Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Live-Webinar: Aktuelle Leitlinien bei Herz-Kreislauf-Erkrankungen

Konkret geht es um den Diabetes-Patienten mit kardiovaskulären Erkrankungen oder Risiken, die Herzinsuffizienz sowie die kardiovaskuläre Primär- und Sekundärprävention. Sind Sie hier schon auf dem neuesten Stand? Unsere Experten beleuchten, wo und warum das bisherige Procedere geändert werden soll und was in der Praxis sinnvoll ist. Holen Sie sich Ihr Update und 2 CME-Punkte beim MMW-Webinar am 24. April von 17.30 bis 19 Uhr. 
Erweiterte Suche
Anmelden
nach oben
Inflammation
Erschienen in: Inflammation 4/2017

06.05.2017 | ORIGINAL ARTICLE

Salidroside Inhibits Inflammation Through PI3K/Akt/HIF Signaling After Focal Cerebral Ischemia in Rats

verfasst von: Yicong Wei, Haimian Hong, Xiaoqin Zhang, Wenfang Lai, Yingzheng Wang, Kedan Chu, John Brown, Guizhu Hong, Lidian Chen

Erschienen in: Inflammation | Ausgabe 4/2017

Einloggen, um Zugang zu erhalten

Abstract

Salidroside is being investigated for its therapeutic potential in stroke because it is neuroprotective over an extended therapeutic window of time. In the present study, we investigated the mechanisms underlying the anti-inflammatory effects of salidroside (50 mg/kg intraperitoneally) in rats, given 1 h after reperfusion of a middle cerebral artery that had been occluded for 2 h. After 24 h, we found that salidroside increased the neuronal nuclear protein NeuN and reduced the marker of microglia and macrophages CD11b in the peri-infarct area of the brain. Salidroside also decreased IL-6, IL-1β, TNF-α, CD14, CD44, and iNOs mRNAs. At the same time, salidroside increased the ratio of phosphorylated protein kinase B (p-Akt) to total Akt. The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 prevented this increase in p-Akt and reversed the inhibitory effects of salidroside on CD11b and inflammatory mediators. Salidroside also elevated the protein levels of hypoxia-inducible factor (HIF) subunits HIF1α, HIF2α, HIF3α, and of erythropoietin (EPO). The stimulatory effects of salidroside on HIFα subunits were blocked by LY294002. Moreover, YC-1, a HIF inhibitor, abolished salidroside-mediated increase of HIF1α and prevented the inhibitory effects of salidroside on CD11b and inflammatory mediators. Taken together, our results provide evidence for the first time that all three HIFα subunits and EPO can be regulated by PI3K/Akt in cerebral tissue, and that salidroside entrains this signaling pathway to induce production of HIFα subunits and EPO, one or more of which mediate the anti-inflammatory effects of salidroside after cerebral IRI.
Literatur
1.
Jin, R., G. Yang, and G. Li. 2010. Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. Journal of Leukocyte Biology 87: 779–789.CrossRefPubMedPubMedCentral
2.
Hallenbeck, J.M. 1997. Cytokines, macrophages, and leukocytes in brain ischemia. Neurology 49: S5–S9.CrossRefPubMed
3.
Han, H.S., Y. Qiao, M. Karabiyikoglu, R.G. Giffard, and M.A. Yenari. 2002. Influence of mild hypothermia on inducible nitric oxide synthase expression and reactive nitrogen production in experimental stroke and inflammation. Journal of Neuroscience 22: 3921–3928.PubMed
4.
Wang, X., L. Xu, H. Wang, Y. Zhan, E. Pure, and G.Z. Feuerstein. 2002. CD44 deficiency in mice protects brain from cerebral ischemia injury. Journal of Neurochemistry 83: 1172–1179.CrossRefPubMed
5.
Muresanu, D.F., A. Buzoianu, S.I. Florian, and T. von Wild. 2012. Towards a roadmap in brain protection and recovery. Journal of Cellular and Molecular Medicine 16: 2861–2871.CrossRefPubMedPubMedCentral
6.
Zhang, W. and D. Stanimirovic. 2002. Current and future therapeutic strategies to target inflammation in stroke. Current Drug Targets. Inflammation and Allergy 1: 151–166.
7.
8.
Weidemann, A., and R.S. Johnson. 2008. Biology of HIF-1alpha. Cell Death and Differentiation 15: 621–627.CrossRefPubMed
9.
Maxwell, P.H., M.S. Wiesener, G.W. Chang, S.C. Clifford, E.C. Vaux, M.E. Cockman, C.C. Wykoff, C.W. Pugh, E.R. Maher, and P.J. Ratcliffe. 1999. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271–275.CrossRefPubMed
10.
Joshi, S., A.R. Singh, M. Zulcic, and D.L. Durden. 2014. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1 and HIF2 stability and tumor growth, angiogenesis, and metastasis. Molecular Cancer Research 12: 1520–1531.CrossRefPubMed
11.
Zhou, J., T. Schmid, R. Frank, and B. Brune. 2004. PI3K/Akt is required for heat shock proteins to protect hypoxia-inducible factor 1alpha from pVHL-independent degradation. Journal of Biological Chemistry 279: 13506–13513.CrossRefPubMed
12.
Treins, C., S. Giorgetti-Peraldi, J. Murdaca, G.L. Semenza, and E. Van Obberghen. 2002. Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. Journal of Biological Chemistry 277: 27975–27981.CrossRefPubMed
13.
Ye, Z., Q. Guo, P. Xia, N. Wang, E. Wang, and Y. Yuan. 2012. Sevoflurane postconditioning involves an up-regulation of HIF-1alpha and HO-1 expression via PI3K/Akt pathway in a rat model of focal cerebral ischemia. Brain Research 1463: 63–74.CrossRefPubMed
14.
Eltzschig, H.K., D.L. Bratton, and S.P. Colgan. 2014. Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nature Reviews Drug Discovery 13: 852–869.CrossRefPubMedPubMedCentral
15.
Baranova, O., L.F. Miranda, P. Pichiule, I. Dragatsis, R.S. Johnson, and J.C. Chavez. 2007. Neuron-specific inactivation of the hypoxia inducible factor 1 increases brain injury in a mouse model of transient focal cerebral ischemia. Journal of Neuroscience 27: 6320–6332.CrossRefPubMed
16.
17.
Wang, C., Z. Wang, X. Zhang, X. Zhang, L. Dong, Y. Xing, Y. Li, Z. Liu, L. Chen, H. Qiao, L. Wang, and C. Zhu. 2012. Protection by silibinin against experimental ischemic stroke: up-regulated pAkt, pmTOR, HIF-1α and Bcl-2, down-regulated Bax, NF-κB expression. Neuroscience Letters 529: 45–50.CrossRefPubMed
18.
Lai, W.F., Z.W. Zheng, X.Q. Zhang, Y.C. Wei, K.D. Chu, J. Brown, G.Z. Hong, and L.D. Chen. 2015. Salidroside-mediated neuroprotection is associated with induction of early growth response genes (Egrs) across a wide therapeutic window. Neurotoxicity Research 28: 108–121.CrossRefPubMed
19.
Shi, T.Y., S.F. Feng, J.H. Xing, Y.M. Wu, X.Q. Li, N. Zhang, Z. Tian, S.B. Liu, and M.G. Zhao. 2012. Neuroprotective effects of salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro. Neurotoxicity Research 21: 358–367.CrossRefPubMed
20.
Zhu, L., T. Wei, X. Chang, H. He, J. Gao, Z. Wen, and T. Yan. 2015. Effects of salidroside on myocardial injury in vivo in vitro via regulation of Nox/NF-kappaB/AP1 pathway. Inflammation 38: 1589–1598.CrossRefPubMed
21.
Hu, H., Z. Li, X. Zhu, R. Lin, and L. Chen. 2014. Salidroside reduces cell mobility via NF-κB and MAPK signaling in LPS-induced BV2 microglial cells. Evidence-based Complementary and Alternative Medicine 2014: 383821.PubMedPubMedCentral
22.
Gao, J., R. Zhou, X. You, F. Luo, H. He, X. Chang, L. Zhu, X. Ding, and T. Yan. 2016. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer’s disease via SIRT1/NF-kappaB pathway. Metabolic Brain Disease 31: 771–778.CrossRefPubMed
23.
Zheng, K.Y., Z.X. Zhang, A.J. Guo, C.W. Bi, K.Y. Zhu, S.L. Xu, J.Y. Zhan, D.T. Lau, T.T. Dong, R.C. Choi, and K.W. Tsim. 2012. Salidroside stimulates the accumulation of HIF-1alpha protein resulted in the induction of EPO expression: a signaling via blocking the degradation pathway in kidney and liver cells. European Journal of Pharmacology 679: 34–39.CrossRefPubMed
24.
Longa, E.Z., P.R. Weinstein, S. Carlson, and R. Cummins. 1989. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20: 84–91.CrossRefPubMed
25.
Nakayama, H., M.D. Ginsberg, and W.D. Dietrich. 1988. (S)-emopamil, a novel calcium channel blocker and serotonin S2 antagonist, markedly reduces infarct size following middle cerebral artery occlusion in the rat. Neurology 38: 1667–1673.CrossRefPubMed
26.
Belayev, L., O.F. Alonso, R. Busto, W. Zhao, and M.D. Ginsberg. 1996. Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model. Stroke 27 (1616–1622): 1623.
27.
Zhao, H., T. Shimohata, J.Q. Wang, G. Sun, D.W. Schaal, R.M. Sapolsky, and G.K. Steinberg. 2005. Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. Journal of Neuroscience 25: 9794–9806.CrossRefPubMed
28.
Zhang, Z., J. Yan, S. Taheri, K.J. Liu, and H. Shi. 2014. Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke. Free Radical Biology and Medicine 68: 8–21.CrossRefPubMed
29.
Sun, M., B. Deng, X. Zhao, C. Gao, L. Yang, H. Zhao, D. Yu, F. Zhang, L. Xu, L. Chen, and X. Sun. 2015. Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation. Scientific Reports 5: 11445.CrossRefPubMedPubMedCentral
30.
Perego, C., S. Fumagalli, and M.G. De Simoni. 2011. Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. Journal of Neuroinflammation 8: 174.CrossRefPubMedPubMedCentral
31.
Guha, M., and N. Mackman. 2002. The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. Journal of Biological Chemistry 277: 32124–32132.CrossRefPubMed
32.
Jin, R., Z. Song, S. Yu, A. Piazza, A. Nanda, J.M. Penninger, D.N. Granger, and G. Li. 2011. Phosphatidylinositol-3-kinase gamma plays a central role in blood-brain barrier dysfunction in acute experimental stroke. Stroke 42: 2033–2044.CrossRefPubMedPubMedCentral
33.
Lai, W.F., X. Tian, Q. Xiang, K.D. Chu, Y. Wei, J.T. Deng, S.P. Zhang, J. Brown, and G.Z. Hong. 2015. 11β-HSD1 modulates LPS-induced innate immune responses in adipocytes by altering expression of PTEN. Molecular Endocrinology 29: 558–570.CrossRefPubMedPubMedCentral
34.
Li, L., D.W. McBride, D. Doycheva, B.J. Dixon, P.R. Krafft, J.H. Zhang, and J.P. Tang. 2015. G-CSF attenuates neuroinflammation and stabilizes the blood–brain barrier via the PI3K/Akt/GSK-3β signaling pathway following neonatal hypoxia-ischemia in rats. Experimental Neurology 272: 135–144.CrossRefPubMedPubMedCentral
35.
Chun, Y.S., E.J. Yeo, E. Choi, C.M. Teng, J.M. Bae, M.S. Kim, and J.W. Park. 2001. Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochemical Pharmacology 61: 947–954.CrossRefPubMed
36.
Li, S.H., D.H. Shin, Y.S. Chun, M.K. Lee, M.S. Kim, and J.W. Park. 2008. A novel mode of action of YC-1 in HIF inhibition: stimulation of FIH-dependent p300 dissociation from HIF-1. Molecular Cancer Therapeutics 7: 3729–3738.CrossRefPubMed
37.
Zhang, L., W. Ding, H. Sun, Q. Zhou, J. Huang, X. Li, Y. Xie, and J. Chen. 2012. Salidroside protects PC12 cells from MPP(+)-induced apoptosis via activation of the PI3K/Akt pathway. Food and Chemical Toxicology 50: 2591–2597.CrossRefPubMed
38.
Zhang, B., Y. Wang, H. Li, R. Xiong, Z. Zhao, X. Chu, Q. Li, S. Sun, and S. Chen. 2016. Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models. Drug Design, Development and Therapy 10: 1335–1343.PubMedPubMedCentral
39.
Chen, S.F., H.J. Tsai, T.H. Hung, C.C. Chen, C.Y. Lee, C.H. Wu, P.Y. Wang, and N.C. Liao. 2012. Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury. PloS One 7: e45763.CrossRefPubMedPubMedCentral
40.
Zhang, W., H. He, H. Song, J. Zhao, T. Li, L. Wu, X. Zhang, and J. Chen. 2016. Neuroprotective effects of salidroside in the MPTP mouse model of Parkinson’s disease: involvement of the PI3K/Akt/GSK3beta pathway. Parkinson's Disease 2016: 9450137.CrossRefPubMedPubMedCentral
41.
Guan, S., H. Feng, B. Song, W. Guo, Y. Xiong, G. Huang, W. Zhong, M. Huo, N. Chen, J. Lu, and X. Deng. 2011. Salidroside attenuates LPS-induced pro-inflammatory cytokine responses and improves survival in murine endotoxemia. International Immunopharmacology 11: 2194–2199.CrossRefPubMed
42.
Zhu, L., T. Wei, J. Gao, X. Chang, H. He, M. Miao, and T. Yan. 2015. Salidroside attenuates lipopolysaccharide (LPS) induced serum cytokines and depressive-like behavior in mice. Neuroscience Letters 606: 1–6.CrossRefPubMed
43.
Wu, D., P. Yuan, C. Ke, H. Xiong, J. Chen, J. Guo, M. Lu, Y. Ding, X. Fan, Q. Duan, F. Shi, and F. Zhu. 2016. Salidroside suppresses solar ultraviolet-induced skin inflammation by targeting cyclooxygenase-2. Oncotarget 7: 25971–25982.PubMedPubMedCentral
44.
Sun, P., S.Z. Song, S. Jiang, X. Li, Y.L. Yao, Y.L. Wu, L.H. Lian, J.X. Nan. 2016. Salidroside regulates inflammatory response in Raw 264.7 macrophages via TLR4/TAK1 and ameliorates inflammation in alcohol binge drinking-induced liver injury. Molecules 21:E 1490.
45.
Sun, H.L., Y.N. Liu, Y.T. Huang, S.L. Pan, D.Y. Huang, J.H. Guh, F.Y. Lee, S.C. Kuo, and C.M. Teng. 2007. YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia. Oncogene 26: 3941–3951.CrossRefPubMed
46.
Ivan, M., K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J.M. Asara, W.S. Lane, and W.J. Kaelin. 2001. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292: 464–468.CrossRefPubMed
47.
Heidbreder, M., F. Frohlich, O. Johren, A. Dendorfer, F. Qadri, and P. Dominiak. 2003. Hypoxia rapidly activates HIF-3alpha mRNA expression. FASEB Journal 17: 1541–1543.PubMed
48.
Zhang, P., Q. Yao, L. Lu, Y. Li, P.J. Chen, and C. Duan. 2014. Hypoxia-inducible factor 3 is an oxygen-dependent transcription activator and regulates a distinct transcriptional response to hypoxia. Cell Reports 6: 1110–1121.CrossRefPubMed
49.
Sarada, S., M. Titto, P. Himadri, S. Saumya, and V. Vijayalakshmi. 2015. Curcumin prophylaxis mitigates the incidence of hypobaric hypoxia-induced altered ion channels expression and impaired tight junction proteins integrity in rat brain. Journal of Neuroinflammation 12: 113.CrossRefPubMedPubMedCentral
50.
Koh, H.S., C.Y. Chang, S. Jeon, H.J. Yoon, Y. Ahn, H. Kim, I. Kim, S.H. Jeon, R.S. Johnson, and E.J. Park. 2015. The HIF-1/glial TIM-3 axis controls inflammation-associated brain damage under hypoxia. Nature Communications 6: 6340.CrossRefPubMedPubMedCentral
51.
Villa, P., P. Bigini, T. Mennini, D. Agnello, T. Laragione, A. Cagnotto, B. Viviani, M. Marinovich, A. Cerami, T.R. Coleman, M. Brines, and P. Ghezzi. 2003. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. Journal of Experimental Medicine 198: 971–975.CrossRefPubMedPubMedCentral
52.
Marti, H.H., R.H. Wenger, L.A. Rivas, U. Straumann, M. Digicaylioglu, V. Henn, Y. Yonekawa, C. Bauer, and M. Gassmann. 1996. Erythropoietin gene expression in human, monkey and murine brain. European Journal of Neuroscience 8: 666–676.CrossRefPubMed
53.
Masuda, S., M. Okano, K. Yamagishi, M. Nagao, M. Ueda, R. Sasaki. 1994. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. Journal of Biological Chemistry 269: 19488–19493.
54.
Rabie, T., and H.H. Marti. 2008. Brain protection by erythropoietin: a manifold task. Physiology 23: 263–274.CrossRefPubMed
Metadaten
Titel
Salidroside Inhibits Inflammation Through PI3K/Akt/HIF Signaling After Focal Cerebral Ischemia in Rats
verfasst von
Yicong Wei
Haimian Hong
Xiaoqin Zhang
Wenfang Lai
Yingzheng Wang
Kedan Chu
John Brown
Guizhu Hong
Lidian Chen
Publikationsdatum
06.05.2017
Verlag
Springer US
Erschienen in
Inflammation / Ausgabe 4/2017
Print ISSN: 0360-3997
Elektronische ISSN: 1573-2576
DOI
https://doi.org/10.1007/s10753-017-0573-x

Weitere Artikel der Ausgabe 4/2017

Inflammation 4/2017 Zur Ausgabe

ORIGINAL ARTICLE

An Active Drimane-Type Lactone from Polygonum jucundum Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Mice Through TLR4-MAPKs Signaling Pathway

ORIGINAL ARTICLE

Roflumilast Reduces Cerebral Inflammation in a Rat Model of Experimental Subarachnoid Hemorrhage

ORIGINAL ARTICLE

A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor κB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis

ORIGINAL ARTICLE

N-(2-Hydroxyphenyl)acetamide: a Novel Suppressor of RANK/RANKL Pathway in Collagen-Induced Arthritis Model in Rats

ORIGINAL ARTICLE

Cavidine Ameliorates Lipopolysaccharide-Induced Acute Lung Injury via NF-κB Signaling Pathway in vivo and in vitro

ORIGINAL ARTICLE

Regulation of iNOS-Derived ROS Generation by HSP90 and Cav-1 in Porcine Reproductive and Respiratory Syndrome Virus-Infected Swine Lung Injury

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

23.04.2024 | Ablationstherapie | Nachrichten

Wie erfolgreich ist eine Re-Ablation nach Rezidiv?

23.04.2024 | Prävention und Rehabilitation in der Kardiologie | Nachrichten

Europäische Ernährungsgewohnheiten: Das sind die häufigsten Fehler

23.04.2024 | Appendizitis | Nachrichten

Hinter dieser Appendizitis steckte ein Erreger

23.04.2024 | Demenz | Nachrichten

Demenzkranke durch Antipsychotika vielfach gefährdet
weitere anzeigen

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise