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Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

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Neurotherapeutics

Abstract

Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases ½ (ERK½), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT2 antagonist PD123319. Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.

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References

  1. Leker RR, Shohami E. Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Brain Res Rev 2002;39:55-73.

    Article  PubMed  Google Scholar 

  2. Loane DJ, Faden AI. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 2010;31:596-604.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Rosenfeld JV, Maas AI, Bragge P, Morganti-Kossmann MC, Manley GT, Gruen RL. Early management of severe traumatic brain injury. Lancet 2012;380:1088-1098.

    Article  PubMed  Google Scholar 

  4. Tigerstedt R, Bergman PG. Niere und Kreislauf. Skandinavisches Archiv Physiologie 1898:223-271.

  5. Ganten D, Minnich JL, Granger P, et al. Angiotensin-forming enzyme in brain tissue. Science 1971;173:64-65.

    Article  CAS  PubMed  Google Scholar 

  6. Premer C, Lamondin C, Mitzey A, Speth RC, Brownfield MS. Immunohistochemical localization of AT1a, AT1b, and AT2 angiotensin ii receptor subtypes in the rat adrenal, pituitary, and brain with a perspective commentary. Int J Hypertens 2013;2013:175428.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lenkei Z, Palkovits M, Corvol P, Llorens-Cortes C. Distribution of angiotensin II type-2 receptor (AT2) mRNA expression in the adult rat brain. J Comp Neurol 1996;373:322-339.

    Article  CAS  PubMed  Google Scholar 

  8. Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK. Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature 1995;377:744-747.

    Article  CAS  PubMed  Google Scholar 

  9. Ichiki T, Labosky PA, Shiota C, et al. Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor. Nature 1995;377:748-750.

    Article  CAS  PubMed  Google Scholar 

  10. Okuyama S, Sakagawa T, Chaki S, Imagawa Y, Ichiki T, Inagami T. Anxiety-like behavior in mice lacking the angiotensin II type-2 receptor. Brain Res 1999;821:150-159.

    Article  CAS  PubMed  Google Scholar 

  11. Michel MC, Foster C, Brunner HR, Liu L. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev 2013;65:809-848.

    PubMed  Google Scholar 

  12. Walther T, Siems WE, Hauke D, et al. AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats. FASEB J 2002;16:1237-1241.

    Article  CAS  PubMed  Google Scholar 

  13. Saavedra JM. Angiotensin II AT(1) receptor blockers as treatments for inflammatory brain disorders. Clin Sci (Lond) 2012;123:567-590.

    Article  CAS  Google Scholar 

  14. Saavedra JM, Sánchez-Lemus E, Benicky J. Blockade of brain angiotensin II AT1 receptors ameliorates stress, anxiety, brain inflammation and ischemia: Therapeutic implications. Psychoneuroendocrinology 2011;36:1-18.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Tota S, Hanif K, Kamat PK, Najmi AK, Nath C. Role of central angiotensin receptors in scopolamine-induced impairment in memory, cerebral blood flow, and cholinergic function. Psychopharmacology (Berl) 2012;222:185-202.

    Article  CAS  Google Scholar 

  16. Porrello ER, Delbridge LM, Thomas WG. The angiotensin II type 2 (AT2) receptor: an enigmatic seven transmembrane receptor. Front Biosci (Landmark Ed) 2009;14:958-972.

    Article  CAS  Google Scholar 

  17. Plouffe B, Guimond MO, Beaudry H, Gallo-Payet N. Role of tyrosine kinase receptors in angiotensin II AT2 receptor signaling: involvement in neurite outgrowth and in p42/p44mapk activation in NG108-15 cells. Endocrinology 2006;147:4646-4654.

    Article  CAS  PubMed  Google Scholar 

  18. Côté F, Laflamme L, Payet MD, Gallo-Payet N. Nitric oxide, a new second messenger involved in the action of angiotensin II on neuronal differentiation of NG108-15 cells. Endocr Res 1998;24:403-407.

    Article  PubMed  Google Scholar 

  19. Hashikawa-Hobara N, Hashikawa N, Inoue Y, et al. Candesartan cilexetil improves angiotensin II type 2 receptor-mediated neurite outgrowth via the PI3K-Akt pathway in fructose-induced insulin-resistant rats. Diabetes 2012;61:925-932.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Namsolleck P, Boato F, Schwengel K, et al. AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression. Neurobiol Dis 2013;51:177-191.

    Article  CAS  PubMed  Google Scholar 

  21. Meffert S, Stoll M, Steckelings UM, Bottari SP, Unger T. The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells. Mol Cell Endocrinol 1996;122:59-67.

    Article  CAS  PubMed  Google Scholar 

  22. Laflamme L, Gasparo M, Gallo JM, Payet MD, Gallo-Payet N. Angiotensin II induction of neurite outgrowth by AT2 receptors in NG108-15 cells. Effect counteracted by the AT1 receptors. J Biol Chem 1996;271:22729-22735.

    Article  CAS  PubMed  Google Scholar 

  23. Côté F, Do TH, Laflamme L, Gallo JM, Gallo-Payet N. Activation of the AT(2) receptor of angiotensin II induces neurite outgrowth and cell migration in microexplant cultures of the cerebellum. J Biol Chem 1999;274:31686-31692.

    Article  PubMed  Google Scholar 

  24. Gendron L, Payet MD, Gallo-Payet N. The angiotensin type 2 receptor of angiotensin II and neuronal differentiation: from observations to mechanisms. J Mol Endocrinol 2003;31:359-372.

    Article  CAS  PubMed  Google Scholar 

  25. Guimond MO, Gallo-Payet N. How does angiotensin AT(2) receptor activation help neuronal differentiation and improve neuronal pathological situations? Front Endocrinol (Lausanne) 2012;3:164.

    CAS  Google Scholar 

  26. Maul B, von Bohlen und Halbach O, Becker A, et al. Impaired spatial memory and altered dendritic spine morphology in angiotensin II type 2 receptor-deficient mice. J Mol Med (Berl) 2008;86:563-571.

    Article  CAS  Google Scholar 

  27. Steckelings UM, Rompe F, Kaschina E, et al. The past, present and future of angiotensin II type 2 receptor stimulation. J Renin Angiotensin Aldosterone Syst 2010;11:67-73.

    Article  CAS  PubMed  Google Scholar 

  28. Jing F, Mogi M, Sakata A, et al. Direct stimulation of angiotensin II type 2 receptor enhances spatial memory. J Cereb Blood Flow Metab 2012;32:248-255.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Chao J, Yang L, Buch S, Gao L. Angiotensin II increased neuronal stem cell proliferation: role of AT2R. PLoS One 2013;8:e63488.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Li J, Culman J, Hörtnagl H, et al. Angiotensin AT2 receptor protects against cerebral ischemia-induced neuronal injury. FASEB J 2005;19:617-619.

    CAS  PubMed  Google Scholar 

  31. McCarthy CA, Vinh A, Callaway JK, Widdop RE. Angiotensin AT2 receptor stimulation causes neuroprotection in a conscious rat model of stroke. Stroke 2009;40:1482-1489.

    Article  CAS  PubMed  Google Scholar 

  32. McCarthy CA, Vinh A, Broughton BR, Sobey CG, Callaway JK, Widdop RE. Angiotensin II type 2 receptor stimulation initiated after stroke causes neuroprotection in conscious rats. Hypertension 2012;60:1531-1537.

    Article  CAS  PubMed  Google Scholar 

  33. Lucius R, Gallinat S, Rosenstiel P, Herdegen T, Sievers J, Unger T. The angiotensin II type 2 (AT2) receptor promotes axonal regeneration in the optic nerve of adult rats. J Exp Med 1998;188:661-670.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Reinecke K, Lucius R, Reinecke A, Rickert U, Herdegen T, Unger T. Angiotensin II accelerates functional recovery in the rat sciatic nerve in vivo: role of the AT2 receptor and the transcription factor NF-kappaB. FASEB J 2003;17:2094-2096.

    CAS  PubMed  Google Scholar 

  35. Chen Y, Constantini S, Trembovler V, Weinstock M, Shohami E. An experimental model of closed head injury in mice: pathophysiology, histopathology, and cognitive deficits. J Neurotrauma 1996;13:557-568.

    Article  CAS  PubMed  Google Scholar 

  36. Macova M, Pavel J, Saavedra JM. A peripherally administered, centrally acting angiotensin II AT2 antagonist selectively increases brain AT1 receptors and decreases brain tyrosine hydroxylase transcription, pituitary vasopressin and ACTH. Brain Res 2009;1250:130-140.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Naruse M, Tanabe A, Sato A, et al. Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension 2002;40:28-33.

    Article  CAS  PubMed  Google Scholar 

  38. Thau-Zuchman O, Shohami E, Alexandrovich AG, Leker RR. Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J Cereb Blood Flow Metab 2010;30:1008-1016.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Paxions G, Franklin KBJ. The mouse brain in stereotaxic coordinates. Academic Press, San Diego, CA, 1997.

  40. Beni-Adani L, Gozes I, Cohen Y, et al. A peptide derived from activity-dependent neuroprotective protein (ADNP) ameliorates injury response in closed head injury in mice. J Pharmacol Exp Ther 2001;296:57-63.

    CAS  PubMed  Google Scholar 

  41. Tsenter J, Beni-Adani L, Assaf Y, Alexandrovich AG, Trembovler V, Shohami E. Dynamic changes in the recovery after traumatic brain injury in mice: effect of injury severity on T2-weighted MRI abnormalities, and motor and cognitive functions. J Neurotrauma 2008;25:324-333.

    Article  PubMed  Google Scholar 

  42. Umschwief G, Shein NA, Alexandrovich AG, Trembovler V, Horowitz M, Shohami E. Heat acclimation provides sustained improvement in functional recovery and attenuates apoptosis after traumatic brain injury. J Cereb Blood Flow Metab 2010;30:616-627.

    Article  PubMed Central  PubMed  Google Scholar 

  43. Geddes DM, LaPlaca MC, Cargill RS. Susceptibility of hippocampal neurons to mechanically induced injury. Exp Neurol 2003;184:420-427.

    Article  CAS  PubMed  Google Scholar 

  44. Li NC, Lee A, Whitmer RA, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ 2010;340:b5465.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Mogi M, Li JM, Iwanami J, et al. Angiotensin II type-2 receptor stimulation prevents neural damage by transcriptional activation of methyl methanesulfonate sensitive 2. Hypertension 2006;48:141-148.

    Article  CAS  PubMed  Google Scholar 

  46. Jöhren O, Dendorfer A, Dominiak P. Cardiovascular and renal function of angiotensin II type-2 receptors. Cardiovasc Res 2004;62:460-467.

    Article  PubMed  Google Scholar 

  47. Mogi M, Horiuchi M. Effect of angiotensin II type 2 receptor on stroke, cognitive impairment and neurodegenerative diseases. Geriatr Gerontol Int 2013;13:13-18.

    Article  PubMed  Google Scholar 

  48. Kiprianova I, Sandkühler J, Schwab S, Hoyer S, Spranger M. Brain-derived neurotrophic factor improves long-term potentiation and cognitive functions after transient forebrain ischemia in the rat. Exp Neurol 1999;159:511-519.

    Article  CAS  PubMed  Google Scholar 

  49. Yaka R, Biegon A, Grigoriadis N, et al. D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 2007;21:2033-2041.

    Article  CAS  PubMed  Google Scholar 

  50. Shein NA, Tsenter J, Alexandrovich AG, Horowitz M, Shohami E. Akt phosphorylation is required for heat acclimation-induced neuroprotection. J Neurochem 2007;103:1523-1529.

    Article  CAS  PubMed  Google Scholar 

  51. Zhao S, Fu J, Liu X, Wang T, Zhang J, Zhao Y. Activation of Akt/GSK-3beta/beta-catenin signaling pathway is involved in survival of neurons after traumatic brain injury in rats. Neurol Res 2012;34:400-407.

    Article  CAS  PubMed  Google Scholar 

  52. Noshita N, Lewén A, Sugawara T, Chan PH. Akt phosphorylation and neuronal survival after traumatic brain injury in mice. Neurobiol Dis 2002;9:294-304.

    Article  CAS  PubMed  Google Scholar 

  53. Carrillo-Sepúlveda MA, Ceravolo GS, Furstenau CR, et al. Emerging role of angiotensin type 2 receptor (AT2R)/Akt/NO pathway in vascular smooth muscle cell in the hyperthyroidism. PLoS One 2013;8:e61982.

    Article  PubMed Central  PubMed  Google Scholar 

  54. Caruso-Neves C, Kwon SH, Guggino WB. Albumin endocytosis in proximal tubule cells is modulated by angiotensin II through an AT2 receptor-mediated protein kinase B activation. Proc Natl Acad Sci U S A 2005;102:17513-17518.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest 1997;100:264-269.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Gendron L, Côté F, Payet MD, Gallo-Payet N. Nitric oxide and cyclic GMP are involved in angiotensin II AT(2) receptor effects on neurite outgrowth in NG108-15 cells. Neuroendocrinology 2002;75:70-81.

    Article  CAS  PubMed  Google Scholar 

  57. Iwai M, Liu HW, Chen R, et al. Possible inhibition of focal cerebral ischemia by angiotensin II type 2 receptor stimulation. Circulation 2004;110:843-848.

    Article  CAS  PubMed  Google Scholar 

  58. Ma Y, Liu W, Wang Y, et al. VEGF protects rat cortical neurons from mechanical trauma injury induced apoptosis via the MEK/ERK pathway. Brain Res Bull 2011;86:441-446.

    Article  CAS  PubMed  Google Scholar 

  59. Cohen-Yeshurun A, Trembovler V, Alexandrovich A, et al. N-arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J Cereb Blood Flow Metab 2011;31:1768-1777.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Hetman M, Kanning K, Cavanaugh JE, Xia Z. Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 1999;274:22569-22580.

    Article  CAS  PubMed  Google Scholar 

  61. Gendron L, Laflamme L, Rivard N, Asselin C, Payet MD, Gallo-Payet N. Signals from the AT2 (angiotensin type 2) receptor of angiotensin II inhibit p21ras and activate MAPK (mitogen-activated protein kinase) to induce morphological neuronal differentiation in NG108-15 cells. Mol Endocrinol 1999;13:1615-1626.

    Article  CAS  PubMed  Google Scholar 

  62. Stroth U, Blume A, Mielke K, Unger T. Angiotensin AT(2) receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells. Brain Res Mol Brain Res 2000;78:175-180.

    Article  CAS  PubMed  Google Scholar 

  63. Skaper SD. The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 2008;7:46-62.

    Article  CAS  PubMed  Google Scholar 

  64. Chao MV, Rajagopal R, Lee FS. Neurotrophin signalling in health and disease. Clin Sci (Lond) 2006;110:167-173.

    Article  CAS  Google Scholar 

  65. Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res 2006;66:4249-4255.

    Article  CAS  PubMed  Google Scholar 

  66. Nakamura K, Tan F, Li Z, Thiele CJ. NGF activation of TrkA induces vascular endothelial growth factor expression via induction of hypoxia-inducible factor-1α. Mol Cell Neurosci 2011;46:498-506.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Umschweif G, Alexandrovich AG, Trembovler V, Horowitz M, Shohami E. Hypoxia-inducible factor 1 is essential for spontaneous recovery from traumatic brain injury and is a key mediator of heat acclimation induced neuroprotection. J Cereb Blood Flow Metab 2013;33:524-531.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  68. Weishaupt N, Blesch A, Fouad K. BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol 2012;238:254-264.

    Article  CAS  PubMed  Google Scholar 

  69. Hafko R, Villapol S, Nostramo R, et al. Commercially available angiotensin II At2 receptor antibodies are nonspecific. PLoS One 2013;8:e69234.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  70. Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008;132:645-660.

    Article  CAS  PubMed  Google Scholar 

  71. Lois C, Alvarez-Buylla A. Proliferating subventricular zone cells in the adult mammalian forebrain can differentiate into neurons and glia. Proc Natl Acad Sci U S A 1993;90:2074-2077.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Altman J, Das GD. Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 1965;124:319-335.

    Article  CAS  PubMed  Google Scholar 

  73. Dash PK, Mach SA, Moore AN. Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury. J Neurosci Res 2001;63:313-319.

    Article  CAS  PubMed  Google Scholar 

  74. Salman H, Ghosh P, Kernie SG. Subventricular zone neural stem cells remodel the brain following traumatic injury in adult mice. J Neurotrauma 2004;21:283-292.

    Article  PubMed  Google Scholar 

  75. Kernie SG, Parent JM. Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 2010;37:267-274.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005;28:223-250.

    Article  CAS  PubMed  Google Scholar 

  77. Sun D, Colello RJ, Daugherty WP, et al. Cell proliferation and neuronal differentiation in the dentate gyrus in juvenile and adult rats following traumatic brain injury. J Neurotrauma 2005;22:95-105.

    Article  PubMed  Google Scholar 

  78. Kan I, Barhum Y, Melamed E, Offen D. Mesenchymal stem cells stimulate endogenous neurogenesis in the subventricular zone of adult mice. Stem Cell Rev 2011;7:404-412.

    Article  PubMed  Google Scholar 

  79. Suh H, Deng W, Gage FH. Signaling in adult neurogenesis. Annu Rev Cell Dev Biol 2009;25:253-275.

    Article  CAS  PubMed  Google Scholar 

  80. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000;290:1775-1779.

    Article  CAS  PubMed  Google Scholar 

  81. Fournier NM, Lee B, Banasr M, Elsayed M, Duman RS. Vascular endothelial growth factor regulates adult hippocampal cell proliferation through MEK/ERK- and PI3K/Akt-dependent signaling. Neuropharmacology 2012;63:642-652.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  82. Lao CL, Lu CS, Chen JC. Dopamine D3 receptor activation promotes neural stem/progenitor cell proliferation through AKT and ERK1/2 pathways and expands type-B and -C cells in adult subventricular zone. Glia 2013;61:475-489.

    Article  PubMed  Google Scholar 

  83. Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 2013;138:155-175.

    Article  CAS  PubMed  Google Scholar 

  84. Wan Y, Wallinder C, Plouffe B, et al. Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist. J Med Chem 2004;47:5995-6008.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported, in part, by grants (to ES) from the Brettler Foundation at the School of Pharmacy, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).

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Authors and Affiliations

  1. Department of Pharmacology, The Hebrew University, Jerusalem, Israel

    Gali Umschweif, Sigal Liraz-Zaltsman, Dalia Shabashov, Alexander Alexandrovich, Victoria Trembovler & Esther Shohami

  2. Laboratory of Environmental Physiology, The Hebrew University, Jerusalem, Israel

    Gali Umschweif & Michal Horowitz

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  1. Gali Umschweif
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  2. Sigal Liraz-Zaltsman
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Correspondence to Esther Shohami.

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Umschweif, G., Liraz-Zaltsman, S., Shabashov, D. et al. Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury. Neurotherapeutics 11, 665–678 (2014). https://doi.org/10.1007/s13311-014-0286-x

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