Growth factor therapy sequesters inflammation in affording neuroprotection in cerebrovascular diseases

References

• American Association of Neurological Surgeons [Internet]. Cerebrovascular disease. Rolling Meadows (IL): American Association of Neurological Surgeons; 2005 [cited 2016 Feb 3]. Available from: http://www.aans.org/patient%20information/conditions%20and%20treatments/cerebrovascular%20disease.aspx
   Google Scholar
• Acosta SA, Tajiri N, Shinozuka K, et al. Combination therapy of human umbilical cord blood cells and granulocyte colony stimulating factor reduces histopathological and motor impairments in an experimental model of chronic traumatic brain injury. PLoS One. 2014;9:e90953.
   PubMed Web of Science ®Google Scholar
• Jickling GC, Liu D, Stamova B, et al. Hemorrhagic transformation after ischemic stroke in animals and humans. J Cereb Blood Flow Metab. 2014;34:185–199.
   PubMed Web of Science ®Google Scholar
• Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the american heart association. Circulation. 2015;131:e29–e322.
   PubMed Web of Science ®Google Scholar
• Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl. 2005;6:3–11.
   PubMed Web of Science ®Google Scholar
• Uchida H, Morita T, Niizuma K, et al. Transplantation of unique subpopulation of fibroblasts, muse cells, ameliorates experimental stroke possibly via robust neuronal differentiation. Stem Cells. 2016;34:160–173.
   PubMed Web of Science ®Google Scholar
• Acosta SA, Tajiri N, Hoover J, et al. Intravenous bone marrow stem cell grafts preferentially migrate to spleen and abrogate chronic inflammation in stroke. Stroke. 2015;46:2616–2627.
   PubMed Web of Science ®Google Scholar
• Blennow K, Hardy J, Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 2012;76:886–899.
   PubMed Web of Science ®Google Scholar
• Frieden TR, Houry D, Baldwin G. Report to congress on traumatic brain injury in the United States: epidemiology and rehabilitation. Atlanta (GA): Centers for Disease Control and Prevention; 2015. Available from: http://www.cdc.gov/traumaticbraininjury/pdf/TBI_Report_to_Congress_Epi_and_Rehab-a.pdf
   Google Scholar
• Shlosberg D, Benifla M, Kaufer D, et al. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol. 2010;6:393–403.
   PubMed Web of Science ®Google Scholar
• Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci. 2013;14:128–142.
   PubMed Web of Science ®Google Scholar
• Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352:1685–1695.
   PubMed Web of Science ®Google Scholar
• Acosta SA, Tajiri N, Shinozuka K, et al. Long-term upregulation of inflammation and suppression of cell proliferation in the brain of adult rats exposed to traumatic brain injury using the controlled cortical impact model. PLoS One. 2013;8:e53376.
   PubMed Web of Science ®Google Scholar
• Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808.
   PubMed Web of Science ®Google Scholar
• Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045–2051.
   PubMed Web of Science ®Google Scholar
• Nahrendorf M, Swirski FK. Immunology. Neutrophil-macrophage communication in inflammation and atherosclerosis. Science. 2015;349:237–238.
   PubMed Web of Science ®Google Scholar
• Sun X, He S, Wara AK, et al. Systemic delivery of microRNA-181b inhibits nuclear factor-κB activation, vascular inflammation, and atherosclerosis in apolipoprotein E-deficient mice. Circ Res. 2014;114:32–40.
   PubMed Web of Science ®Google Scholar
• Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161–166.
   PubMed Web of Science ®Google Scholar
• Teasdale GM, Nicoll JA, Murray G, et al. Association of apolipoprotein e polymorphism with outcome after head injury. Lancet. 1997;350:1069–1071.
   PubMed Web of Science ®Google Scholar
• Rom S, Dykstra H, Zuluaga-Ramirez V, et al. Mir-98 and let-7g* protect the blood-brain barrier under neuroinflammatory conditions. J Cereb Blood Flow Metab. 2015;35:1957–1965.
   PubMed Web of Science ®Google Scholar
• Friedman G, Froom P, Sazbon L, et al. Apolipoprotein E-epsilon4 genotype predicts a poor outcome in survivors of traumatic brain injury. Neurology. 1999;52:244–248.
   PubMed Web of Science ®Google Scholar
• Lai C-H, Wang K-C, Lee F-T, et al. Toll-like receptor 4 is essential in the development of abdominal aortic aneurysm. PLoS One. 2016;11:e0146565.
   PubMedGoogle Scholar
• Gyoneva S, Ransohoff RM. Inflammatory reaction after traumatic brain injury: therapeutic potential of targeting cell-cell communication by chemokines. Trends Pharmacol Sci. 2015;36:471–480.
   PubMed Web of Science ®Google Scholar
• DelaPeña I, Sanberg PR, Acosta S, et al. Stem cells and G-CSF for treating neuroinflammation in traumatic brain injury: aging as a comorbidity factor. J Neurosurg Sci. 2014;58:145–149.
   PubMed Web of Science ®Google Scholar
• Zhao L-R, Singhal S, Duan W-M, et al. Brain repair by hematopoietic growth factors in a rat model of stroke. Stroke. 2007;38:2584–2591.
   PubMed Web of Science ®Google Scholar
• Yang Y, Rosenberg GA. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011;42:3323–3328.
   PubMed Web of Science ®Google Scholar
• Doll DN, Hu H, Sun J, et al. Mitochondrial crisis in cerebrovascular endothelial cells opens the blood-brain barrier. Stroke. 2015;46:1681–1689.
   PubMed Web of Science ®Google Scholar
• Shimotake J, Derugin N, Wendland M, et al. Vascular endothelial growth factor receptor-2 inhibition promotes cell death and limits endothelial cell proliferation in a neonatal rodent model of stroke. Stroke. 2010;41:343–349.
   PubMed Web of Science ®Google Scholar
• Thau-Zuchman O, Shohami E, Alexandrovich AG, et al. Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J Cereb Blood Flow Metab. 2010;30:1008–1016.
   PubMed Web of Science ®Google Scholar
• Hof PR, Mobbs CV. Handbook of the neuroscience of aging. Burlington: AP; 2010.
   Google Scholar
• Konishi Y, Yang L-B, He P, et al. Deficiency of GDNF receptor GFRα1 in Alzheimer’s neurons results in neuronal death. J Neurosci. 2014;34:13127–13138.
   PubMed Web of Science ®Google Scholar
• Airaksinen MS, Saarma M. The gdnf family: signalling, biological functions and therapeutic value. Nat Rev Neurosci. 2002;3:383–394.
   PubMed Web of Science ®Google Scholar
• Jensen P, Ducray AD, Widmer HR, et al. Effects of forskolin on trefoil factor 1 expression in cultured ventral mesencephalic dopaminergic neurons. Neuroscience. 2015;310:699–708.
   PubMed Web of Science ®Google Scholar
• Zhao Y, Zhang Q, Xi J, et al. Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/β-catenin dependent pathways in a mice model of Parkinson’s disease. Int J Clin Exp Pathol. 2015;8:2354–2364.
   PubMed Web of Science ®Google Scholar
• Kim EK, Choi E-J. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396–405.
   PubMed Web of Science ®Google Scholar
• Hoban DB, Howard L, Dowd E. GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of parkinson’s disease. Neuroscience. 2015;303:402–411.
   PubMed Web of Science ®Google Scholar
• Sumbria RK, Boado RJ, Pardridge WM. Combination stroke therapy in the mouse with blood-brain barrier penetrating IgG-GDNF and IgG-TNF decoy receptor fusion proteins. Brain Res. 2013;1507:91–96.
   PubMed Web of Science ®Google Scholar
• Degeorge ML, Marlowe D, Werner E, et al. Combining glial cell line-derived neurotrophic factor gene delivery (AdGDNF) with l-arginine decreases contusion size but not behavioral deficits after traumatic brain injury. Brain Res. 2011;1403:45–56.
   PubMed Web of Science ®Google Scholar
• Minnich JE, Mann SL, Stock M, et al. Glial cell line-derived neurotrophic factor (GDNF) gene delivery protects cortical neurons from dying following a traumatic brain injury. Restor Neurol Neurosci. 2010;28:293–309.
   PubMed Web of Science ®Google Scholar
• U.S. National Institutes of Health. AAV2-GDNF for advanced Parkinson’s disease. Bethesda (MD): U.S. National Institutes of Health; 2015 [cited 2016 Mar 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT01621581?term=gdnf&rank=1
   Google Scholar
• U.S. National Institutes of Health. Continuously infused intracerebral (IC) recombinant-methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) for the treatment of idiopathic Parkinson’s disease. Bethesda (MD): U.S. National Institutes of Health; 2005 [cited 2016 Mar 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT00006488?term=gdnf&rank=5
   Google Scholar
• Wang S, Cheng H, Dai G, et al. Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013;1532:76–84.
   PubMed Web of Science ®Google Scholar
• Reyes S, Tajiri N, Borlongan CV. Developments in intracerebral stem cell grafts. Expert Rev Neurother. 2015;15:381–393.
   PubMed Web of Science ®Google Scholar
• Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. Faseb J. 1999;13:9–22.
   PubMed Web of Science ®Google Scholar
• Cydzik M, Abdul-Wahid A, Park S, et al. Slow binding kinetics of secreted protein, acidic, rich in cysteine-VEGF interaction limit VEGF activation of VEGF receptor 2 and attenuate angiogenesis. Faseb J. 2015;29:3493–3505.
   PubMed Web of Science ®Google Scholar
• Larpthaveesarp A, Ferriero DM, Gonzalez FF. Growth factors for the treatment of ischemic brain injury (growth factor treatment). Brain Sci. 2015;5:165–177.
   PubMed Web of Science ®Google Scholar
• Dzietko M, Derugin N, Wendland MF, et al. Delayed vegf treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res. 2013;4:189–200.
   PubMed Web of Science ®Google Scholar
• Siddiq I, Park E, Liu E, et al. Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A. J Neurotrauma. 2012;29:2647–2659.
   PubMed Web of Science ®Google Scholar
• Argaw AT, Asp L, Zhang J, et al. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in cns inflammatory disease. J Clin Invest. 2012;122:2454–2468.
   PubMed Web of Science ®Google Scholar
• Adibhatla RM, Hatcher JF. Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets. 2008;7:243–253.
   PubMed Web of Science ®Google Scholar
• Manoonkitiwongsa PS, Schultz RL, Whitter EF, et al. Contraindications of VEGF -based therapeutic angiogenesis: effects on macrophage density and histology of normal and ischemic brains. Vascul Pharmacol. 2006;44:316–325.
   PubMed Web of Science ®Google Scholar
• Vila-Coro AJ, Rodríguez-Frade JM, Martín De Ana A, et al. The chemokine SDF −1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. Faseb J. 1999;13:1699–1710.
   PubMed Web of Science ®Google Scholar
• Ma Q, Jones D, Borghesani PR, et al. Impaired b-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998;95:9448–9453.
   PubMed Web of Science ®Google Scholar
• Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393:595–599.
   PubMed Web of Science ®Google Scholar
• Nagasawa T, Hirota S, Tachibana K, et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the cxc chemokine PBSF/SDF-1. Nature. 1996;382:635–638.
   PubMed Web of Science ®Google Scholar
• Lazarini F, Tham TN, Casanova P, et al. Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia. 2003;42:139–148.
   PubMed Web of Science ®Google Scholar
• Ratajczak MZ, Zuba-Surma E, Kucia M, et al. The pleiotropic effects of the SDF-1- CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia. 2006;20:1915–1924.
   PubMed Web of Science ®Google Scholar
• De La Luz Sierra M, Yang F, Narazaki M, et al. Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood. 2004;103:2452–2459.
   PubMed Web of Science ®Google Scholar
• Horuk R. Chemokine receptors. Cytokine Growth Factor Rev. 2001;12:313–335.
   PubMed Web of Science ®Google Scholar
• Hill WD, Hess DC, Martin-Studdard A, et al. SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol. 2004;63:84–96.
   PubMed Web of Science ®Google Scholar
• Strieter RM, Burdick MD, Mestas J, et al. Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer. 2006;42:768–778.
   PubMed Web of Science ®Google Scholar
• Bagri A, Gurney T, He X, et al. The chemokine SDF1 regulates migration of dentate granule cells. Development. 2002;129:4249–4260.
   PubMed Web of Science ®Google Scholar
• Schier AF. Chemokine signaling: rules of attraction. Curr Biol. 2003;13:R192–R194.
   PubMed Web of Science ®Google Scholar
• Man S, Tucky B, Cotleur A, et al. CXCL12-induced monocyte-endothelial interactions promote lymphocyte transmigration across an in vitro blood-brain barrier. Sci Transl Med. 2012;4:119ra14.
   PubMed Web of Science ®Google Scholar
• Cartier L, Hartley O, Dubois-Dauphin M, et al. Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Brain Res Rev. 2005;48:16–42.
   PubMed Web of Science ®Google Scholar
• Chernock RD, Cherla RP, Ganju RK. Shp2 and cbl participate in alpha-chemokine receptor CXCR4-mediated signaling pathways. Blood. 2001;97:608–615.
   PubMed Web of Science ®Google Scholar
• Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for parkinson’s disease clinical trials. Acta Neuropathol. 2014;127:861–879.
   PubMed Web of Science ®Google Scholar
• Cheng X, Lian YJ, Ma YQ, et al. Elevated serum levels of CXC chemokine ligand-12 are associated with unfavorable functional outcome and mortality at 6-month follow-up in chinese patients with acute ischemic stroke. Mol Neurobiol. 2016. doi:10.1007/s12035-015-9645-9.
   Google Scholar
• Schajnovitz A, Itkin T, D’Uva G, et al. CXCL12 secretion by bone marrow stromal cells is dependent on cell contact and mediated by connexin-43 and connexin-45 gap junctions. Nat Immunol. 2011;12:391–398.
   PubMed Web of Science ®Google Scholar
• Timotijević G, MostaricaStojković M, Miljković D. CXCL12: role in neuroinflammation. Int J Biochem Cell Biol. 2012;44:838–841.
   PubMed Web of Science ®Google Scholar
• Gear AR, Suttitanamongkol S, Viisoreanu D, et al. Adenosine diphosphate strongly potentiates the ability of the chemokines MDC, TARC, and SDF-1 to stimulate platelet function. Blood. 2001;97:937–945.
   PubMed Web of Science ®Google Scholar
• Liu X, Zhou C, Li Y, et al. SDF-1 promotes endochondral bone repair during fracture healing at the traumatic brain injury condition. PLoS One. 2013;8:e54077.
   PubMed Web of Science ®Google Scholar
• Bogoslovsky T, Spatz M, Chaudhry A, et al. Stromal-derived factor-1[alpha] correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients. Stroke. 2011;42:618–625.
   PubMed Web of Science ®Google Scholar
• Gu XL, Liu L, Lu XD, et al. Serum CXCL12 levels as a novel predictor of future stroke recurrence in patients with acute ischemic stroke. Mol Neurobiol. 2015. doi:10.1007/s12035-015-9151-0.
   Web of Science ®Google Scholar
• Ruscher K, Kuric E, Liu Y, et al. Inhibition of CXCL12 signaling attenuates the postischemic immune response and improves functional recovery after stroke. J Cereb Blood Flow Metab. 2013;33:1225–1234.
   PubMed Web of Science ®Google Scholar
• Takami S, Minami M, Nagata I, et al. Chemokine receptor antagonist peptide, viral MIP-II, protects the brain against focal cerebral ischemia in mice. J Cereb Blood Flow Metab. 2001;21:1430–1435.
   PubMed Web of Science ®Google Scholar
• Peled A, Kollet O, Ponomaryov T, et al. The chemokine sdf-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of nod/scid mice. Blood. 2000;95:3289–3296.
   PubMed Web of Science ®Google Scholar
• Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through hif-1 induction of SDF-1. Nat Med. 2004;10:858–864.
   PubMed Web of Science ®Google Scholar
• Fan Y, Shen F, Frenzel T, et al. Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010;67:488–497.
   PubMed Web of Science ®Google Scholar
• Jaerve A, Schira J, Muller HW. Concise review: the potential of stromal cell-derived factor 1 and its receptors to promote stem cell functions in spinal cord repair. Stem Cells Transl Med. 2012;1:732–739.
   PubMed Web of Science ®Google Scholar
• Cui X, Chen J, Zacharek A, et al. Nitric oxide donor upregulation of stromal cell-derived factor-1/chemokine (CXC motif) receptor 4 enhances bone marrow stromal cell migration into ischemic brain after stroke. Stem Cells. 2007;25:2777–2785.
   PubMed Web of Science ®Google Scholar
• Imitola J, Raddassi K, Park KI, et al. Directed migration of neural stem cells to sites of cns injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc Natl Acad Sci U S A. 2004;101:18117–18122.
   PubMed Web of Science ®Google Scholar
• Robin AM, Zhang ZG, Wang L, et al. Stromal cell-derived factor 1alpha mediates neural progenitor cell motility after focal cerebral ischemia. J Cereb Blood Flow Metab. 2006;26:125–134.
   PubMed Web of Science ®Google Scholar
• Borlongan CV. Bone marrow stem cell mobilization in stroke: a ‘bonehead’ may be good after all! Leukemia. 2011;25:1674–1686.
   PubMed Web of Science ®Google Scholar
• Kent D, Copley M, Benz C, et al. Regulation of hematopoietic stem cells by the steel factor/kit signaling pathway. Clin Cancer Res. 2008;14:1926–1930.
   PubMed Web of Science ®Google Scholar
• Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–334.
   PubMed Web of Science ®Google Scholar
• Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014;20:833–846.
   PubMed Web of Science ®Google Scholar
• Meng F, Francis H, Glaser S, et al. Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration. Hepatology. 2012;55:209–221.
   PubMed Web of Science ®Google Scholar
• Motro B, van der Kooy D, Rossant J, et al. Contiguous patterns of c-kit and steel expression: analysis of mutations at the w and sl loci. Development. 1991;113:1207–1221.
   PubMed Web of Science ®Google Scholar
• Anderson DM, Lyman SD, Baird A, et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell. 1990;63:235–243.
   PubMed Web of Science ®Google Scholar
• Lennartsson J, Ronnstrand L. Stem cell factor receptor/c-kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–1649.
   PubMed Web of Science ®Google Scholar
• Ronnstrand L. Signal transduction via the stem cell factor receptor/c-kit. Cell Mol Life Sci. 2004;61:2535–2548.
   PubMed Web of Science ®Google Scholar
• Huang Z, Ruan HB, Xian L, et al. The stem cell factor/kit signalling pathway regulates mitochondrial function and energy expenditure. Nat Commun. 2014;5:4282.
   PubMed Web of Science ®Google Scholar
• Kitamura Y, Hirotab S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004;61:2924–2931.
   PubMed Web of Science ®Google Scholar
• Zeng S, Xu Z, Lipkowitz S, et al. Regulation of stem cell factor receptor signaling by cbl family proteins (Cbl-b/c-Cbl). Blood. 2005;105:226–232.
   PubMed Web of Science ®Google Scholar
• Hirata T, Morii E, Morimoto M, et al. Stem cell factor induces outgrowth of c-kit-positive neurites and supports the survival of c-kit-positive neurons in dorsal root ganglia of mouse embryos. Development. 1993;119:49–56.
   PubMed Web of Science ®Google Scholar
• Park M, Kim WK, Song M, et al. Protein kinase C-δ-mediated recycling of active KIT in colon cancer. Clin Cancer Res. 2013;19:4961–4971.
   PubMed Web of Science ®Google Scholar
• Corti S, Locatelli F, Strazzer S, et al. Modulated generation of neuronal cells from bone marrow by expansion and mobilization of circulating stem cells with in vivo cytokine treatment. Exp Neurol. 2002;177:443–452.
   PubMed Web of Science ®Google Scholar
• Jin K, Mao XO, Sun Y, et al. Stem cell factor stimulates neurogenesis in vitro and in vivo. J Clin Invest. 2002;110:311–319.
   PubMed Web of Science ®Google Scholar
• Lanfranconi S, Locatelli F, Corti S, et al. Growth factors in ischemic stroke. J Cell Mol Med. 2011;15:1645–1687.
   PubMed Web of Science ®Google Scholar
• Nervi B, Link DC, DiPersio JF. Cytokines and hematopoietic stem cell mobilization. J Cell Biochem. 2006;99:690–705.
   PubMed Web of Science ®Google Scholar
• Huang B, Lei Z, Zhang G-M, et al. SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood. 2008;112:1269–1279.
   PubMed Web of Science ®Google Scholar
• Sun L, Lee J, Fine HA. Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest. 2004;113:1364–1374.
   PubMed Web of Science ®Google Scholar
• Kawada H, Takizawa S, Takanashi T, et al. Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells. Circulation. 2006;113:701–710.
   PubMed Web of Science ®Google Scholar
• Toth ZE, Leker RR, Shahar T, et al. The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow-derived endothelial cells in brains of mice following cerebral ischemia. Blood. 2008;111:5544–5552.
   PubMed Web of Science ®Google Scholar
• Liu X-Y, Gonzalez-Toledo ME, Fagan A, et al. Stem cell factor and granulocyte colony-stimulating factor exhibit therapeutic effects in a mouse model of cadasil. Neurobiol Dis. 2015;73:189–203.
   PubMed Web of Science ®Google Scholar
• Cui L, Duchamp NS, Boston DJ, et al. NF-κB is involved in brain repair by stem cell factor and granulocyte-colony stimulating factor in chronic stroke. Exp Neurol. 2015;263:17–27.
   PubMed Web of Science ®Google Scholar
• Zhang SC, Fedoroff S. Expression of stem cell factor and c-kit receptor in neural cells after brain injury. Acta Neuropathol. 1999;97:393–398.
   PubMed Web of Science ®Google Scholar
• Hernandez-Ontiveros DG, Tajiri N, Acosta S, et al. Microglia activation as a biomarker for traumatic brain injury. Front Neurol. 2013;4:30.
   PubMed Web of Science ®Google Scholar
• Zhang SC, Fedoroff S. Modulation of microglia by stem cell factor. J Neurosci Res. 1998;53:29–37.
   PubMed Web of Science ®Google Scholar
• Tajiri N, Acosta SA, Shahaduzzaman M, et al. Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci. 2014;34:313–326.
   PubMed Web of Science ®Google Scholar
• Lozano D, Gonzales-Portillo GS, Acosta S, et al. Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities. Neuropsychiatr Dis Treat. 2015;11:97–106.
   PubMed Web of Science ®Google Scholar
• Ghitza UE, Zhai H, Wu P, et al. Role of BDNF and GDNF in drug reward and relapse: a review. Neurosci Biobehav Rev. 2010;35:157–171.
   PubMed Web of Science ®Google Scholar
• Wu JQ, Chen DC, Tan YL, et al. Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia. Psychopharmacology (Berl). 2015;232:223–232.
   PubMed Web of Science ®Google Scholar
• Angelucci F, Brenè S, Mathé AA. BDNF in schizophrenia, depression and corresponding animal models. Mol Psychiatry. 2005;10:345–352.
   PubMed Web of Science ®Google Scholar
• Lin D, De La Pena I, Lin L, et al. The neuroprotective role of acupuncture and activation of the bdnf signaling pathway. Int J Mol Sci. 2014;15:3234–3252.
   PubMed Web of Science ®Google Scholar
• Qin L, Jing D, Parauda S, et al. An adaptive role for BDNF Val66Met polymorphism in motor recovery in chronic stroke. J Neurosci. 2014;34:2493–2502.
   PubMed Web of Science ®Google Scholar
• Chan A, Yan J, Csurhes P, et al. Circulating brain derived neurotrophic factor (BDNF) and frequency of bdnf positive T cells in peripheral blood in human ischemic stroke: effect on outcome. J Neuroimmunol. 2015;286:42–47.
   PubMed Web of Science ®Google Scholar
• Failla MD, Kumar RG, Peitzman AB, et al. Variation in the BDNF gene interacts with age to predict mortality in a prospective, longitudinal cohort with severe tbi. Neurorehabil Neural Repair. 2015;29:234–246.
   PubMed Web of Science ®Google Scholar
• Mowla SJ, Farhadi HF, Pareek S, et al. Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. J Biol Chem. 2001;276:12660–12666.
   PubMed Web of Science ®Google Scholar
• Fayard B, Loeffler S, Weis J, et al. The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. J Neurosci Res. 2005;80:18–28.
   PubMed Web of Science ®Google Scholar
• Notaras M, Hill R, van den Buuse M. A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev. 2015;51:15–30.
   PubMed Web of Science ®Google Scholar
• Teng HK, Teng KK, Lee R, et al. Pro-BDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005;25:5455–5463.
   PubMed Web of Science ®Google Scholar
• Atif F, Yousuf S, Sayeed I, et al. Combination treatment with progesterone and vitamin d hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection. Neuropharmacology. 2013;67:78–87.
   PubMed Web of Science ®Google Scholar
• Qin L, Kim E, Ratan R, et al. Genetic variant of BDNF (Val66Met) polymorphism attenuates stroke-induced angiogenic responses by enhancing anti-angiogenic mediator cd36 expression. J Neurosci. 2011;31:775–783.
   PubMed Web of Science ®Google Scholar
• Schäbitz WR, Sommer C, Zoder W, et al. Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke. 2000;31:2212–2217.
   PubMed Web of Science ®Google Scholar
• Kim H-J, Lee J-H, Kim S-H. Therapeutic effects of human mesenchymal stem cells on traumatic brain injury in rats: secretion of neurotrophic factors and inhibition of apoptosis. J Neurotrauma. 2010;27:131–138.
   PubMed Web of Science ®Google Scholar
• Yenari MA, Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci. 2012;13:267–278.
   PubMed Web of Science ®Google Scholar
• Umschweif G, Shabashov D, Alexandrovich AG, et al. Neuroprotection after traumatic brain injury in heat-acclimated mice involves induced neurogenesis and activation of angiotensin receptor type 2 signaling. J Cereb Blood Flow Metab. 2014;34:1381–1390.
   PubMed Web of Science ®Google Scholar
• Wu H, Lu D, Jiang H, et al. Simvastatin-mediated upregulation of VEGF and BDNF, activation of the PI3K/AKT pathway, and increase of neurogenesis are associated with therapeutic improvement after traumatic brain injury. J Neurotrauma. 2008;25:130–139.
   PubMed Web of Science ®Google Scholar
• Kim J, Yang M, Kim J, et al. Developmental and degenerative modulation of brain-derived neurotrophic factor transcript variants in the mouse hippocampus. Int J Dev Neurosci. 2014;38:68–73.
   PubMed Web of Science ®Google Scholar
• Isgor C, Pare C, McDole B, et al. Expansion of the dentate mossy fiber-ca3 projection in the brain-derived neurotrophic factor-enriched mouse hippocampus. Neuroscience. 2015;288:10–23.
   PubMed Web of Science ®Google Scholar
• Shen F, Kuo R, Milon-Camus M, et al. Intravenous delivery of adeno-associated viral vector serotype 9 mediates effective gene expression in ischemic stroke lesion and brain angiogenic foci. Stroke. 2013;44:252–254.
   PubMed Web of Science ®Google Scholar
• Sumbria RK, Boado RJ, Pardridge WM. Brain protection from stroke with intravenous TNFα decoy receptor-trojan horse fusion protein. J Cereb Blood Flow Metab. 2012;32:1933–1938.
   PubMed Web of Science ®Google Scholar
• Emerich DF, Orive G, Thanos C, et al. Encapsulated cell therapy for neurodegenerative diseases: from promise to product. Adv Drug Deliv Rev. 2014;67–68:131–141.
   PubMed Web of Science ®Google Scholar
• Rhim T, Lee DY, Lee M. Drug delivery systems for the treatment of ischemic stroke. Pharm Res. 2013;30:2429–2444.
   PubMed Web of Science ®Google Scholar
• Zhu Y, Bu Q, Liu X, et al. Neuroprotective effect of TAT-14-3-3ε fusion protein against cerebral ischemia/reperfusion injury in rats. PLoS One. 2014;9:e93334.
   PubMed Web of Science ®Google Scholar
• Brockman EC, Bayir H, Blasiole B, et al. Polynitroxylated-pegylated hemoglobin attenuates fluid requirements and brain edema in combined traumatic brain injury plus hemorrhagic shock in mice. J Cereb Blood Flow Metab. 2013;33:1457–1464.
   PubMed Web of Science ®Google Scholar
• Yemisci M, Caban S, Gursoy-Ozdemir Y, et al. Systemically administered brain-targeted nanoparticles transport peptides across the blood-brain barrier and provide neuroprotection. J Cereb Blood Flow Metab. 2015;35:469–475.
   PubMed Web of Science ®Google Scholar
• Gauberti M, Montagne A, Marcos-Contreras OA, et al. Ultra-sensitive molecular mri of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes. Stroke. 2013;44:1988–1996.
   PubMed Web of Science ®Google Scholar
• Liu DZ, Jickling GC, Ander BP, et al. Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 2015. doi:10.1177/0271678X15610786.
   Google Scholar
• Panagiotou S, Saha S. Therapeutic benefits of nanoparticles in stroke. Front Neurosci. 2015;9:182.
   PubMed Web of Science ®Google Scholar