
  34. Miao L. Yang L. Huang H. Liang F. Ling C. Hu Y. mTORC1 is necessary but mTORC2 and GSK3β are inhibitory for AKT3-induced axon regeneration in the central nervous system. eLife 2016 5 e14908 10.7554/eLife.14908 27026523
    [Google Scholar]
  35. Sterner R.C. Sterner R.M. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front. Immunol. 2023 13 1084101 10.3389/fimmu.2022.1084101 36685598
    [Google Scholar]
/content/journals/cgt/10.2174/0115665232330349241225074627
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Plasmalogens Activate AKT/mTOR Signaling to Attenuate Reactive Oxygen Species Production in Spinal Cord Injury
Bentham Science Publishers ; https://doi.org/10.2174/0115665232330349241225074627
/content/journals/cgt/10.2174/0115665232330349241225074627
/content/journals/cgt/10.2174/0115665232330349241225074627
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  • Article Type:     Research Article
Keywords: neuronal apoptosis ; Plasmalogens ; ROS ; AKT/mTOR ; spinal cord injury

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