Abstract
Background
Early brain injury (EBI) is the vital factor in determining the outcome of subarachnoid hemorrhage (SAH). Schizandrin A (Sch A), the bioactive ingredient extracted from Schisandra chinensis, has been proved to exert beneficial effects in multiple human diseases. However, the effect of Sch A on SAH remains unknown. The current study was designed to explored role and mechanism of Sch A in the pathophysiological process of EBI following SAH.
Method
A total of 74 male C57BL/6 J mice were subjected to endovascular perforation to establish the SAH model. Different dosages of Sch A were administrated post-modeling. The post-modeling assessments included neurological test, brain water content, RT-PCR, immunofluorescence, Nissl staining. Oxygenated hemoglobin was introduced into microglia to establish a SAH model in vitro.
Result
Sch A significantly alleviated SAH-induced brain edema and neurological impairment. Moreover, application of Sch A remarkably inhibited SAH-induced neuroinflammation, evidenced by the decreased microglial activation and downregulated TNF-α, IL-1β and IL-6 and expression. Additionally, Sch A, both in vivo and in vitro, protected neurons against SAH-induced inflammatory injury. Mechanismly, administration of Sch A inhibited miR-155/NF-κB axis and attenuated neuroinflammation, as well as alleviating neuronal injury.
Conclusion
Our data suggested that Sch A could attenuated EBI following SAH via modulating neuroinflammation. The anti-inflammatory effect was exerted, at least partly through the miR-155/NF-κB axis, which may shed light on a possible therapeutic target for SAH.
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Data Availability
All raw data used in this manuscript are available on reasonable request.
References
Haverkamp C, Kaier K, Shah M, von Zur Mühlen C, Beck J, Urbach H, Meckel S (2023): Cerebral aneurysms: Germany-wide real-world outcome data of endovascular or neurosurgical treatment from 2007 to 2019. Journal of neurointerventional surgery
Tu WJ, Wang LD (2023) China Stroke surveillance report 2021. Military Med Res 10(1):33
Kanamaru H, Kawakita F, Nishikawa H, Nakano F, Asada R, Suzuki H (2021) Clarithromycin ameliorates early brain Injury after Subarachnoid Hemorrhage via suppressing periostin-related pathways in mice. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics 18(3):1880–1890
Yamada H, Kase Y, Okano Y, Kim D, Goto M, Takahashi S, Okano H, Toda M (2022) Subarachnoid Hemorrhage triggers neuroinflammation of the entire cerebral cortex, leading to neuronal cell death. Inflamm Regeneration 42(1):61
Zhang Z, Zhang A, Liu Y, Hu X, Fang Y, Wang X, Luo Y, Lenahan C, Chen S (2022) New mechanisms and targets of subarachnoid Hemorrhage: a focus on Mitochondria. Curr Neuropharmacol 20(7):1278–1296
Zeyu Z, Yuanjian F, Cameron L, Sheng C (2021) The role of immune inflammation in aneurysmal subarachnoid Hemorrhage. Exp Neurol 336:113535
Jeong MJ, Kim SR, Jung UJ (2019) Schizandrin A supplementation improves nonalcoholic fatty Liver Disease in mice fed a high-fat and high-cholesterol diet. Nutr Res (New York NY) 64:64–71
Fu K, Zhou H, Wang C, Gong L, Ma C, Zhang Y, Li Y (2022) A review: Pharmacology and pharmacokinetics of Schisandrin A. Phytother Res 36(6):2375–2393
Deng Y, Zhang Z, Hong Y, Feng L, Su Y, Xu D (2022) Schisandrin A alleviates mycophenolic acid-induced intestinal toxicity by regulating cell apoptosis and oxidative damage. Toxicol Mech Methods 32(8):580–587
Zhou F, Wang M, Ju J, Wang Y, Liu Z, Zhao X, Yan Y, Yan S, Luo X, Fang Y (2019) Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation. Am J Translational Res 11(1):199–209
Wang Q, Liu L, Guan H, Zhou Y, Li Q (2021) Schizandrin A ameliorates cognitive functions via modulating microglial polarisation in Alzheimer’s Disease mice. Pharm Biol 59(1):860–867
Yan T, Mao Q, Zhang X, Wu B, Bi K, He B, Jia Y (2021) Schisandra chinensis protects against dopaminergic neuronal oxidative stress, neuroinflammation and apoptosis via the BDNF/Nrf2/NF-κB pathway in 6-OHDA-induced Parkinson’s Disease mice. Food Funct 12(9):4079–4091
Demura M, Ishii H, Takarada-Iemata M, Kamide T, Yoshikawa A, Nakada M, Hori O (2023) Sympathetic nervous hyperactivity impairs Microcirculation leading to early brain Injury after Subarachnoid Hemorrhage. Stroke 54(6):1645–1655
Liu R, Cao S, Hua Y, Keep RF, Huang Y, Xi G (2017) CD163 expression in neurons after experimental intracerebral Hemorrhage. Stroke 48(5):1369–1375
Peng Y, Zhuang J, Ying G, Zeng H, Zhou H, Cao Y, Chen H, Xu C, Fu X, Xu H et al (2020) Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid Hemorrhage. J Neuroinflamm 17(1):165
Lynch DG, Shah KA, Powell K, Wadolowski S, Tambo W, Strohl JJ, Unadkat P, Eidelberg D, Huerta PT, Li C (2023) Neurobehavioral impairments predict specific cerebral damage in Rat Model of Subarachnoid Hemorrhage. Translational stroke research
Huang Y, Guo Y, Huang L, Fang Y, Li D, Liu R, Lu Q, Ren R, Tang L, Lian L et al (2021) Kisspeptin-54 attenuates oxidative stress and neuronal apoptosis in early brain injury after subarachnoid Hemorrhage in rats via GPR54/ARRB2/AKT/GSK3β signaling pathway. Free Radic Biol Med 171:99–111
Vaughan LE, Ranganathan PR, Kumar RG, Wagner AK, Rubin JE (2018) A mathematical model of neuroinflammation in severe clinical traumatic brain injury. J Neuroinflammation 15(1):345
Song F, Zeng K, Liao L, Yu Q, Tu P, Wang X (2016) Schizandrin A inhibits microglia-mediated neuroninflammation through inhibiting TRAF6-NF-κB and Jak2-Stat3 signaling pathways. PLoS ONE 11(2):e0149991
Liu J, Han Y, Zhu T, Yang Q, Wang H, Zhang H (2021) Dendrobium Nobile Lindl. Polysaccharides reduce cerebral ischemia/reperfusion injury in mice by increasing myeloid cell Leukemia 1 via the downregulation of miR-134. NeuroReport 32(3):177–187
Zhang Y, Li L, Jia L, Li T, Di Y, Wang P, Deng H, Fan H, Li Y, Cheng X et al (2021): Neutrophil counts as promising marker for Predicting In-Hospital mortality in Aneurysmal Subarachnoid Hemorrhage. Stroke: Strokeaha120034024
Macdonald RL (2021): Age and outcome after aneurysmal Subarachnoid Haemorrhage. J Neurol Neurosurg Psychiatry
Bechstein M, Gansukh A, Regzengombo B, Byambajav O, Meyer L, Schönfeld M, Kniep H, Hanning U, Broocks G, Gansukh T et al (2021): Risk Factors for Cerebral Aneurysm Rupture in Mongolia. Clinical neuroradiology
Zhang T, Zuo G, Zhang H (2021): GPR18 agonist resolvin D2 reduces early Brain Injury in a rat model of subarachnoid Hemorrhage by multiple protective mechanisms. Cell Mol Neurobiol
Yuan JY, Chen Y, Kumar A, Zlepper Z, Jayaraman K, Aung WY, Clarke JV, Allen M, Athiraman U, Osbun J et al (2021) Automated quantification of reduced sulcal volume identifies early brain Injury after Aneurysmal Subarachnoid Hemorrhage. Stroke 52(4):1380–1389
Wang H, Che J, Cui K, Zhuang W, Li H, Sun J, Chen J, Wang C (2021) Schisantherin a ameliorates liver fibrosis through TGF-β1mediated activation of TAK1/MAPK and NF-κB pathways in vitro and in vivo. Phytomedicine: Int J Phytotherapy Phytopharmacology 88:153609
Kopustinskiene DM, Bernatoniene J (2021): Antioxidant effects of Schisandra chinensis fruits and their active constituents. Antioxid (Basel Switzerland) 10(4)
Qin JH, Lin JR, Ding WF, Wu WH (2019) Schisandrin B improves the renal function of IgA Nephropathy rats through inhibition of the NF-κB signalling pathway. Inflammation 42(3):884–894
Qiao Z, Du X, Zhuang W, Yang S, Li H, Sun J, Chen J, Wang C (2020) Schisandra Chinensis Acidic Polysaccharide improves the Insulin Resistance in type 2 Diabetic rats by inhibiting inflammation. J Med Food 23(4):358–366
Ni S, Qian Z, Yuan Y, Li D, Zhong Z, Ghorbani F, Zhang X, Zhang F, Zhang Z, Liu Z et al (2020) Schisandrin A restrains osteoclastogenesis by inhibiting reactive oxygen species and activating Nrf2 signalling. Cell Prolif 53(10):e12882
Yeon M, Choi H, Jun HS (2020): Preventive effects of Schisandrin A, a bioactive component of Schisandra chinensis, on Dexamethasone-Induced muscle atrophy. Nutrients 12(5)
Song Y, Shan B, Zeng S, Zhang J, Jin C, Liao Z, Wang T, Zeng Q, He H, Wei F et al (2021) Raw and wine processed Schisandra chinensis attenuate anxiety like behavior via modulating gut microbiota and lipid metabolism pathway. J Ethnopharmacol 266:113426
Wei M, Liu Y, Pi Z, Li S, Hu M, He Y, Yue K, Liu T, Liu Z, Song F et al (2019): Systematically Characterize the Anti-Alzheimer’s Disease Mechanism of Lignans from S. chinensis based on In-Vivo Ingredient Analysis and Target-Network Pharmacology Strategy by UHPLC-Q-TOF-MS. Molecules 24(7)
Han YW, Liu XJ, Zhao Y, Li XM (2018) Role of oleanolic acid in maintaining BBB integrity by targeting p38MAPK/VEGF/Src signaling pathway in rat model of subarachnoid Hemorrhage. Eur J Pharmacol 839:12–20
Choi HA, Bajgur SS, Jones WH, Savarraj JP, Ko SB, Edwards NJ, Chang TR, Hergenroeder GW, Dannenbaum MJ, Chen PR et al (2016) Quantification of cerebral Edema after Subarachnoid Hemorrhage. Neurocrit Care 25(1):64–70
Cook AM, Morgan Jones G, Hawryluk GWJ, Mailloux P, McLaughlin D, Papangelou A, Samuel S, Tokumaru S, Venkatasubramanian C, Zacko C et al (2020) Guidelines for the Acute treatment of cerebral edema in Neurocritical Care patients. Neurocrit Care 32(3):647–666
Xu H, Li J, Wang Z, Feng M, Shen Y, Cao S, Li T, Peng Y, Fan L, Chen J et al (2017) Methylene blue attenuates neuroinflammation after subarachnoid Hemorrhage in rats through the Akt/GSK-3β/MEF2D signaling pathway. Brain Behav Immun 65:125–139
Fan H, Ding R, Liu W, Zhang X, Li R, Wei B, Su S, Jin F, Wei C, He X et al (2021) Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid Hemorrhage in rats. Redox Biol 40:101856
Liu Y, Zhang T, Wang Y, Wu P, Li Y, Wang C, Xu S, Shi H (2019) Apelin-13 attenuates early brain injury following subarachnoid Hemorrhage via suppressing neuronal apoptosis through the GLP-1R/PI3K/Akt signaling. Biochem Biophys Res Commun 513(1):105–111
Sita G, Graziosi A, Hrelia P, Morroni F (2021): NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration. Int J Mol Sci 22(13)
Hajinejad M, Sahab-Negah S (2021): Neuroinflammation: the next target of exosomal microRNAs derived from mesenchymal stem cells in the context of neurological disorders. J Cell Physiol
Daidone M, Cataldi M, Pinto A, Tuttolomondo A (2021) Non-coding RNAs and other determinants of neuroinflammation and endothelial dysfunction: regulation of gene expression in the acute phase of ischemic Stroke and possible therapeutic applications. Neural Regeneration Research 16(11):2154–2158
Alexaki VI (2021): The impact of obesity on microglial function: Immune, metabolic and endocrine perspectives. Cells 10(7)
Schmidt EKA, Raposo PJF, Torres-Espin A, Fenrich KK, Fouad K (2021) Beyond the lesion site: minocycline augments inflammation and anxiety-like behavior following SCI in rats through action on the gut microbiota. J Neuroinflammation 18(1):144
Hanscom M, Loane DJ, Aubretch T, Leser J, Molesworth K, Hedgekar N, Ritzel RM, Abulwerdi G, Shea-Donohue T, Faden AI (2021) Acute Colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits. J Neuroinflammation 18(1):24
Walsh J, Tozer DJ, Sari H, Hong YT, Drazyk A, Williams G, Shah NJ, O’Brien JT, Aigbirhio FI, Rosenberg G et al (2021) Microglial activation and blood-brain barrier permeability in cerebral small vessel Disease. Brain 144(5):1361–1371
Cardinale A, Calabrese V, de Iure A, Picconi B (2021): Alpha-Synuclein as a Prominent Actor in the Inflammatory Synaptopathy of Parkinson’s Disease. Int J Mol Sci 22(12)
Khey KMW, Huard A, Mahmoud SH (2019) Inflammatory pathways following subarachnoid Hemorrhage. Cell Mol Neurobiol
Zheng ZV, Lyu H, Lam SYE, Lam PK, Poon WS, Wong GKC (2020) The dynamics of Microglial polarization reveal the Resident neuroinflammatory responses after subarachnoid Hemorrhage. Transl Stroke Res 11(3):433–449
Liu GJ, Tao T, Wang H, Zhou Y, Gao X, Gao YY, Hang CH, Li W (2020) Functions of resolvin D1-ALX/FPR2 receptor interaction in the hemoglobin-induced microglial inflammatory response and neuronal injury. J Neuroinflammation 17(1):239
Segherlou ZH, Saldarriaga L, Azizi E, Vo KA, Reddy R, Siyanaki MRH, Lucke-Wold B (2023): MicroRNAs’ Role in Diagnosis and Treatment of Subarachnoid Hemorrhage. Dis (Basel Switzerland) 11(2)
Tabarestani A, Patel A, Reddy A, Sharaf R, Lucke-Wold B (2023) Vasospasm Management Strategies. Int J Med Pharm Res 4(2):150–160
Zingale VD, Gugliandolo A, Mazzon E (2021): MiR-155: an important Regulator of Neuroinflammation. Int J Mol Sci 23(1)
Wang C, Liu C, Shi J, Li H, Jiang S, Zhao P, Zhang M, Du G, Fu S, Li S et al (2023) Nicotine exacerbates endothelial dysfunction and drives Atherosclerosis via extracellular vesicle-miRNA. Cardiovascular Res 119(3):729–742
Li P, Luo X, Luo Z, He GL, Shen TT, Yu XT, Wang ZZ, Tan YL, Liu XQ, Yang XS (2022) Increased miR-155 in Microglial Exosomes following heat stress accelerates neuronal Autophagy via their transfer into neurons. Front Cell Neurosci 16:865568
Ke F, Wang H, Geng J, Jing X, Fang F, Fang C, Zhang BH (2023) MiR-155 promotes inflammation and apoptosis via targeting SIRT1 in hypoxic-ischemic brain damage. Exp Neurol 362:114317
Gao L, Li T, Li S, Song Z, Chang Y, Yuan L (2022): Schisandrin A protects against isoproterenol–induced chronic Heart Failure via miR–155. Mol Med Rep 25(1)
Yan H, Guo M (2020) Schizandrin A inhibits cellular phenotypes of Breast cancer cells by repressing miR-155. IUBMB Life 72(8):1640–1648
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J.J., C.M. and W.H. performed the SAH model, RT-PCR and Western blots. L.S. and M.L. performed cell culture and immunostaining. J.J. and W.B. design the project and wrote the main manuscript. All authors reviewed the manuscript.
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This study was performed in line with the Chinese laboratory animal guideline for ethical and animal welfare. Approval was granted by the Institutional Animal Care and Use Committee of Li Huili Hospital, Ningbo Medical Center. (Date: 09/2021/No: 2021065).
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Jin, J., Chen, M., Wang, H. et al. Schizandrin A attenuates early brain injury following subarachnoid hemorrhage through suppressing neuroinflammation. Mol Biol Rep 51, 236 (2024). https://doi.org/10.1007/s11033-023-08956-7
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DOI: https://doi.org/10.1007/s11033-023-08956-7