Abstract
Resveratrol (RSV) attenuates early brain injury (EBI) after subarachnoid hemorrhage (SAH). This study aimed to investigate whether the effects of RSV on SAH-induced EBI were mediated via the AMPK/SIRT1/autophagy pathway. A SAH rat model was established and oxyhemoglobin (Oxyhb)-induced primary cortical neurons were prepared to mimic SAH in vitro. The results showed that RSV significantly reduced microglia activation and the release of inflammatory cytokines, resulting in the alleviation of neurological behavior impairment, brain edema and neural apoptosis at 24 h post-SAH. However, RSV failed to ameliorate neurological deficits, brain edema and neural apoptosis when SAH injury lasted for 72 h. Additionally, at 24 h post-SAH, RSV-administered rats showed a significant increase in the LC3-II/I ratio and the phosphorylation state of AMPK and SIRT1 protein expression in brain tissues. Further in vitro studies revealed that RSV notably reduced the release of inflammatory cytokines and neural apoptosis in neurons at 24 post-Oxyhb, which was abolished by 3MA (an autophagy inhibitor) and Compound C (an AMPK inhibitor). Moreover, Compound C decreased LC3-II/I ratio and inhibited SIRT1 protein expression, whereas 3MA had no significant effects on AMPK/SIRT1-related proteins. In conclusion, the AMPK/SIRT1/autophagy pathway plays an important role in the alleviation of SAH-induced EBI by RSV.
Conflict of interest statement: All authors declared no conflicts of interest.
References
Ates, O., Cayli, S., Altinoz, E., Gurses, I., Yucel, N., Sener, M., Kocak, A., and Yologlu, S. (2007). Neuroprotection by resveratrol against traumatic brain injury in rats. Mol. Cell. Biochem. 294, 137–144.10.1007/s11010-006-9253-0Search in Google Scholar
Baur, J.A. and Sinclair, D.A. (2006). Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Discov. 5, 493–506.10.1038/nrd2060Search in Google Scholar
Bederson, J.B., Germano, I.M., and Guarino, L. (1995). Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke 26, 1091–1092.10.1161/01.STR.26.6.1086Search in Google Scholar
Cantó, C. and Auwerx, J. (2009). PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20, 98–105.10.1097/MOL.0b013e328328d0a4Search in Google Scholar
Cantó, C., Gerharthines, Z., Feige, J.N., Lagouge, M., Noriega, L., Milne, J.C., Elliott, P.J., Puigserver, P., and Auwerx, J. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060.10.1038/nature07813Search in Google Scholar
Chau, M.D.L. and Keating, M.T. (2010). Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc. Natl. Acad. Sci. USA 107, 12553–12558.10.1073/pnas.1006962107Search in Google Scholar
Chen, S., Feng, H., Sherchan, P., Klebe, D., Zhao, G., Sun, X., Zhang, J., Tang, J., and Zhang, J.H. (2014). Controversies and evolving new mechanisms in subarachnoid hemorrhage. Prog. Neurobiol. 115, 64–91.10.1016/j.pneurobio.2013.09.002Search in Google Scholar
Gallardomontejano, V.I., Saxena, G., Kusminski, C.M., Yang, C., Mcafee, J.L., Hahner, L., Hoch, K., Dubinsky, W., Narkar, V.A., and Bickel, P.E. (2016). Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function. Nat. Commun. 7, 12723.10.1038/ncomms12723Search in Google Scholar
Gijn, J.V., Kerr, R.S., and Rinkel, G.J. (2007). Subarachnoid haemorrhage. Lancet 369, 904.10.1016/S0140-6736(07)60442-5Search in Google Scholar
Going, J.J. (1994). Efficiently estimated histologic cell counts. Hum. Pathol. 25, 333–336.10.1016/0046-8177(94)90139-2Search in Google Scholar
Guo, D., Xie, J., Zhao, J., Huang, T., Guo, X., and Song, J. (2018). Resveratrol protects early brain injury after subarachnoid hemorrhage by activating autophagy and inhibiting apoptosis mediated by the Akt/mTOR pathway. Neuroreport 29, 368–379.10.1097/WNR.0000000000000975Search in Google Scholar PubMed PubMed Central
Hardie, D.G., Carling, D., and Carlson, M. (1998). The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem. 67, 821–855.10.1146/annurev.biochem.67.1.821Search in Google Scholar PubMed
Jung, S.N., Yang, W.K., Kim, J., Kim, H.S., Kim, E.J., Yun, H., Park, H., Kim, S.S., Choe, W., and Kang, I. (2008). Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. Carcinogenesis 29, 713–721.10.1093/carcin/bgn032Search in Google Scholar PubMed
Kikuchi, T., Okuda, Y., Kaito, N., and Abe, T. (1995). Cytokine production in cerebrospinal fluid after subarachnoid haemorrhage. Neurol. Res. 17, 106–108.10.1080/01616412.1995.11740296Search in Google Scholar PubMed
Kim, M.Y., Lim, J.H., Youn, H.H., Hong, Y.A., Yang, K.S., Park, H.S., Chung, S., Koh, S.H., Shin, S.J., and Choi, B.S. (2012). Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice. Diabetologia 56, 204–217.10.1007/s00125-012-2747-2Search in Google Scholar PubMed
Kitada, M., Kume, S., Imaizumi, N., and Koya, D. (2011). Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes. 60, 634–643.10.2337/db10-0386Search in Google Scholar PubMed PubMed Central
Klionsky, D.J., Cuervo, A.M., and Seglen, P.O. (2007). Methods for monitoring autophagy from yeast to human. Autophagy 3, 181–206.10.4161/auto.3678Search in Google Scholar PubMed
Lee, J.Y., He, Y., Sagher, O., Keep, R., Hua, Y., and Xi, G. (2009). Activated autophagy pathway in experimental subarachnoid hemorrhage. Brain Res. 1287, 126–135.10.1016/j.brainres.2009.06.028Search in Google Scholar PubMed
Li, Z., Fang, F., Wang, Y., and Wang, L. (2016). Resveratrol protects CA1 neurons against focal cerebral ischemic reperfusion-induced damage via the ERK-CREB signaling pathway in rats. Pharmacol. Biochem. Behav. 146–147, 21–27.10.1016/j.pbb.2016.04.007Search in Google Scholar PubMed
Liu, C.L., Chen, S., Dietrich, D., and Hu, B.R. (2008). Changes in autophagy after traumatic brain injury. J. Cereb. Blood Flow Metab. 28, 674–683.10.1038/sj.jcbfm.9600587Search in Google Scholar PubMed PubMed Central
Luo, C., Yi, B., Chen, Z., Tang, W., Chen, Y., Hu, R., Liu, Z., Feng, H., and Zhang, J.H. (2011). PKGIα inhibits the proliferation of cerebral arterial smooth muscle cell induced by oxyhemoglobin after subarachnoid hemorrhage. Acta Neurochir. (Suppl.) 110, 167–171.10.1007/978-3-7091-0353-1_29Search in Google Scholar
Manoel, A.L.D.O., Mansur, A., Murphy, A., Turkelparrella, D., Macdonald, M., Macdonald, R.L., Montanera, W., Marotta, T.R., Bharatha, A., and Effendi, K. (2014). Aneurysmal subarachnoid haemorrhage from a neuroimaging perspective. Crit. Care 18, 1–13.10.1186/s13054-014-0557-2Search in Google Scholar
Miller, B.A., Turan, N., Chau, M., and Pradilla, G. (2014). Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. BioMed Res. Int. 2014, 1327–1338.10.1155/2014/384342Search in Google Scholar PubMed PubMed Central
Milne, J.C., Lambert, P.D., Schenk, S., Carney, D.P., Smith, J.J., Gagne, D.J., Lei, J., Boss, O., Perni, R.B., and Chi, B.V. (2007). Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 450, 712–716.10.1038/nature06261Search in Google Scholar PubMed PubMed Central
Mizushima, N. (2011). Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397–402.10.1101/sqb.2011.76.011023Search in Google Scholar PubMed
Narayanan, S.V., Dave, K.R., Saul, I., and Perezpinzon, M.A. (2015). Resveratrol preconditioning protects against cerebral ischemic injury via nuclear erythroid 2-related factor 2. Stroke 46, 1626.10.1161/STROKEAHA.115.008921Search in Google Scholar PubMed PubMed Central
Ostrowski, R.P., Colohan, A.R., and Zhang, J.H. (2005). Mechanisms of hyperbaric oxygen-induced neuroprotection in a rat model of subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 25, 554–571.10.1038/sj.jcbfm.9600048Search in Google Scholar PubMed
Pan, T. and Kondo, S.W. (2008). Neuroprotection of rapamycin in lactacystin-induced neurodegeneration via autophagy enhancement. Neurobiol. Dis. 32, 16–25.10.1016/j.nbd.2008.06.003Search in Google Scholar PubMed
Perry, V.H., Nicoll, J.A., and Holmes, C. (2010). Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201.10.1038/nrneurol.2010.17Search in Google Scholar PubMed
Price, N.L., Gomes, A.P., Ling, A.J., Duarte, F.V., Martin-Montalvo, A., North, B.J., Agarwal, B., Ye, L., Ramadori, G., and Teodoro, J.S. (2012). SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690.10.1016/j.cmet.2012.04.003Search in Google Scholar PubMed PubMed Central
Rami, A., Langhagen, A., and Steiger, S. (2008). Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol. Dis. 29, 132–141.10.1016/j.nbd.2007.08.005Search in Google Scholar PubMed
Ren, J., Fan, C., Chen, N., Huang, J., and Yang, Q. (2011). Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem. Res. 36, 2352–2362.10.1007/s11064-011-0561-8Search in Google Scholar PubMed
Rivest, S. (2009). Regulation of innate immune responses in the brain. Nat. Rev. Immunol. 9, 429–439.10.1038/nri2565Search in Google Scholar
Saiko, P., Szakmary, A., Jaeger, W., and Szekeres, T. (2008). Resveratrol and its analogs: defense against cancer, coronary disease and neurodegenerative maladies or just a fad? Mutat. Res. 658, 68–94.10.1016/j.mrrev.2007.08.004Search in Google Scholar
Sehba, F.A. and Bederson, J.B. (2006). Mechanisms of acute brain injury after subarachnoid hemorrhage. Neurol. Res. 28, 381–398.10.1179/016164106X114991Search in Google Scholar
Sehba, F.A., Hou, J., Pluta, R.M., and Zhang, J.H. (2012). The importance of early brain injury after subarachnoid hemorrhage. Prog. Neurobiol. 97, 14–37.10.1016/j.pneurobio.2012.02.003Search in Google Scholar
Sercombe, R., Dinh, Y.R., and Gomis, P. (2002). Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn. J. Pharmacol. 88, 227–249.10.1254/jjp.88.227Search in Google Scholar
Shao, A.W., Wu, H.J., Chen, S., Ammar, A.B., Zhang, J.M., and Hong, Y. (2014). Resveratrol attenuates early brain injury after subarachnoid hemorrhage through inhibition of NF-κB-dependent inflammatory/MMP-9 pathway. CNS Neurosci. Ther. 20, 182–185.10.1111/cns.12194Search in Google Scholar
Sheng, C., Ma, Q., Krafft, P.R., Qin, H., William Rolland, I., Sherchan, P., Zhang, J., Tang, J., and Zhang, J.H. (2013). P2X7R/cryopyrin inflammasome axis inhibition reduces neuroinflammation after SAH. Neurobiol. Dis. 58, 296–307.10.1016/j.nbd.2013.06.011Search in Google Scholar
Singh, N. and Agrawal, M. (2013). Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models. ACS Chem. Neurosci. 4, 1151–1162.10.1021/cn400094wSearch in Google Scholar
Soleas, G., Grass, L., Josephy, D., and Diamandis, E.P. (2000). Resveratrol, a red wine constituent, has anticarcinogenic properties. Clin. Biochem. 33, 240–240.10.1016/S0009-9120(00)00128-4Search in Google Scholar
Song, J., Cheon, S.Y., Jung, W., Lee, W.T., and Lee, J.E. (2014). Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia. Int. J. Mol. Sci. 15, 15512–15529.10.3390/ijms150915512Search in Google Scholar PubMed PubMed Central
Sun, Q., Wu, W., Hu, Y.C., Li, H., Zhang, D., Li, S., Li, W., Li, W.D., Ma, B., and Zhu, J.H. (2014). Early release of high-mobility group box 1 (HMGB1) from neurons in experimental subarachnoid hemorrhage in vivo and in vitro. J. Neuroinflamm. 11, 106–106.10.1186/1742-2094-11-106Search in Google Scholar PubMed PubMed Central
Tian, Y., Ma, J., Wang, W., Zhang, L., Xu, J., Wang, K., and Li, D. (2016). Resveratrol supplement inhibited the NF-κB inflammation pathway through activating AMPKα-SIRT1 pathway in mice with fatty liver. Mol. Cell. Biochem. 422, 75–84.10.1007/s11010-016-2807-xSearch in Google Scholar PubMed
Topkoru, B.C., Altay, O., Duris, K., Krafft, P.R., Yan, J., and Zhang, J.H. (2013). Nasal administration of recombinant osteopontin attenuates early brain injury after subarachnoid hemorrhage. Stroke 44, 3189–3194.10.1161/STROKEAHA.113.001574Search in Google Scholar PubMed PubMed Central
Tran, A.T., Ramalinga, M., Kedir, H., Clarke, R., and Kumar, D. (2015). Autophagy inhibitor 3-methyladenine potentiates apoptosis induced by dietary tocotrienols in breast cancer cells. Eur. J. Nutr. 54, 265–272.10.1007/s00394-014-0707-ySearch in Google Scholar PubMed PubMed Central
Wang, Z., Shi, X.Y., Yin, J., Zuo, G., Zhang, J., and Chen, G. (2012). Role of autophagy in early brain injury after experimental subarachnoid hemorrhage. J. Mol. Neurosci. 46, 192–202.10.1007/s12031-011-9575-6Search in Google Scholar PubMed
Wang, Z., Wang, Y., Tian, X., Shen, H., Dou, Y., Li, H., and Chen, G. (2016a). Transient receptor potential channel 1/4 reduces subarachnoid hemorrhage-induced early brain injury in rats via calcineurin-mediated NMDAR and NFAT dephosphorylation. Sci Rep. 6, 33577.10.1038/srep33577Search in Google Scholar PubMed PubMed Central
Wang, X.H., Zhu, L., Hong, X., Wang, Y.T., Wang, F., Bao, J.P., Xie, X.H., Liu, L., and Wu, X.T. (2016b). Resveratrol attenuated TNF-α-induced MMP-3 expression in human nucleus pulposus cells by activating autophagy via AMPK/SIRT1 signaling pathway. Exp. Biol. Med. 241, 848–853.10.1177/1535370216637940Search in Google Scholar PubMed PubMed Central
West, T., Atzeva, M., and Holtzman, D.M. (2007). Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury. Dev. Neurosci. 29, 363–372.10.1159/000105477Search in Google Scholar PubMed PubMed Central
Wu, Y., Li, X., Zhu, J.X., Xie, W., Le, W., Fan, Z., Jankovic, J., and Pan, T. (2011). Resveratrol-activated AMPK/SIRT1/Autophagy in cellular models of Parkinson’s disease. Neuro-Signals 19, 163–174.10.1159/000328516Search in Google Scholar PubMed PubMed Central
Wu, H., Niu, H., Cheng, W., Yong, L., Wang, K., Zhang, J., Wang, Y., and Yang, S. (2016). The autophagy–lysosomal system in subarachnoid haemorrhage. J. Cell. Mol. Med. 20, 1770–1778.10.1111/jcmm.12855Search in Google Scholar PubMed PubMed Central
Yan, P., Bai, L., Lu, W., Gao, Y., Bi, Y., and Lv, G. (2017). Regulation of autophagy by AMP-activated protein kinase/sirtuin 1 pathway reduces spinal cord neurons damage. Iran. J. Basic Med. Sci. 20, 1029–1036.Search in Google Scholar
Zhang, X., Li, W., Wu, Q., Wu, L., Ye, Z., Liu, J., Zhuang, Z., Zhou, M., Zhang, X., and Hang, C. (2016a). Resveratrol attenuates acute inflammatory injury in experimental subarachnoid hemorrhage in rats via inhibition of TLR4 pathway. Int. J. Mol. Sci. 17, pii: E1331.10.3390/ijms17081331Search in Google Scholar PubMed PubMed Central
Zhang, X.S., Wu, Q., Wu, L.Y., Ye, Z.N., Jiang, T.W., Li, W., Zhuang, Z., Zhou, M.L., Zhang, X., and Hang, C.H. (2016b). Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. Cell Death Dis. 7, e2416.10.1038/cddis.2016.292Search in Google Scholar PubMed PubMed Central
Zhang, X., Wu, Q., Zhang, Q., Lu, Y., Liu, J., Li, W., Lv, S., Zhou, M., Zhang, X., and Hang, C. (2017). Resveratrol attenuates early brain injury after experimental subarachnoid hemorrhage via inhibition of NLRP3 inflammasome activation. Front. Neurosci. 11, 611.10.3389/fnins.2017.00611Search in Google Scholar PubMed PubMed Central
Zhao, X., Terkeltaub, R., Lotz, M., and Liu-Bryan, R. (2013). AMPK-SIRT1-PGC-1α signaling regulates mitochondrial function in human articular chondrocytes. Osteoarthr. Cartilage 21, S128.10.1016/j.joca.2013.02.269Search in Google Scholar
Zhou, X.M., Zhou, M.L., Zhang, X.S., Zhuang, Z., Li, T., Shi, J.X., and Zhang, X. (2014). Resveratrol prevents neuronal apoptosis in an early brain injury model. J. Surg. Res. 189, 159–165.10.1016/j.jss.2014.01.062Search in Google Scholar PubMed
©2018 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Reviews
- Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk
- Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)
- Modifications in small nuclear RNAs and their roles in spliceosome assembly and function
- Minireview
- Transcriptional regulation of human defense peptides: a new direction in infection control
- Research Articles/Short Communications
- Cell Biology and Signaling
- Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer
- p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate
- MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells
- Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing
- IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways
- Resveratrol alleviates early brain injury following subarachnoid hemorrhage: possible involvement of the AMPK/SIRT1/autophagy signaling pathway
Articles in the same Issue
- Frontmatter
- Reviews
- Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk
- Five decades of research on mitochondrial NADH-quinone oxidoreductase (complex I)
- Modifications in small nuclear RNAs and their roles in spliceosome assembly and function
- Minireview
- Transcriptional regulation of human defense peptides: a new direction in infection control
- Research Articles/Short Communications
- Cell Biology and Signaling
- Down-regulated paxillin suppresses cell proliferation and invasion by inhibiting M2 macrophage polarization in colon cancer
- p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate
- MAC30 knockdown involved in the activation of the Hippo signaling pathway in breast cancer cells
- Inhibition of JAK2/STAT3 signaling suppresses bone marrow stromal cells proliferation and osteogenic differentiation, and impairs bone defect healing
- IL-37 affects the occurrence and development of endometriosis by regulating the biological behavior of endometrial stromal cells through multiple signaling pathways
- Resveratrol alleviates early brain injury following subarachnoid hemorrhage: possible involvement of the AMPK/SIRT1/autophagy signaling pathway