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Dendrobium Alkaloids Promote Neural Function After Cerebral Ischemia–Reperfusion Injury Through Inhibiting Pyroptosis Induced Neuronal Death in both In Vivo and In Vitro Models

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Abstract

Pyroptosis is a newly identified lytic form of programmed cell death which is characterized by plasma membrane blebbing and rupture. Pyroptosis occurs in cerebral ischemia injury, and contributes to the activation and secretion of the inflammatory cytokines interleukin (IL)-1β, IL-18, and IL-6. Previous reports have found that Dendrobium alkaloids (DNLA) can exert neuroprotective effects against oxygen–glucose deprivation/reperfusion (OGD/R) damage in vitro, but the mechanisms underlying these effects remain elusive. In this study, we investigated whether DNLA exerted therapeutic benefits against cerebral ischemia–reperfusion (CIR) damage via ameliorating pyroptosis and inflammation. OGD/R damage was induced in HT22 cells pretreated with DNLA (0.03, 0.3, or 3 mg/ml, 24 h prior to OGD/R), MCC950 (10 ng/ml, 1 h prior), and VX765 (10 ng/ml, 1 h prior). Neuronal apoptosis, necrosis, pyroptosis, and pathological changes were analyzed 24 h following OGD/R. Further to this, male C57/BL mice pretreated with different concentrations of DNLA (0.5 or 5 mg/kg, ip.) for 24 h and VX765 (50 mg/kg, ip., 1 h before CIR) underwent transient middle cerebral artery occlusion and reperfusion. We found that DNLA pretreatment resulted in a lower neurologic deficit score, a reduced infarct volume, fewer pyroptotic cells, and reduced levels of inflammatory factors 24 h after CIR. Furthermore, DNLA administration also reduced the levels of the pyroptosis-associated proteins Caspase-1 and gasdermin-D, particularly in the hippocampal CA1 region. Similar decreases were observed in the levels of the inflammatory factors IL-1β, IL-6, and IL-18. OGD/R-associated ultrastructural damage was seen to improve following DNLA administration, likely due to the regulation of the tight junction protein Pannexin-1 by DNLA. Overall, these findings demonstrate that DNLA can protect against CIR damage through inhibiting pyroptosis-induced neuronal death, providing new therapeutic insights for CIR injury.

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References

  1. Jain KK (2000) Neuroprotection in cerebrovascular disease. Expert Opin Invest Drugs 9:695–711

    CAS  Google Scholar 

  2. Chi MS, Chan LY (2017) Thrombolytic therapy in acute ischemic stroke in patients not fulfilling conventional criteria. Neurologist 22:219–226

    PubMed  Google Scholar 

  3. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87:779–789

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573–1584

    PubMed  PubMed Central  Google Scholar 

  5. Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (2014) Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell 54:133–146

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Xi H, Zhang Y, Xu Y, Yang WY, Jiang X, Sha X, Cheng X, Wang J, Qin X, Yu J, Ji Y, Yang X, Wang H (2016) Caspase-1 inflammasome activation mediates homocysteine-induced pyrop-apoptosis in endothelial cells. Circ Res 118:1525–1539

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Silverman WR, de Rivero Vaccari JP, Locovei S, Qiu F, Carlsson SK, Scemes E, Keane RW, Dahl G (2009) The pannexin 1 channel activates the inflammasome in neurons and astrocytes. J Biol Chem 284:18143–18151

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Li SJ, Zhang YF, Ma SH, Yi Y, Yu HY, Pei L, Feng D (2018) The role of NLRP3 inflammasome in stroke and central poststroke pain. Medicine (Baltimore) 97:e11861

    CAS  Google Scholar 

  10. Lamkanfi M, Mueller JL, Vitari AC, Misaghi S, Fedorova A, Deshayes K, Lee WP, Hoffman HM, Dixit VM (2009) Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J Cell Biol 187:61–70

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, Zhuang Y, Cai T, Wang F, Shao F (2015) Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526:660–665

    CAS  PubMed  Google Scholar 

  12. Kovacs SB, Miao EA (2017) Gasdermins: effectors of pyroptosis. Trends Cell Biol 27:673–684

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhao Y, Shi J, Shao F (2018) Inflammatory caspases: activation and cleavage of gasdermin-D in vitro and during pyroptosis. Methods Mol Biol 1714:131–148

    CAS  PubMed  Google Scholar 

  14. He WT, Wan H, Hu L, Chen P, Wang X, Huang Z, Yang ZH, Zhong CQ, Han J (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1beta secretion. Cell Res 25:1285–1298

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ren H, Kong Y, Liu Z, Zang D, Yang X, Wood K, Li M, Liu Q (2018) Selective NLRP3 (pyrin domain-containing protein 3) inflammasome inhibitor reduces brain injury after intracerebral hemorrhage. Stroke 49:184–192

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, Rainone V, Nemni R, Mancuso R, Clerici M (2016) The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer's disease. Mol Neurodegener 11:23

    PubMed  PubMed Central  Google Scholar 

  17. Wannamaker W, Davies R, Namchuk M, Pollard J, Ford P, Ku G, Decker C, Charifson P, Weber P, Germann UA, Kuida K, Randle JC (2007) (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoy l)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1beta and IL-18. J Pharmacol Exp Ther 321:509–516

    CAS  PubMed  Google Scholar 

  18. Zheng SQ, Hong XD, Chen TS, Luo PF, Xiao SC (2017) Effects of caspase-1 inhibitor VX765 on cold-restraint stress-induced acute gastric ulcer in mice. Zhonghua Shao Shang Za Zhi 33:688–693

    CAS  PubMed  Google Scholar 

  19. Flores J, Noel A, Foveau B, Lynham J, Lecrux C, LeBlanc AC (2018) Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer's disease mouse model. Nat Commun 9:3916

    PubMed  PubMed Central  Google Scholar 

  20. Audia JP, Yang XM, Crockett ES, Housley N, Haq EU, O'Donnell K, Cohen MV, Downey JM, Alvarez DF (2018) Caspase-1 inhibition by VX-765 administered at reperfusion in P2Y12 receptor antagonist-treated rats provides long-term reduction in myocardial infarct size and preservation of ventricular function. Basic Res Cardiol 113:32

    PubMed  PubMed Central  Google Scholar 

  21. Ismael S, Zhao L, Nasoohi S, Ishrat T (2018) Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke. Sci Rep 8:5971

    PubMed  PubMed Central  Google Scholar 

  22. Ebrahimi T, Rust M, Kaiser SN, Slowik A, Beyer C, Koczulla AR, Schulz JB, Habib P, Bach JP (2018) alpha1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid beta1-42-stimulated murine astrocytes. J Neuroinflamm 15:282

    CAS  Google Scholar 

  23. Xing YM, Chen J, Cui JL, Chen XM, Guo SX (2011) Antimicrobial activity and biodiversity of endophytic fungi in Dendrobium devonianum and Dendrobium thyrsiflorum from Vietnam. Curr Microbiol 62:1218–1224

    CAS  PubMed  Google Scholar 

  24. Yu Z, Gong C, Lu B, Yang L, Sheng Y, Ji L, Wang Z (2015) Dendrobium chrysotoxum Lindl. alleviates diabetic retinopathy by preventing retinal inflammation and tight junction protein decrease. J Diabetes Res https://doi.org/10.1155/2015/518317

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang GN, Zhong LY, Bligh SW, Guo YL, Zhang CF, Zhang M, Wang ZT, Xu LS (2005) Bi-bicyclic and bi-tricyclic compounds from Dendrobium thyrsiflorum. Phytochemistry 66:1113–1120

    CAS  PubMed  Google Scholar 

  26. Li LS, Lu YL, Nie J, Xu YY, Zhang W, Yang WJ, Gong QH, Lu YF, Lu Y, Shi JS (2017) Dendrobium nobile Lindl alkaloid, a novel autophagy inducer, protects against axonal degeneration induced by Abeta25-35 in hippocampus neurons in vitro. CNS Neurosci Ther 23:329–340

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang AL, Yu M, Xu HH, Si JP (2013) Constituents of Dendrobium devonianum and their antioxidant activity. Zhongguo Zhong Yao Za Zhi 38:844–847

    CAS  PubMed  Google Scholar 

  28. Zhang Q, An R, Tian X, Yang M, Li M, Lou J, Xu L, Dong Z (2017) Beta-caryophyllene pretreatment alleviates focal cerebral ischemia-reperfusion injury by activating PI3K/Akt signaling pathway. Neurochem Res 42:1459–1469

    CAS  PubMed  Google Scholar 

  29. Wang Q, Gong Q, Wu Q, Shi J (2010) Neuroprotective effects of Dendrobium alkaloids on rat cortical neurons injured by oxygen-glucose deprivation and reperfusion. Phytomedicine 17:108–115

    PubMed  Google Scholar 

  30. Rayamajhi M, Zhang Y, Miao EA (2013) Detection of pyroptosis by measuring released lactate dehydrogenase activity. Methods Mol Biol 1040:85–90

    CAS  PubMed  PubMed Central  Google Scholar 

  31. DiPeso L, Ji DX, Vance RE, Price JV (2017) Cell death and cell lysis are separable events during pyroptosis. Cell Death Discov 3:17070

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A (2010) Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11:1136–1142

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang M, Lv Y, Tian X, Lou J, An R, Zhang Q, Li M, Xu L, Dong Z (2017) neuroprotective effect of beta-caryophyllene on cerebral ischemia-reperfusion injury via regulation of necroptotic neuronal death and inflammation: in vivo and in vitro. Front Neurosci 11:583

    PubMed  PubMed Central  Google Scholar 

  34. Chen D, Yu J, Zhang L (2016) Necroptosis: an alternative cell death program defending against cancer. Biochim Biophys Acta 1865:228–236

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Ichim G, Tait SW (2016) A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer 16:539–548

    CAS  PubMed  Google Scholar 

  36. Ribeiro SC, Muratori M, De Geyter M, De Geyter C (2017) TUNEL labeling with BrdUTP/anti-BrdUTP greatly underestimates the level of sperm DNA fragmentation in semen evaluation. PLoS ONE 12:e0181802

    PubMed  PubMed Central  Google Scholar 

  37. Han J, Zhong CQ, Zhang DW (2011) Programmed necrosis: backup to and competitor with apoptosis in the immune system. Nat Immunol 12:1143–1149

    CAS  PubMed  Google Scholar 

  38. Zhang Y, Chen X, Gueydan C, Han J (2018) Plasma membrane changes during programmed cell deaths. Cell Res 28:9–21

    CAS  PubMed  Google Scholar 

  39. Russo HM, Rathkey J, Boyd-Tressler A, Katsnelson MA, Abbott DW, Dubyak GR (2016) Active caspase-1 induces plasma membrane pores that precede pyroptotic lysis and are blocked by lanthanides. J Immunol 197:1353–1367

    CAS  PubMed  Google Scholar 

  40. Brennan MA, Cookson BT (2000) Salmonella induces macrophage death by caspase-1-dependent necrosis. Mol Microbiol 38:31–40

    CAS  PubMed  Google Scholar 

  41. Lamkanfi M, Dixit VM (2014) Mechanisms and functions of inflammasomes. Cell 157:1013–1022

    CAS  PubMed  Google Scholar 

  42. Mahla RS, Reddy MC, Prasad DV, Kumar H (2013) Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology. Front Immunol 4:248

    PubMed  PubMed Central  Google Scholar 

  43. Shichita T, Ito M, Yoshimura A (2014) Post-ischemic inflammation regulates neural damage and protection. Front Cell Neurosci 8:319

    PubMed  PubMed Central  Google Scholar 

  44. Rai V, Agrawal DK (2017) The role of damage- and pathogen-associated molecular patterns in inflammation-mediated vulnerability of atherosclerotic plaques. Can J Physiol Pharmacol 95:1245–1253

    CAS  PubMed  Google Scholar 

  45. Nossek H, Thierichen A (1989) Dependence of bleeding provocation on the probing force for diagnostics and progress evaluation of inflammatory periodontal diseases. Stomatol DDR 39:530–536

    CAS  PubMed  Google Scholar 

  46. Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73:1907–1916

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kufer TA, Sansonetti PJ (2007) Sensing of bacteria: NOD a lonely job. Curr Opin Microbiol 10:62–69

    CAS  PubMed  Google Scholar 

  48. Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, Morita R (2015) Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun 6:7360

    PubMed  Google Scholar 

  49. Li Y, Xu L, Zeng K, Xu Z, Suo D, Peng L, Ren T, Sun Z, Yang W, Jin X, Yang L (2017) Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARalpha/gamma dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses. Brain Behav Immun 66:289–301

    CAS  PubMed  Google Scholar 

  50. Zhao GC, Yuan YL, Chai FR, Ji FJ (2017) Effect of Melilotus officinalis extract on the apoptosis of brain tissues by altering cerebral thrombosis and inflammatory mediators in acute cerebral ischemia. Biomed Pharmacother 89:1346–1352

    CAS  PubMed  Google Scholar 

  51. Sobowale OA, Parry-Jones AR, Smith CJ, Tyrrell PJ, Rothwell NJ, Allan SM (2016) Interleukin-1 in stroke: from bench to bedside. Stroke 47:2160–2167

    PubMed  Google Scholar 

  52. Wytrykowska A, Prosba-Mackiewicz M, Nyka WM (2016) IL-1beta, TNF-alpha, and IL-6 levels in gingival fluid and serum of patients with ischemic stroke. J Oral Sci 58:509–513

    CAS  PubMed  Google Scholar 

  53. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HW, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M (2012) Myocardial infarction accelerates atherosclerosis. Nature 487:325–329

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Slaats J, Ten Oever J, van de Veerdonk FL, Netea MG (2016) IL-1beta/IL-6/CRP and IL-18/ferritin: distinct inflammatory programs in infections. PLoS Pathog 12:e1005973

    PubMed  PubMed Central  Google Scholar 

  55. Toldo S, Mezzaroma E, O'Brien L, Marchetti C, Seropian IM, Voelkel NF, Van Tassell BW, Dinarello CA, Abbate A (2014) Interleukin-18 mediates interleukin-1-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 306:H1025–H1031

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Kayagaki N, Stowe IB, Lee BL, O'Rourke K, Anderson K, Warming S, Cuellar T, Haley B, Roose-Girma M, Phung QT, Liu PS, Lill JR, Li H, Wu J, Kummerfeld S, Zhang J, Lee WP, Snipas SJ, Salvesen GS, Morris LX, Fitzgerald L, Zhang Y, Bertram EM, Goodnow CC, Dixit VM (2015) Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526:666–671

    CAS  PubMed  Google Scholar 

  57. Ding J, Wang K, Liu W, She Y, Sun Q, Shi J, Sun H, Wang DC, Shao F (2016) Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535:111–116

    CAS  PubMed  Google Scholar 

  58. Sborgi L, Ruhl S, Mulvihill E, Pipercevic J, Heilig R, Stahlberg H, Farady CJ, Muller DJ, Broz P, Hiller S (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J 35:1766–1778

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Brody H (2003) Bounce of a tennis ball. J Sci Med Sport 6:113–119

    CAS  PubMed  Google Scholar 

  60. Thompson RJ, Zhou N, MacVicar BA (2006) Ischemia opens neuronal gap junction hemichannels. Science 312:924–927

    CAS  PubMed  Google Scholar 

  61. Braun J, Schultek T, Tegtmeier KF, Florenz A, Rohde C, Wood WG (1986) Luminometric assays of seven acute-phase proteins in minimal volumes of serum, plasma, sputum, and bronchioalveolar lavage. Clin Chem 32:743–747

    CAS  PubMed  Google Scholar 

  62. Yang D, He Y, Munoz-Planillo R, Liu Q, Nunez G (2015) Caspase-11 requires the pannexin-1 channel and the purinergic P2X7 pore to mediate pyroptosis and endotoxic shock. Immunity 43:923–932

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang L, Deng T, Sun Y, Liu K, Yang Y, Zheng X (2008) Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation. J Neurosci Res 86:2281–2291

    CAS  PubMed  Google Scholar 

  64. Dvoriantchikova G, Ivanov D, Barakat D, Grinberg A, Wen R, Slepak VZ, Shestopalov VI (2012) Genetic ablation of Pannexin1 protects retinal neurons from ischemic injury. PLoS ONE 7:e31991

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Michalski D, Pitsch R, Pillai DR, Mages B, Aleithe S, Grosche J, Martens H, Schlachetzki F, Hartig W (2017) Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors. PLoS ONE 12:e0174996

    PubMed  PubMed Central  Google Scholar 

  66. Shan J, Sun L, Wang D, Li X (2015) Comparison of the neuroprotective effects and recovery profiles of isoflurane, sevoflurane and desflurane as neurosurgical pre-conditioning on ischemia/reperfusion cerebral injury. Int J Clin Exp Pathol 8:2001–2009

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Wu D, Zhang J (2016) In vivo mapping of macroscopic neuronal projections in the mouse hippocampus using high-resolution diffusion MRI. Neuroimage 125:84–93

    PubMed  Google Scholar 

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Funding

This study was supported financially by the China and Chongqing Science and Technology Commission (KJ1600235) and Chongqing Science and Technology Commission (CSTC2016jcyj A0268, CSTC2016jcyjA0373).

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  1. Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, College of Pharmacy, Chongqing Medical University, District of Yuzhong, Chongqing, 400016, China

    Daohang Liu, Zhi Dong, Fei Xiang, Hailin Liu, Yuchun Wang, Qian Wang & Jiangyan Rao

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Liu, D., Dong, Z., Xiang, F. et al. Dendrobium Alkaloids Promote Neural Function After Cerebral Ischemia–Reperfusion Injury Through Inhibiting Pyroptosis Induced Neuronal Death in both In Vivo and In Vitro Models. Neurochem Res 45, 437–454 (2020). https://doi.org/10.1007/s11064-019-02935-w

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