Ever since the discovery of small interfering ribonucleic acid (siRNA) a little over a decade ago, it has been highly sought after for its potential as a therapeutic agent for many diseases. In this review, we discuss the promising possibility of siRNA to be used as a drug to treat acute brain injuries such as stroke and traumatic brain injury. First, we will give a brief and basic overview of the principle of RNA interference as an effective mechanism to decrease specific protein expression. Then, we will review recent in vivo studies describing siRNA research experiments/treatment options for acute brain diseases. Lastly, we will discuss the future of siRNA as a clinical therapeutic strategy against brain diseases and injuries, while addressing the current obstacles to effective brain delivery.
References
[1]
Burnett, J.C.; Rossi, J.J.; Tiemann, K. Current progress of siRNA/shRNA therapeutics in clinical trials. Biotechnol. J. 2011, 6, 1130–1146.
[2]
Burnett, J.C.; Rossi, J.J. RNA-based therapeutics: Current progress and future prospects. Chem. Biol. 2012, 19, 60–71, doi:10.1016/j.chembiol.2011.12.008.
[3]
Brower, V. RNA interference advances to early-stage clinical trials. J. Nat. Cancer Inst. 2010, 102, 1459–1461, doi:10.1093/jnci/djq405.
[4]
Fire, A.; Xu, S.; Montgomery, M.K.; Kostas, S.A.; Driver, S.E.; Mello, C.C. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 1998, 391, 806–811, doi:10.1038/35888.
[5]
Carthew, R.W.; Sontheimer, E.J. Origins and mechanisms of miRNAs and siRNAs. Cell 2009, 136, 642–655, doi:10.1016/j.cell.2009.01.035.
[6]
Bernstein, E.; Caudy, A.A.; Hammond, S.M.; Hannon, G.J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 2001, 409, 363–366, doi:10.1038/35053110.
[7]
Ketting, R.F.; Fischer, S.E.; Bernstein, E.; Sijen, T.; Hannon, G.J.; Plasterk, R.H. Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Gene. Dev. 2001, 15, 2654–2659, doi:10.1101/gad.927801.
[8]
Montgomery, M.K.; Xu, S.; Fire, A. RNA as a target of double-stranded RNA-mediated genetic interference in Caenorhabditis elegans. Proc. Nat. Acad. Sci. USA 1998, 95, 15502–15507, doi:10.1073/pnas.95.26.15502.
[9]
Tabernero, J.; Shapiro, G.I.; Lorusso, P.M.; Cervantes, A.; Schwartz, G.K.; Weiss, G.J.; Paz-Ares, L.; Cho, D.C.; Infante, J.R.; Alsina, M.; et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 2013, 3, 406–417, doi:10.1158/2159-8290.CD-12-0429.
[10]
Thanvi, B.R.; Sprigg, N.; Munshi, S.K. Advances in spontaneous intracerebral haemorrhage. Int. J. Clin. Pract. 2012, 66, 556–564, doi:10.1111/j.1742-1241.2012.02925.x.
[11]
Caner, B.; Hou, J.; Altay, O.; Fuj, M., 2nd.; Zhang, J.H. Transition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage. J. Neurochem. 2012, 123, 12–21, doi:10.1111/j.1471-4159.2012.07939.x.
[12]
He, Z.; Ostrowski, R.P.; Sun, X.; Ma, Q.; Huang, B.; Zhan, Y.; Zhang, J.H. CHOP silencing reduces acute brain injury in the rat model of subarachnoid hemorrhage. Stroke 2012, 43, 484–490, doi:10.1161/STROKEAHA.111.626432.
Yan, J.; Li, L.; Khatibi, N.H.; Yang, L.; Wang, K.; Zhang, W.; Martin, R.D.; Han, J.; Zhang, J.; Zhou, C. Blood-brain barrier disruption following subarchnoid hemorrhage may be faciliated through PUMA induction of endothelial cell apoptosis from the endoplasmic reticulum. Exp. Neurol. 2011, 230, 240–247, doi:10.1016/j.expneurol.2011.04.022.
[15]
Ma, Q.; Manaenko, A.; Khatibi, N.H.; Chen, W.; Zhang, J.H.; Tang, J. Vascular adhesion protein-1 inhibition provides antiinflammatory protection after an intracerebral hemorrhagic stroke in mice. J. Cerebr. Blood Flow Metabol. 2011, 31, 881–893, doi:10.1038/jcbfm.2010.167.
[16]
Zhang, J.H.; Badaut, J.; Tang, J.; Obenaus, A.; Hartman, R.; Pearce, W.J. The vascular neural network—A new paradigm in stroke pathophysiology. Nat. Rev. Neurol. 2012, 8, 711–716, doi:10.1038/nrneurol.2012.210.
[17]
Roger, V.L.; Go, A.S.; Lloyd-Jones, D.M.; Adams, R.J.; Berry, J.D.; Brown, T.M.; Carnethon, M.R.; Dai, S.; de Simone, G.; Ford, E.S.; et al. Heart disease and stroke statistics—2011 update: A report from the American Heart Association. Circulation 2011, 123, e18–e209, doi:10.1161/CIR.0b013e3182009701.
[18]
Rosamond, W.; Flegal, K.; Friday, G.; Furie, K.; Go, A.; Greenlund, K.; Haase, N.; Ho, M.; Howard, V.; Kissela, B.; et al. Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007, 115, e69–e171, doi:10.1161/CIRCULATIONAHA.106.179918.
[19]
Saver, J.L. Time is brain—Quantified. Stroke 2006, 37, 263–266, doi:10.1161/01.STR.0000196957.55928.ab.
[20]
Hacke, W.; Kaste, M.; Bluhmki, E.; Brozman, M.; Davalos, A.; Guidetti, D.; Larrue, V.; Lees, K.R.; Medeghri, Z.; Machnig, T.; et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med. 2008, 359, 1317–1329, doi:10.1056/NEJMoa0804656.
[21]
Saver, J.L.; Gornbein, J.; Grotta, J.; Liebeskind, D.; Lutsep, H.; Schwamm, L.; Scott, P.; Starkman, S. Number needed to treat to benefit and to harm for intravenous tissue plasminogen activator therapy in the 3- to 4.5-hour window: Joint outcome table analysis of the ECASS 3 trial. Stroke 2009, 40, 2433–2437, doi:10.1161/STROKEAHA.108.543561.
[22]
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 1995, 333, 1581–1587, doi:10.1056/NEJM199512143332401.
[23]
The National Institute of Neurological Disorders and Stroke t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997, 28, 2109–2118, doi:10.1161/01.STR.28.11.2109.
Dirnagl, U.; Iadecola, C.; Moskowitz, M.A. Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci. 1999, 22, 391–397, doi:10.1016/S0166-2236(99)01401-0.
[26]
Zheng, Y.Q.; Liu, J.X.; Li, X.Z.; Xu, L.; Xu, Y.G. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol. Sin. 2009, 30, 919–927, doi:10.1038/aps.2009.79.
[27]
Al-Jamal, K.T.; Gherardini, L.; Bardi, G.; Nunes, A.; Guo, C.; Bussy, C.; Herrero, M.A.; Bianco, A.; Prato, M.; Kostarelos, K.; et al. Functional motor recovery from brain ischemic insult by carbon nanotube-mediated siRNA silencing. Proc. Nat. Acad. Sci. USA 2011, 108, 10952–10957, doi:10.1073/pnas.1100930108.
[28]
Kim, H.W.; Cho, K.J.; Lee, S.K.; Kim, G.W. Apoptosis signal-regulating kinase 1 (Ask1) targeted small interfering RNA on ischemic neuronal cell death. Brain Res. 2011, 1412, 73–78.
[29]
Zhang, J.; Wang, Y.; Zhu, P.; Wang, X.; Lv, M.; Feng, H. siRNA-mediated silence of protease-activated receptor-1 minimizes ischemic injury of cerebral cortex through HSP70 and MAP2. J. Neurol. Sci. 2012, 320, 6–11, doi:10.1016/j.jns.2012.05.040.
[30]
Price, M.; Badaut, J.; Thevenet, J.; Hirt, L. Activation of c-Jun in the nuclei of neurons of the CA-1 in thrombin preconditioning occurs via PAR-1. J. Neurosci. Res. 2010, 88, 1338–1347.
[31]
Thevenet, J.; Angelillo-Scherrer, A.; Price, M.; Hirt, L. Coagulation factor Xa activates thrombin in ischemic neural tissue. J. Neurochem. 2009, 111, 828–836, doi:10.1111/j.1471-4159.2009.06369.x.
[32]
Chen, C.; Hu, Q.; Yan, J.; Yang, X.; Shi, X.; Lei, J.; Chen, L.; Huang, H.; Han, J.; Zhang, J.H.; et al. Early inhibition of HIF-1alpha with small interfering RNA reduces ischemic-reperfused brain injury in rats. Neurobiol. Dis. 2009, 33, 509–517, doi:10.1016/j.nbd.2008.12.010.
[33]
Zhao, B.; Zhao, C.Z.; Zhang, X.Y.; Huang, X.Q.; Shi, W.Z.; Fang, S.H.; Lu, Y.B.; Zhang, W.P.; Xia, Q.; Wei, E.Q. The new P2Y-like receptor G protein-coupled receptor 17 mediates acute neuronal injury and late microgliosis after focal cerebral ischemia in rats. Neuroscience 2012, 202, 42–57, doi:10.1016/j.neuroscience.2011.11.066.
[34]
Ciana, P.; Fumagalli, M.; Trincavelli, M.L.; Verderio, C.; Rosa, P.; Lecca, D.; Ferrario, S.; Parravicini, C.; Capra, V.; Gelosa, P.; et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J. 2006, 25, 4615–4627, doi:10.1038/sj.emboj.7601341.
[35]
Lecca, D.; Trincavelli, M.L.; Gelosa, P.; Sironi, L.; Ciana, P.; Fumagalli, M.; Villa, G.; Verderio, C.; Grumelli, C.; Guerrini, U.; et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One 2008, 3, e3579.
[36]
Fukuda, A.M.; Badaut, J. Aquaporin 4: A player in cerebral edema and neuroinflammation. J. Neuroinflammation 2012, 9, 279, doi:10.1186/1742-2094-9-279.
[37]
Loane, D.J.; Byrnes, K.R. Role of microglia in neurotrauma. Neurotherapeutics 2010, 7, 366–377, doi:10.1016/j.nurt.2010.07.002.
[38]
Bianchi, M.E.; Manfredi, A.A. High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol. Rev. 2007, 220, 35–46, doi:10.1111/j.1600-065X.2007.00574.x.
[39]
Kim, I.D.; Lim, C.M.; Kim, J.B.; Nam, H.Y.; Nam, K.; Kim, S.W.; Park, J.S.; Lee, J.K. Neuroprotection by biodegradable PAMAM ester (e-PAM-R)-mediated HMGB1 siRNA delivery in primary cortical cultures and in the postischemic brain. J. Control. Release 2010, 142, 422–430, doi:10.1016/j.jconrel.2009.11.011.
[40]
Kim, J.B.; Sig Choi, J.; Yu, Y.M.; Nam, K.; Piao, C.S.; Kim, S.W.; Lee, M.H.; Han, P.L.; Park, J.S.; Lee, J.K. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J. Neurosci. 2006, 26, 6413–6421, doi:10.1523/JNEUROSCI.3815-05.2006.
[41]
Kim, I.D.; Shin, J.H.; Kim, S.W.; Choi, S.; Ahn, J.; Han, P.L.; Park, J.S.; Lee, J.K. Intranasal delivery of HMGB1 siRNA confers target gene knockdown and robust neuroprotection in the postischemic brain. Mol. Ther. 2012, 20, 829–839, doi:10.1038/mt.2011.291.
[42]
Thorne, R.G.; Emory, C.R.; Ala, T.A.; Frey, W.H., 2nd. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res. 1995, 692, 278–282.
[43]
Thorne, R.G.; Hanson, L.R.; Ross, T.M.; Tung, D.; Frey, W.H., 2nd. Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience 2008, 152, 785–797, doi:10.1016/j.neuroscience.2008.01.013.
[44]
Thorne, R.G.; Pronk, G.J.; Padmanabhan, V.; Frey, W.H., 2nd. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004, 127, 481–496, doi:10.1016/j.neuroscience.2004.05.029.
[45]
Liu, X.F.; Fawcett, J.R.; Thorne, R.G.; DeFor, T.A.; Frey, W.H., 2nd. Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J. Neurol. Sci. 2001, 187, 91–97, doi:10.1016/S0022-510X(01)00532-9.
[46]
Faul, M.; Xu, L.; Wald, M.M.; Coronado, V. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths,2002–2006; CDC, National Center for Injury Prevention and Control: Atlanta, GA, USA, 2010.
[47]
Pop, V.; Badaut, J. A neurovascular perspective for long-term changes after brain trauma. Transl. Stroke Res. 2011, 2, 533–545, doi:10.1007/s12975-011-0126-9.
[48]
Morales, D.M.; Marklund, N.; Lebold, D.; Thompson, H.J.; Pitkanen, A.; Maxwell, W.L.; Longhi, L.; Laurer, H.; Maegele, M.; Neugebauer, E.; et al. Experimental models of traumatic brain injury: Do we really need to build a better mousetrap? Neuroscience 2005, 136, 971–989, doi:10.1016/j.neuroscience.2005.08.030.
[49]
Miyashita, R.; Chen, L.; Oshiro, H.; Uchino, H.; Shibasaki, F. Int6 silencing causes induction of angiogenic factors in neuronal cells via accumulation of hypoxia-inducible factor 2alpha and decreases brain damage in rats. Neurosci. Lett. 2012, 528, 83–88, doi:10.1016/j.neulet.2012.08.033.
[50]
Woodcock, T.; Morganti-Kossmann, M.C. The role of markers of inflammation in traumatic brain injury. Front. Neurol. 2013, 4, 18.
[51]
Campbell, M.; Hanrahan, F.; Gobbo, O.L.; Kelly, M.E.; Kiang, A.S.; Humphries, M.M.; Nguyen, A.T.; Ozaki, E.; Keaney, J.; Blau, C.W.; et al. Targeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury. Nat. Commun. 2012, 3, 849, doi:10.1038/ncomms1852.
[52]
Badaut, J.; Ashwal, S.; Obenaus, A. Aquaporins in cerebrovascular disease: A target for treatment of brain edema? Cerebrovasc. Dis. 2011, 31, 521–531, doi:10.1159/000324328.
[53]
Fukuda, A.M.; Pop, V.; Spagnoli, D.; Ashwal, S.; Obenaus, A.; Badaut, J. Delayed increase of astrocytic aquaporin 4 after juvenile traumatic brain injury: Possible role in edema resolution? Neuroscience 2012, 222, 366–378, doi:10.1016/j.neuroscience.2012.06.033.
[54]
Fukuda, A.M.; Adami, A.; Pop, V.; Bellone, J.A.; Coats, J.S.; Hartman, R.E.; Ashwal, S.; Obenaus, A.; Badaut, J. Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery. J. Cerebr. Blood Flow Metabol. 2013, doi:10.1038/jcbfm.2013.118.
[55]
Niu, L.J.; Xu, R.X.; Zhang, P.; Du, M.X.; Jiang, X.D. Suppression of Frizzled-2-mediated Wnt/Ca(2)(+) signaling significantly attenuates intracellular calcium accumulation in vitro and in a rat model of traumatic brain injury. Neuroscience 2012, 213, 19–28, doi:10.1016/j.neuroscience.2012.03.057.
[56]
Schanne, F.A.; Kane, A.B.; Young, E.E.; Farber, J.L. Calcium dependence of toxic cell death: A final common pathway. Science 1979, 206, 700–702.
[57]
Mathupala, S.P. Delivery of small-interfering RNA (siRNA) to the brain. Expert Opin. Ther. Patents 2009, 19, 137–140, doi:10.1517/13543770802680195.
Shim, M.S.; Kwon, Y.J. Efficient and targeted delivery of siRNA in vivo. FEBS J. 2010, 277, 4814–4827, doi:10.1111/j.1742-4658.2010.07904.x.
[60]
Van de Water, F.M.; Boerman, O.C.; Wouterse, A.C.; Peters, J.G.; Russel, F.G.; Masereeuw, R. Intravenously administered short interfering RNA accumulates in the kidney and selectively suppresses gene function in renal proximal tubules. Drug Metab. Dispos. 2006, 34, 1393–1397, doi:10.1124/dmd.106.009555.
[61]
Walton, S.P.; Wu, M.; Gredell, J.A.; Chan, C. Designing highly active siRNAs for therapeutic applications. FEBSJ. 2010, 277, 4806–4813, doi:10.1111/j.1742-4658.2010.07903.x.
[62]
Danielyan, L.; Schafer, R.; von Ameln-Mayerhofer, A.; Buadze, M.; Geisler, J.; Klopfer, T.; Burkhardt, U.; Proksch, B.; Verleysdonk, S.; Ayturan, M.; et al. Intranasal delivery of cells to the brain. Eur. J. Cell Biol. 2009, 88, 315–324, doi:10.1016/j.ejcb.2009.02.001.
[63]
Danielyan, L.; Klein, R.; Hanson, L.R.; Buadze, M.; Schwab, M.; Gleiter, C.H.; Frey, W.H. Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer disease. Rejuv. Res. 2010, 13, 195–201, doi:10.1089/rej.2009.0944.
Hanson, L.R.; Frey, W.H., 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci. 2008, 9, S5, doi:10.1186/1471-2202-9-S3-S5.
[66]
Hanson, L.R.; Roeytenberg, A.; Martinez, P.M.; Coppes, V.G.; Sweet, D.C.; Rao, R.J.; Marti, D.L.; Hoekman, J.D.; Matthews, R.B.; Frey, W.H., 2nd.; et al. Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J. Pharmacol. Exp. Ther. 2009, 330, 679–686, doi:10.1124/jpet.108.149807.
[67]
Liu, X.F.; Fawcett, J.R.; Thorne, R.G.; Frey, W.H., 2nd. Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neurosci. Lett. 2001, 308, 91–94.
Renner, D.B.; Frey, W.H., 2nd.; Hanson, L.R. Intranasal delivery of siRNA to the olfactory bulbs of mice via the olfactory nerve pathway. Neurosci. Lett. 2012, 513, 193–197, doi:10.1016/j.neulet.2012.02.037.
Massaro, D.; Massaro, G.D.; Clerch, L.B. Noninvasive delivery of small inhibitory RNA and other reagents to pulmonary alveoli in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 2004, 287, L1066–L1070, doi:10.1152/ajplung.00067.2004.
[73]
Thorne, R.G.; Frey, W.H., 2nd. Delivery of neurotrophic factors to the central nervous system: Pharmacokinetic considerations. Clin. Pharmacokinet. 2001, 40, 907–946, doi:10.2165/00003088-200140120-00003.
[74]
Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011, 29, 341–345.
[75]
El Andaloussi, S.; Lakhal, S.; Mager, I.; Wood, M.J. Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 2013, 65, 391–397, doi:10.1016/j.addr.2012.08.008.
[76]
Wahlgren, J.; Karlson, T.D.L.; Brisslert, M.; Vaziri Sani, F.; Telemo, E.; Sunnerhagen, P.; Valadi, H. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucl. Acids Res. 2012, 40, e130, doi:10.1093/nar/gks463.
[77]
Cossetti, C.; Smith, J.A.; Iraci, N.; Leonardi, T.; Alfaro-Cervello, C.; Pluchino, S. Extracellular membrane vesicles and immune regulation in the brain. Front. Physiol. 2012, 3, 117.
[78]
Lai, C.P.; Breakefield, X.O. Role of exosomes/microvesicles in the nervous system and use in emerging therapies. Front. Physiol. 2012, 3, 228.
[79]
Badaut, J.; Ashwal, S.; Adami, A.; Tone, B.; Recker, R.; Spagnoli, D.; Ternon, B.; Obenaus, A. Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J. Cerebr. Blood Flow Metabol. 2011, 31, 819–831, doi:10.1038/jcbfm.2010.163.
[80]
Davis, M.E.; Chen, Z.G.; Shin, D.M. Nanoparticle therapeutics: An emerging treatment modality for cancer. Nat. Rev. Drug Discov. 2008, 7, 771–782, doi:10.1038/nrd2614.
[81]
Petros, R.A.; DeSimone, J.M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 2010, 9, 615–627, doi:10.1038/nrd2591.
[82]
Mishima, T.; Mizuguchi, Y.; Kawahigashi, Y.; Takizawa, T.; Takizawa, T. RT-PCR-based analysis of microRNA (miR-1 and -124) expression in mouse CNS. Brain Res. 2007, 1131, 37–43, doi:10.1016/j.brainres.2006.11.035.
[83]
Saugstad, J.A. MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J. Cerebr. Blood Flow Metabol. 2010, 30, 1564–1576, doi:10.1038/jcbfm.2010.101.
[84]
Linsen, S.E.; de Wit, E.; de Bruijn, E.; Cuppen, E. Small RNA expression and strain specificity in the rat. BMC Genomics 2010, 11, 249, doi:10.1186/1471-2164-11-249.
[85]
Hu, Z.; Yu, D.; Almeida-Suhett, C.; Tu, K.; Marini, A.M.; Eiden, L.; Braga, M.F.; Zhu, J.; Li, Z. Expression of miRNAs and their cooperative regulation of the pathophysiology in traumatic brain injury. PLoS One 2012, 7, e39357.
[86]
Liu, N.K.; Xu, X.M. MicroRNA in central nervous system trauma and degenerative disorders. Physiol. Genomics 2011, 43, 571–580, doi:10.1152/physiolgenomics.00168.2010.
[87]
Ziu, M.; Fletcher, L.; Rana, S.; Jimenez, D.F.; Digicaylioglu, M. Temporal differences in microRNA expression patterns in astrocytes and neurons after ischemic injury. PLoS One 2011, 6, e14724.