Abstract
Xyloketal B (Xyl-B) is a novel marine compound isolated from mangrove fungus Xylaria sp. We previously demonstrated that pretreatment with Xyl-B exerted neuroprotective effects and attenuated hypoxic-ischemic brain injury in neonatal mice. In the present study we investigated the neuroprotective effects of pre- and post-treatment with Xyl-B in adult mice using a transient middle cerebral artery occlusion (tMCAO) model, and explored the underlying mechanisms. Adult male C57 mice were subjected to tMCAO surgery. For the pre-treatment, Xyl-B was given via multiple injections (12.5, 25, and 50 mg·kg−1·d−1, ip) 48 h, 24 h and 30 min before ischemia. For the post-treatment, a single dose of Xyl-B (50 mg/kg, ip) was injected at 0, 1 or 2 h after the onset of ischemia. The regional cerebral perfusion was monitored using a laser-Doppler flowmeter. TTC staining was performed to determine the brain infarction volume. We found that both pre-treatment with Xyl-B (50 mg/kg) and post-treatment with Xyl-B (50 mg/kg) significantly reduced the infarct volume, but had no significant hemodynamic effects. Treatment with Xyl-B also significantly alleviated the neurological deficits in tMCAO mice. Furthermore, treatment with Xyl-B significantly attenuated ROS overproduction in brain tissues; increased the MnSOD protein levels, suppressed TLR4, NF-κB and iNOS protein levels; and downregulated the mRNA levels of proinflammatory cytokines, including IL-1β, TNF-α, IL-6 and IFN-γ. Moreover, Xyl-B also protected blood-brain barrier integrity in tMCAO mice. In conclusion, Xyl-B administered within 2 h after the onset of stroke effectively protects against focal cerebral ischemia; the underlying mechanism may be related to suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway.
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References
Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase beyond 3h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET):a placebo-controlled randomised trial. Lancet Neurol 2008; 7: 299–309.
Simats A, Garcia-Berrocoso T, Montaner J . Neuroinflammatory biomarkers: from stroke diagnosis and prognosis to therapy. Biochim Biophys Acta 2016; 1862: 411–24.
Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O . Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 2014; 34: 1573–84.
Jin R, Yang G, Li G . Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukocyte Biol 2010; 87: 779–89.
Hyakkoku K, Hamanaka J, Tsuruma K, Shimazawa M, Tanaka H, Uematsu S, et al. Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia. Neuroscience 2010; 171: 258–67.
Belinga VF, Wu GJ, Yan FL, Limbenga EA . Splenectomy following MCAO inhibits the TLR4-NF-kappaB signaling pathway and protects the brain from neurodegeneration in rats. J Neuroimmunol 2016; 293: 105–13.
Shih RH, Wang CY, Yang CM . NF-kappaB signaling pathways in neurological inflammation: a mini review. Frontiers Mol Neurosci 2015; 8: 77.
Lin Y, Wu X, Feng S, Jiang G, Luo J, Zhou S, et al. Five unique compounds: xyloketals from mangrove fungus Xylaria sp from the South China Sea coast. J Org Chem 2001; 66: 6252–6.
Chen WL, Qian Y, Meng WF, Pang JY, Lin YC, Guan YY, et al. A novel marine compound xyloketal B protects against oxidized LDL-induced cell injury in vitro. Biochem Pharmacol 2009; 78: 941–50.
Zhao J, Li L, Ling C, Li J, Pang JY, Lin YC, et al. Marine compound Xyloketal B protects PC12 cells against OGD-induced cell damage. Brain Res 2009; 1302: 240–7.
Lu XL, Yao XL, Liu Z, Zhang H, Li W, Li Z, et al. Protective effects of xyloketal B against MPP+-induced neurotoxicity in Caenorhabditis elegans and PC12 cells. Brain Res 2010; 1332: 110–9.
Li S, Shen C, Guo W, Zhang X, Liu S, Liang F, et al. Synthesis and neuroprotective action of xyloketal derivatives in Parkinson's disease models. Marine Drugs 2013; 11: 5159–89.
Li ZX, Chen JW, Yuan F, Huang YY, Zhao LY, Li J, et al. Xyloketal B exhibits its antioxidant activity through induction of HO-1 in vascular endothelial cells and zebrafish. Marine Drugs 2013; 11: 504–22.
Chen WL, Turlova E, Sun CL, Kim JS, Huang S, Zhong X, et al. Xyloketal B suppresses glioblastoma cell proliferation and migration in vitro through inhibiting TRPM7-regulated PI3K/Akt and MEK/ERK signaling pathways. Marine Drugs 2015; 13: 2505–25.
Zhao LY, Li J, Yuan F, Li M, Zhang Q, Huang YY, et al. Xyloketal B attenuates atherosclerotic plaque formation and endothelial dysfunction in apolipoprotein e deficient mice. Marine Drugs 2015; 13: 2306–26.
Zeng Y, Guo W, Xu G, Wang Q, Feng L, Long S, et al. Xyloketal-derived small molecules show protective effect by decreasing mutant Huntingtin protein aggregates in Caenorhabditis elegans model of Huntington's disease. Drug Design Development Ther 2016; 10: 1443–51.
Xiao AJ, Chen W, Xu B, Liu R, Turlova E, Barszczyk A, et al. Marine compound xyloketal B reduces neonatal hypoxic-ischemic brain injury. Marine Drugs 2015; 13: 29–47
Huang J, Li Y, Tang Y, Tang G, Yang GY, Wang Y . CXCR4 antagonist AMD3100 protects blood-brain barrier integrity and reduces inflammatory response after focal ischemia in mice. Stroke 2013; 44: 190–7.
Bederson JB, Pitts LH, Miles T, Nishimura MC, David RL, Henry B . Rat middle cerebral artery occlusion: evaluation of the model and development of a neuroligic examination. Stroke 1986; 17: 472–6.
Huang YY, Huang XQ, Zhao LY, Sun FY, Chen WL, Du JY, et al. ClC-3 deficiency protects preadipocytes against apoptosis induced by palmitate in vitro and in type 2 diabetes mice. Apoptosis 2014; 19: 1559–70.
Sun YY, Li Y, Wali B, Lee J, Heinmiller A, Abe K, et al. Prophylactic edaravone prevents transient hypoxic-ischemic brain injury: implications for perioperative neuroprotection. Stroke 2015; 46: 1947–55.
Yu S, Liu X, Shen Y, Xu H, Yang Y, Ding F . Therapeutic benefits of combined treatment with tissue plasminogen activator and 2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-beta-d-pyranoside in an animal model of ischemic stroke. Neuroscience 2016; 327: 44–52.
Wang T, Gu J, Wu PF, Wang F, Xiong Z, Yang YJ, et al. Protection by tetrahydroxystilbene glucoside against cerebral ischemia: involvement of JNK, SIRT1, and NF-kappaB pathways and inhibition of intracellular ROS/RNS generation. Free Radical Biol Med 2009; 47: 229–40.
Kim GW, Kondo T, Noshita N, Chan PH . Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice. Implications for the production and role of superoxide radicals. Stroke 2002; 33: 809–15.
Huang HF, Guo F, Cao YZ, Shi W, Xia Q . Neuroprotection by manganese superoxide dismutase (MnSOD) mimics: antioxidant effect and oxidative stress regulation in acute experimental stroke. CNS Neurosci Ther 2012; 18: 811–8.
Wang Q, Tang XN, Yenari MA . The inflammatory response in stroke. J Neuroimmunol 2007; 184: 53–68.
Emsley HC, Hopkins SJ . Acute ischaemic stroke and infection: recent and emerging concepts. Lancet Neurol 2008; 7: 341–53.
McColl BW, Allan SM, Rothwell NJ . Systemic infection, inflammation and acute ischemic stroke. Neuroscience 2009; 158: 1049–61.
Chelluboina B, Klopfenstein JD, Pinson DM, Wang DZ, Vemuganti R, Veeravalli KK . Matrix metalloproteinase-12 induces blood-brain barrier damage after focal cerebral ischemia. Stroke 2015; 46: 3523–31.
Abdullah Z, Rakkar K, Bath PM, Bayraktutan U . Inhibition of TNF-alpha protects in vitro brain barrier from ischaemic damage. Mol Cell Neurosci 2015; 69: 65–79.
Zhang J, Fu B, Zhang X, Chen L, Zhang L, Zhao X, et al. Neuroprotective effect of bicyclol in rat ischemic stroke: down-regulates TLR4, TLR9, TRAF6, NF-kappaB, MMP-9 and up-regulates claudin-5 expression. Brain Res 2013; 1528: 80–8.
Caso JR, Pradillo JM, Hurtado O, Leza JC, Moro MA, Lizasoain I . Toll-Like receptor 4 is involved in subacute stress–induced neuroinflammation and in the worsening of experimental stroke. Stroke 2008; 39: 1314–20.
Ahn KS, Aggarwal BB . Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann New York Acad Sci 2005; 1056: 218–33.
Anthony Jalin AM, Lee JC, Cho GS, Kim C, Ju C, Pahk K, et al. Simvastatin reduces lipopolysaccharides-accelerated cerebral ischemic injury via inhibition of nuclear factor-kappa B activity. Biomol Ther 2015; 23: 531–8.
Sarmiento D, Montorfano I, Caceres M, Echeverria C, Fernandez R, Cabello-Verrugio C, et al. Endotoxin-induced vascular endothelial cell migration is dependent on TLR4/NF-kappaB pathway, NAD(P)H oxidase activation, and transient receptor potential melastatin 7 calcium channel activity. Int J Biochem Cell Biol 2014; 55: 11–23.
Sontia B, Montezano AC, Paravicini T, Tabet F, Touyz RM . Downregulation of renal TRPM7 and increased inflammation and fibrosis in aldosterone-infused mice: effects of magnesium. Hypertension 2008; 51: 915–21.
Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (No 81370897, 81441115, 21172271, 81402926, 81430046), the NSFC-CIHR Joint Health Research Initiative Proposal (No 81361128011), the Canadian Institutes of Health Research CIHR-NSFC China-Canada Joint Health Research Initiative (CIHR, FRN #132571), the Guangdong Provincial Department of Science and Technology (No 2016A050502023), the National Key New Drug Creation Program (No 2009ZX09103-039), the Research Funds for Provincial Key Laboratory from the Department of Education of Guangdong Province (No 50000-3211105), and the Youth Program from Guangzhou City Bureau of Education (No 2012C204).
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Pan, N., Lu, Ly., Li, M. et al. Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway. Acta Pharmacol Sin 38, 1236–1247 (2017). https://doi.org/10.1038/aps.2017.22
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DOI: https://doi.org/10.1038/aps.2017.22
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