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.
Similar content being viewed by others
References
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
Blakeley J, Llinas R (2007) Thrombolytic therapy for acute ischemic stroke. J Neurol Sci 261:55–62
Ogata K, Kosaka T (2002) Structural and quantitative analysis of astrocytes in the mouse hippocampus. Neuroscience 113:221–233
Bushong E, Martone M, Jones Y, Ellisman M (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192
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
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
Rouach N, Glowinski J, Giaume C (2000) Activity-dependent neuronal control of gap-junctional communication in astrocytes. J Cell Biol 149:1513–1526
Araque A, Sanzgiri R, Parpura V, Haydon P (1999) Astrocyte-induced modulation of synaptic transmission. Can J Physiol Pharmacol 77:699–706
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
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
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
Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434
Swanson R, Ying W, Kauppinen T (2004) Astrocyte influences on ischemic neuronal death. Curr Mol Med 4:193–205
Zhao Y, Rempe D (2010) Targeting astrocytes for stroke therapy. Neurotherapeutics 7:439–451
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
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
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
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
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
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
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
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
Green D, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112
Tait SWG, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11:621–632
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
Webster KA (2012) Mitochondrial membrane permeabilization and cell death during myocardial infarction: roles of calcium and reactive oxygen species. Future Cardiol 8:863–884
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
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
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
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
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
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
Adams J, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol 19:488–496
Parsons M, Green D (2010) Mitochondria in cell death. Essays Biochem 47:99–114
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
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
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
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
Ouyang Y, Giffard R (2012) ER-mitochondria crosstalk during cerebral ischemia: molecular chaperones and ER-mitochondrial calcium transfer. Int J Cell Biol 2012:493934
Ouyang Y, Stary C, Yang G, Giffard R (2013) Micrornas: innovative targets for cerebral ischemia and stroke. Curr Drug Targets 14:90–101
Hertz L (2008) Bioenergetics of cerebral ischemia: a cellular perspective. Neuropharmacology 55:289–309
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
Hertz L, Dienel G (2002) Energy metabolism in the brain. Int Rev Neurobiol 51:1–102
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
Fox P, Raichle M, Mintun M, Dence C (1988) Nonoxidative glucose consumption during focal physiologic neural activity. Science 241:462–464
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
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
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
Rose CR, Ransom BR (1997) Gap junctions equalize intracellular Na + concentration in astrocytes. Glia 20:299–307
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
Martinez A, Saez J (2000) Regulation of astrocyte gap junctions by hypoxia-reoxygenation. Brain Res Brain Res Rev 32:250–258
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
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
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
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
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
Kernagis D, Laskowitz D (2012) Evolving role of biomarkers in acute cerebrovascular disease. Ann Neurol 71:289–303
Chopp M, Li Y (1996) Apoptosis in focal cerebral ischemia. Acta Neurochir Suppl 66:21–26
Mattson M, Culmsee C, Yu Z (2000) Apoptotic and antiapoptotic mechanisms in stroke. Cell Tissue Res 301:173–187
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
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
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
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
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
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
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
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
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
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
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
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
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
Acknowledgments
Supported by NIH T32-GM089626 to CMS, and NIH grants NS084396, NS053898, and NS080177 to RGG
Conflict of interest
The authors have no conflicting financial interests
Author information
Authors and Affiliations
Corresponding author
Additional information
Special issue: In honor of Michael Norenberg
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-014-1373-4