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Advances in Astrocyte-targeted Approaches for Stroke Therapy: An Emerging Role for Mitochondria and microRNAS

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Abstract

Astrocytes are critical regulators of neuronal function and an effective target for stroke therapy in animal models. Identifying individual targets with the potential for simultaneous activation of multiple downstream pathways that regulate astrocyte homeostasis may be a necessary element for successful clinical translation. Mitochondria and microRNAs each represent individual targets with multi-modal therapeutic potential. Mitochondria regulate metabolism and apoptosis, while microRNAs have the capacity to bind and inhibit numerous mRNAs. By combining strategies targeted at maintaining astrocyte function during and following cerebral ischemia, a synergistic therapeutic effect may be achieved.

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References

  1. Roger V, Go A, Lloyd-Jones D, Adams R, Berry J, Brown T, Carnethon M, Dai S, de Simone G, Ford E, Fox C, Fullerton H, Gillespie C, Greenlund K, Hailpern S, Heit J, Ho P, Howard V, Kissela B, Kittner S, Lackland D, Lichtman J, Lisabeth L, Makuc D, Marcus G, Marelli A, Matchar D, McDermott M, Meigs J, Moy C, Mozaffarian D, Mussolino M, Nichol G, Paynter N, Rosamond W, Sorlie P, Stafford R, Turan T, Turner M, Wong N, Wylie-Rosett J (2011) Heart disease and stroke statistics–2011 update: a report from the American Heart Association. Circulation 123:e18–e209

    Article  PubMed  Google Scholar 

  2. Blakeley J, Llinas R (2007) Thrombolytic therapy for acute ischemic stroke. J Neurol Sci 261:55–62

    Article  CAS  PubMed  Google Scholar 

  3. Ogata K, Kosaka T (2002) Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113:221–233

    Article  CAS  PubMed  Google Scholar 

  4. Bushong E, Martone M, Jones Y, Ellisman M (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    CAS  PubMed  Google Scholar 

  5. Halassa M, Fellin T, Takano H, Dong J, Haydon P (2007) Synaptic islands defined by the territory of a single astrocyte. J Neurosci 27:6473–6477

    Article  CAS  PubMed  Google Scholar 

  6. Bass N, Hess H, Pope A, Thalheimer C (1971) Quantitative cytoarchitectonic distribution of neurons, glia, and DNA in rat cerebral cortex. J Comp Neurol 143:481–490

    Article  CAS  PubMed  Google Scholar 

  7. Rouach N, Glowinski J, Giaume C (2000) Activity-dependent neuronal control of gap-junctional communication in astrocytes. J Cell Biol 149:1513–1526

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Araque A, Sanzgiri R, Parpura V, Haydon P (1999) Astrocyte-induced modulation of synaptic transmission. Can J Physiol Pharmacol 77:699–706

    Article  CAS  PubMed  Google Scholar 

  9. Giordano G, Kavanagh T, Costa L (2009) Mouse cerebellar astrocytes protect cerebellar granule neurons against toxicity of the polybrominated diphenyl ether (PBDE) mixture DE-71. Neurotoxicology 30:326–329

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Noguchi Y, Shinozaki Y, Fujishita K, Shibata K, Imura Y, Morizawa Y, Gachet C, Koizumi S (2013) Astrocytes protect neurons against methylmercury via ATP/P2Y(1) receptor-mediated pathways in astrocytes. PLoS One 8:e57898

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Rathinam M, Watts L, Narasimhan M, Riar A, Mahimainathan L, Henderson G (2012) Astrocyte mediated protection of fetal cerebral cortical neurons from rotenone and paraquat. Environ Toxicol Pharmacol 33:353–360

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434

    Article  PubMed  Google Scholar 

  13. Swanson R, Ying W, Kauppinen T (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4:193–205

    Article  CAS  PubMed  Google Scholar 

  14. Zhao Y, Rempe D (2010) Targeting astrocytes for stroke therapy. Neurotherapeutics 7:439–451

    Article  CAS  PubMed  Google Scholar 

  15. Ferrer I, Planas A (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62:329–339

    PubMed  Google Scholar 

  16. Qu W, Wang Y, Wang J, Tang Y, Zhang Q, Tian D, Yu Z, Xie M, Wang W (2010) Galectin-1 enhances astrocytic BDNF production and improves functional outcome in rats following ischemia. Neurochem Res 35:1716–1724

    Article  CAS  PubMed  Google Scholar 

  17. Miao Y, Qiu Y, Lin Y, Miao Z, Zhang J, Lu X (2011) Protection by pyruvate against glutamate neurotoxicity is mediated by astrocytes through a glutathione-dependent mechanism. Mol Biol Rep 38:3235–3242

    Article  CAS  PubMed  Google Scholar 

  18. Ouyang Y, Voloboueva L, Xu L, Giffard R (2007) Selective dysfunction of hippocampal CA1 astrocytes contributes to delayed neuronal damage after transient forebrain ischemia. J Neurosci 27:4253–4260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Xu L, Emery JF, Ouyang Y-B, Voloboueva LA, Giffard RG (2010) Astrocyte targeted overexpression of Hsp72 or SOD2 reduces neuronal vulnerability to forebrain ischemia. Glia 58:1042–1049

    Article  PubMed Central  PubMed  Google Scholar 

  20. Weller ML, Stone IM, Goss A, Rau T, Rova C, Poulsen DJ (2008) Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia–ischemia. Neuroscience 155:1204–1211

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R (2008) Calcium and apoptosis: ER-mitochondria Ca2 + transfer in the control of apoptosis. Oncogene 27:6407–6418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Ruiz A, Matute C, Alberdi E (2009) Endoplasmic reticulum Ca2 + release through ryanodine and IP3 receptors contributes to neuronal excitotoxicity. Cell Calcium 46:273–281

    Article  CAS  PubMed  Google Scholar 

  23. Green D, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Tait SWG, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632

    Article  CAS  PubMed  Google Scholar 

  25. Penna C, Perrelli M-G, Pagliaro P (2013) Mitochondrial pathways, permeability transition pore, and redox signaling in cardioprotection: therapeutic implications. Antioxid Redox Signal 18:556–599

    Article  CAS  PubMed  Google Scholar 

  26. Webster KA (2012) Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species. Future Cardiol 8:863–884

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Giffard R, Han R, Emery J, Duan M, Pittet J (2008) Regulation of apoptotic and inflammatory cell signaling in cerebral ischemia: the complex roles of heat shock protein 70. Anesthesiology 109:339–348

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Szabadkai G, Bianchi K, Várnai P, De Stefani D, Wieckowski MR, Cavagna D, Nagy AI, Balla T, Rizzuto R (2006) Chaperone-mediated coupling of endoplasmic reticulum and mitochondrial Ca2 + channels. J Cell Biol 175:901–911

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Voloboueva LA, Duan M, Ouyang Y, Emery JF, Stoy C, Giffard RG (2007) Overexpression of mitochondrial Hsp70/Hsp75 protects astrocytes against ischemic injury in vitro. J Cereb Blood Flow Metab 28:1009–1016

    Article  PubMed Central  PubMed  Google Scholar 

  30. Xu L, Voloboueva LA, Ouyang Y, Emery JF, Giffard RG (2009) Overexpression of mitochondrial Hsp70/Hsp75 in rat brain protects mitochondria, reduces oxidative stress, and protects from focal ischemia. J Cereb Blood Flow Metab 29:365–374

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Sun F-C, Wei S, Li C-W, Chang Y-S, Chao C–C, Lai Y-K (2006) Localization of GRP78 to mitochondria under the unfolded protein response. Biochem J 396:31–39

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Ouyang Y, Xu L, Emery J, Lee A, Giffard R (2011) Overexpressing GRP78 influences Ca2 + handling and function of mitochondria in astrocytes after ischemia-like stress. Mitochondrion 11:279–286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Adams J, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19:488–496

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Parsons M, Green D (2010) Mitochondria in cell death. Essays Biochem 47:99–114

    Article  CAS  PubMed  Google Scholar 

  35. Kitagawa K, Matsumoto M, Tsujimoto Y, Ohtsuki T, Kuwabara K, Matsushita K, Yang G, Tanabe H, Martinou J, Hori M, Yanagihara T (1998) Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice. Stroke 29:2616–2621

    Article  CAS  PubMed  Google Scholar 

  36. Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK (2003) Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem 85:1026–1036

    Article  CAS  PubMed  Google Scholar 

  37. Ouyang Y, Carriedo S, Giffard R (2002) Effect of Bcl-x(L) overexpression on reactive oxygen species, intracellular calcium, and mitochondrial membrane potential following injury in astrocytes. Free Radic Biol Med 33:544–551

    Article  CAS  PubMed  Google Scholar 

  38. Szegezdi E, MacDonald DC, Chonghaile TNí, Gupta S, Samali A (2009) Bcl-2 family on guard at the ER. Am J Physiol Cell Physiol 296:C941–C953

    Article  CAS  PubMed  Google Scholar 

  39. Ouyang Y, Giffard R (2012) ER-mitochondria crosstalk during cerebral ischemia: molecular chaperones and ER-mitochondrial calcium transfer. Int J Cell Biol 2012:493934

    Article  PubMed Central  PubMed  Google Scholar 

  40. Ouyang Y, Stary C, Yang G, Giffard R (2013) Micrornas: innovative targets for cerebral ischemia and stroke. Curr Drug Targets 14:90–101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Hertz L (2008) Bioenergetics of cerebral ischemia: a cellular perspective. Neuropharmacology 55:289–309

    Article  CAS  PubMed  Google Scholar 

  42. Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27:1766–1791

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Hertz L, Dienel G (2002) Energy metabolism in the brain. Int Rev Neurobiol 51:1–102

    Article  CAS  PubMed  Google Scholar 

  44. Wender R, Brown AM, Fern R, Swanson RA, Farrell K, Ransom BR (2000) Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci 20:6804–6810

    CAS  PubMed  Google Scholar 

  45. Fox P, Raichle M, Mintun M, Dence C (1988) Nonoxidative glucose consumption during focal physiologic neural activity. Science 241:462–464

    Article  CAS  PubMed  Google Scholar 

  46. Pellerin L, Magistretti P (1994) Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci USA 91:10625–10629

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Amato S, Man H (2011) Bioenergy sensing in the brain: the role of AMP-activated protein kinase in neuronal metabolism, development and neurological diseases. Cell Cycle 10:3452–3460

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. An J, Haile W, Wu F, Torre E, Yepes M (2014) Tissue-type plasminogen activator mediates neuroglial coupling in the central nervous system. Neuroscience 257:41–48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Rose CR, Ransom BR (1997) Gap junctions equalize intracellular Na + concentration in astrocytes. Glia 20:299–307

    Article  CAS  PubMed  Google Scholar 

  50. Nakase T, Sohl G, Theis M, Willecke K, Naus C (2004) Increased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am J Pathol 164:2067–2075

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Martinez A, Saez J (2000) Regulation of astrocyte gap junctions by hypoxia-reoxygenation. Brain Res Brain Res Rev 32:250–258

    Article  CAS  PubMed  Google Scholar 

  52. Lin J, Weigel H, Cotrina M, Liu S, Bueno E, Hansen A, Hansen T, Goldman S, Nedergaard M (1998) Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci 1:494–500

    Article  CAS  PubMed  Google Scholar 

  53. Janssen H, Reesink H, Lawitz E, Zeuzem S, Rodriguez-Torres M, Patel K, van der Meer A, Patick A, Chen A, Zhou Y, Persson R, King B, Kauppinen S, Levin A, Hodges M (2013) Treatment of HCV infection by targeting microRNA. N Engl J Med 368:1685–1694

    Article  CAS  PubMed  Google Scholar 

  54. Dharap A, Bowen K, Place R, Li L, Vemuganti R (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29:675–687

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Jeyaseelan K, Lim K, Armugam A (2008) MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion. Stroke 39:959–966

    Article  CAS  PubMed  Google Scholar 

  56. Liu D, Tian Y, Ander B, Xu H, Stamova B, Zhan X, Turner R, Jickling G, Sharp F (2010) Brain and blood microRNA expression profiling of ischemic stroke, intracerebral hemorrhage, and kainate seizures. J Cereb Blood Flow Metab 30:92–101

    Article  PubMed Central  PubMed  Google Scholar 

  57. Kernagis D, Laskowitz D (2012) Evolving role of biomarkers in acute cerebrovascular disease. Ann Neurol 71:289–303

    Article  CAS  PubMed  Google Scholar 

  58. Chopp M, Li Y (1996) Apoptosis in focal cerebral ischemia. Acta Neurochir Suppl 66:21–26

    CAS  PubMed  Google Scholar 

  59. Mattson M, Culmsee C, Yu Z (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301:173–187

    Article  CAS  PubMed  Google Scholar 

  60. Yin K-J, Deng Z, Huang H, Hamblin M, Xie C, Zhang J, Chen YE (2010) MiR-497 regulates neuronal death in mouse brain after transient focal cerebral ischemia. Neurobiol Dis 38:17–26

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Jovicic A, Roshan R, Moisoi N, Pradervand S, Moser R, Pillai B, Luthi-Carter R (2013) Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J Neurosci 33:5127–5137

    Article  CAS  PubMed  Google Scholar 

  62. Ouyang Y, Xu L, Lu Y, Sun X, Yue S, Xiong X, Giffard R (2013) Astrocyte-enriched miR-29a targets PUMA and reduces neuronal vulnerability to forebrain ischemia. Glia 61:1784–1794

    PubMed  Google Scholar 

  63. Hutchison E, Kawamoto E, Taub D, Lal A, Abdelmohsen K, Zhang Y, Wood Wr, Lehrmann E, Camandola S, Becker K, Gorospe M, Mattson M (2013) Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes. Glia 61:1018–1028

    Article  PubMed  Google Scholar 

  64. Ouyang Y, Xu L, Yue S, Liu S, Giffard R (2014) Neuroprotection by astrocytes in brain ischemia: importance of microRNAs. Neurosci Lett 565C:53–58

    Article  Google Scholar 

  65. Ouyang Y, Lu Y, Yue S, Xu L, Xiong X, White R, Sun X, Giffard R (2012) miR-181 regulates GRP78 and influences outcome from cerebral ischemia in vitro and in vivo. Neurobiol Dis 45:555–563

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Ouyang Y, Lu Y, Yue S, Giffard R (2012) miR-181 targets multiple Bcl-2 family members and influences apoptosis and mitochondrial function in astrocytes. Mitochondrion 12:213–219

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Ouyang Y, Stary C, White R, Giffard R (2014) The use of microRNAs to modulate redox and immune response to stroke. Antioxid redox signal:epub ahead of print

  68. Moon J, Xu L, Giffard R (2013) Inhibition of microRNA-181 reduces forebrain ischemia-induced neuronal loss. J Cereb Blood Flow Metab 33:1976–1982

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Ye Y, Perez-Polo JR, Qian J, Birnbaum Y (2011) The role of microRNA in modulating myocardial ischemia-reperfusion injury. Physiol Genomics 43:534–542

    Article  CAS  PubMed  Google Scholar 

  70. Khanna S, Rink C, Ghoorkhanian R, Gnyawali S, Heigel M, Wijesinghe D, Chalfant C, Chan Y, Banerjee J, Huang Y, Roy S, Sen C (2013) Loss of miR-29b following acute ischemic stroke contributes to neural cell death and infarct size. J Cereb Blood Flow Metab 33:1197–1206

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Sepramaniam S, Tan J-R, Tan K-S, DeSilva D, Tavintharan S, Woon F-P, Wang C-W, Yong F-L, Karolina D-S, Kaur P, Liu F-J, Lim K-Y, Armugam A, Jeyaseelan K (2014) Circulating microRNAs as biomarkers of acute stroke. Int J Mol Sci 15:1418–1432

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Morel L, Regan M, Higashimori H, Ng S, Esau C, Vidensky S, Rothstein J, Yang Y (2013) Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J Biol Chem 288:7105–7116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

Supported by NIH T32-GM089626 to CMS, and NIH grants NS084396, NS053898, and NS080177 to RGG

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The authors have no conflicting financial interests

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Correspondence to Rona G. Giffard.

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Special issue: In honor of Michael Norenberg

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Stary, C.M., Giffard, R.G. Advances in Astrocyte-targeted Approaches for Stroke Therapy: An Emerging Role for Mitochondria and microRNAS. Neurochem Res 40, 301–307 (2015). https://doi.org/10.1007/s11064-014-1373-4

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  • DOI: https://doi.org/10.1007/s11064-014-1373-4

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