Subacute intranasal administration of tissue plasminogen activator promotes neuroplasticity and improves functional recovery following traumatic brain injury in rats

PLoS ONE

Volumn 9, Issue 9, 2014, Pages

  Meng, Yuling ^a   Chopp, Michael ^a,b   Zhang, Yanlu ^a   Liu, Zhongwu ^a   An, Aaron ^a   Mahmood, Asim ^a   Xiong, Ye ^a  

^a HENRY FORD HOSPITAL   (United States)

^b OAKLAND UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; TISSUE PLASMINOGEN ACTIVATOR;

ADULT; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; COGNITION; CONTROLLED STUDY; DENTATE GYRUS; DISEASE COURSE; FUNCTIONAL STATUS; LIMB MOVEMENT; MALE; NERVE CELL PLASTICITY; NERVE SPROUTING; NERVOUS SYSTEM DEVELOPMENT; NONHUMAN; PYRAMIDAL TRACT; RAT; SENSORIMOTOR FUNCTION; TRAUMATIC BRAIN INJURY; TREATMENT OUTCOME; YOUNG ADULT; AGONISTS; ANIMAL; BRAIN INJURIES; BRAIN ISCHEMIA; CONVALESCENCE; DRUG EFFECTS; INTRANASAL DRUG ADMINISTRATION; MAZE TEST; METABOLISM; MOTONEURON; NERVE FIBER; PATHOLOGY; PHYSIOLOGY; SENSORY NERVE CELL; WISTAR RAT;

RATTUS;

ADMINISTRATION, INTRANASAL; ANIMALS; AXONS; BRAIN INJURIES; BRAIN ISCHEMIA; BRAIN-DERIVED NEUROTROPHIC FACTOR; COGNITION; DENTATE GYRUS; MALE; MAZE LEARNING; MOTOR NEURONS; NEUROGENESIS; NEURONAL PLASTICITY; PYRAMIDAL TRACTS; RATS; RATS, WISTAR; RECOVERY OF FUNCTION; SENSORY RECEPTOR CELLS; TISSUE PLASMINOGEN ACTIVATOR;

EID: 84906990948     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0106238     Document Type: Article

References (103)

1. Xiong Y, Mahmood A, Chopp M (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14:128-142.
2. Gean AD, Fischbein NJ (2010) Head trauma. Neuroimaging Clin N Am 20:527-556.
3. Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A, et al. (2002) Clinical trials in head injury. J Neurotrauma 19:503-557.
4. Xiong Y, Zhang Y, Mahmood A, Meng Y, Zhang ZG, et al. (2012) Neuroprotective and neurorestorative effects of thymosin beta4 treatment initiated 6 hours after traumatic brain injury in rats. J Neurosurg 116:1081-1092.
5. Zhang Y, Xiong Y, Mahmood A, Meng Y, Liu Z, et al. (2010) Sprouting of corticospinal tract axons from the contralateral hemisphere into the denervated side of the spinal cord is associated with functional recovery in adult rat after traumatic brain injury and erythropoietin treatment. Brain Res 1353:249-257.
6. Richardson RM, Sun D, Bullock MR (2007) Neurogenesis after traumatic brain injury. Neurosurg Clin N Am 18:169-181, xi.
7. Levin HS (2003) Neuroplasticity following non-penetrating traumatic brain injury. Brain Inj 17:665-674.
8. Garcia AN, Shah MA, Dixon CE, Wagner AK, Kline AE (2011) Biologic and plastic effects of experimental traumatic brain injury treatment paradigms and their relevance to clinical rehabilitation. PMR 3:S18-27.
9. Adibhatla RM, Hatcher JF (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies. CNS Neurol Disord Drug Targets 7:243-253.
10. Yepes M, Lawrence DA (2004) New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. Exp Biol Med (Maywood) 229:1097-1104.
11. Shen LH, Xin H, Li Y, Zhang RL, Cui Y, et al. (2011) Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice. Stroke 42:459-464.
12. Mahmood A, Qu C, Ning R, Wu H, Goussev A, et al. (2011) Treatment of TBI with collagen scaffolds and human marrow stromal cells increases the expression of tissue plasminogen activator. J Neurotrauma 28:1199-1207.
13. Je HS, Yang F, Ji Y, Nagappan G, Hempstead BL, et al. (2012) Role of probrainderived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses. Proc Natl Acad Sci U S A 109:15924-15929.
14. Sun Y, Lim Y, Li F, Liu S, Lu JJ, et al. (2012) ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLoS One 7:e35883.
15. Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29:12764-12767.
16. Koshimizu H, Kiyosue K, Hara T, Hazama S, Suzuki S, et al. (2009) Multiple functions of precursor BDNF to CNS neurons: negative regulation of neurite growth, spine formation and cell survival. Mol Brain 2:27.
17. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, et al. (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487-491.
18. Stein SC, Ganguly K, Belfield CM, Xu X, Swanson EW, et al. (2009) Erythrocyte-bound tissue plasminogen activator is neuroprotective in experimental traumatic brain injury. J Neurotrauma 26:1585-1592.
19. Dhuria SV, Hanson LR, Frey WH 2nd (2010) Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci 99:1654-1673.
20. Liu Z, Li Y, Zhang L, Xin H, Cui Y, et al. (2012) Subacute intranasal administration of tissue plasminogen activator increases functional recovery and axonal remodeling after stroke in rats. Neurobiol Dis 45:804-809.
21. Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL (1991) A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Methods 39:253-262.
22. Liu Z, Li Y, Qu R, Shen L, Gao Q, et al. (2007) Axonal sprouting into the denervated spinal cord and synaptic and postsynaptic protein expression in the spinal cord after transplantation of bone marrow stromal cell in stroke rats. Brain Res 1149:172-180.
23. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH 2nd (2004) Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481-496.
24. Choi SH, Woodlee MT, Hong JJ, Schallert T (2006) A simple modification of the water maze test to enhance daily detection of spatial memory in rats and mice. J Neurosci Methods 156:182-193.
25. Morris RG, Garrud P, Rawlins JN, O'Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681-683.
26. Mahmood A, Lu D, Qu C, Goussev A, Chopp M (2007) Treatment of traumatic brain injury with a combination therapy of marrow stromal cells and atorvastatin in rats. Neurosurgery 60:546-553; discussion 553-544.
27. Baskin YK, Dietrich WD, Green EJ (2003) Two effective behavioral tasks for evaluating sensorimotor dysfunction following traumatic brain injury in mice. J Neurosci Methods 129:87-93.
28. Chen J, Sanberg PR, Li Y, Wang L, Lu M, et al. (2001) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682-2688.
29. Lu D, Mahmood A, Qu C, Hong X, Kaplan D, et al. (2007) Collagen scaffolds populated with human marrow stromal cells reduce lesion volume and improve functional outcome after traumatic brain injury. Neurosurgery 61:596-602; discussion 602-593.
30. Liu Z, Li Y, Zhang X, Savant-Bhonsale S, Chopp M (2008) Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment. Stroke 39:2571-2577.
31. Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Sydney; Orlando: Academic Press. xxvi, 237 p. of plates p.
32. Chen J, Zhang C, Jiang H, Li Y, Zhang L, et al. (2005) Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25:281-290.
33. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, et al. (1990) A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab 10:290-293.
34. Thau-Zuchman O, Shohami E, Alexandrovich AG, Leker RR (2010) Vascular endothelial growth factor increases neurogenesis after traumatic brain injury. J Cereb Blood Flow Metab 30:1008-1016.
35. Lin TN, He YY, Wu G, Khan M, Hsu CY (1993) Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24:117-121.
36. Fox GB, Fan L, Levasseur RA, Faden AI (1998) Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 15:599-614.
37. Marklund N, Morales D, Clausen F, Hanell A, Kiwanuka O, et al. (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540-551.
38. Qu C, Mahmood A, Ning R, Xiong Y, Zhang L, et al. (2010) The treatment of traumatic brain injury with velcade. J Neurotrauma 27:1625-1634.
39. Xiong Y, Mahmood A, Meng Y, Zhang Y, Qu C, et al. (2010) Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose. J Neurosurg 113:598-608.
40. Zhang C, Raghupathi R, Saatman KE, Smith DH, Stutzmann JM, et al. (1998) Riluzole attenuates cortical lesion size, but not hippocampal neuronal loss, following traumatic brain injury in the rat. J Neurosci Res 52:342-349.
41. Zhang RL, Chopp M, Zhang ZG, Divine G (1998) Early (1h) administration of tissue plasminogen activator reduces infarct volume without increasing hemorrhagic transformation after focal cerebral embolization in rats. J Neurol Sci 160:1-8.
42. Wang Y, Zhang ZG, Rhodes K, Renzi M, Zhang RL, et al. (2007) Postischemic treatment with erythropoietin or carbamylated erythropoietin reduces infarction and improves neurological outcome in a rat model of focal cerebral ischemia. Br J Pharmacol 151:1377-1384.
43. Xiong Y, Mahmood A, Meng Y, Zhang Y, Zhang ZG, et al. (2011) Treatment of traumatic brain injury with thymosin beta (4) in rats. J Neurosurg 114:102-115.
44. Xiong Y, Lu D, Qu C, Goussev A, Schallert T, et al. (2008) Effects of erythropoietin on reducing brain damage and improving functional outcome after traumatic brain injury in mice. J Neurosurg 109:510-521.
45. Meng Y, Xiong Y, Mahmood A, Zhang Y, Qu C, et al. (2011) Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats. J Neurosurg 115:550-560.
46. Ning R, Xiong Y, Mahmood A, Zhang Y, Meng Y, et al. (2011) Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury. Brain Res 1384:140-150.
47. Xiong Y, Mahmood A, Qu C, Kazmi H, Zhang ZG, et al. (2010) Erythropoietin improves histological and functional outcomes after traumatic brain injury in mice in the absence of the neural erythropoietin receptor. J Neurotrauma 27:205-215.
48. Zhang Y, Xiong Y, Mahmood A, Meng Y, Qu C, et al. (2009) Therapeutic effects of erythropoietin on histological and functional outcomes following traumatic brain injury in rats are independent of hematocrit. Brain Res 1294:153-164.
49. Singleton RH, Yan HQ, Fellows-Mayle W, Dixon CE (2010) Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury. J Neurotrauma 27:1091-1099.
50. Han X, Tong J, Zhang J, Farahvar A, Wang E, et al. (2011) Imipramine treatment improves cognitive outcome associated with enhanced hippocampal neurogenesis after traumatic brain injury in mice. J Neurotrauma 28:995-1007.
51. Barha CK, Ishrat T, Epp JR, Galea LA, Stein DG (2011) Progesterone treatment normalizes the levels of cell proliferation and cell death in the dentate gyrus of the hippocampus after traumatic brain injury. Exp Neurol 231:72-81.
52. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, et al. (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675-2680.
53. Xiong Y, Mahmood A, Lu D, Qu C, Kazmi H, et al. (2008) Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system. Brain Res 1230:247-257.
54. Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, et al. (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675-2680.
55. Xin H, Li Y, Shen LH, Liu X, Hozeska-Solgot A, et al. (2011) Multipotent mesenchymal stromal cells increase tPA expression and concomitantly decrease PAI-1 expression in astrocytes through the sonic hedgehog signaling pathway after stroke (in vitro study). J Cereb Blood Flow Metab 31:2181-2188.
56. Friberger P, Knos M, Gustavsson S, Aurell L, Claeson G (1978) Methods for determination of plasmin, antiplasmin and plasminogen by means of substrate S-2251. Haemostasis 7:138-145.
57. Festoff BW, Reddy RB, Van Becelaere M, Smirnova I, Chao J (1994) Activation of serpins and their cognate proteases in muscle after crush injury. J Cell Physiol 159:11-18.
58. Ding Q, Ying Z, Gomez-Pinilla F (2011) Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing. Neuroscience 192:773-780.
59. Ahn MY, Zhang ZG, Tsang W, Chopp M (1999) Endogenous plasminogen activator expression after embolic focal cerebral ischemia in mice. Brain Res 837:169-176.
60. Miskin R, Soreq H (1981) Sensitive autoradiographic quantification of electrophoretically separated proteases. Anal Biochem 118:252-258.
61. Nagai T, Yamada K, Yoshimura M, Ishikawa K, Miyamoto Y, et al. (2004) The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. Proc Natl Acad Sci U S A 101:3650-3655.
62. Wu H, Lu D, Jiang H, Xiong Y, Qu C, et al. (2008) 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 25:130-139.
63. Glover LE, Tajiri N, Lau T, Kaneko Y, van Loveren H, et al. (2012) Immediate, but not delayed, microsurgical skull reconstruction exacerbates brain damage in experimental traumatic brain injury model. PLoS One 7:e33646.
64. Khan M, Im YB, Shunmugavel A, Gilg AG, Dhindsa RK, et al. (2009) Administration of S-nitrosoglutathione after traumatic brain injury protects the neurovascular unit and reduces secondary injury in a rat model of controlled cortical impact. J Neuroinflammation 6:32.
65. Hall ED, Sullivan PG, Gibson TR, Pavel KM, Thompson BM, et al. (2005) Spatial and temporal characteristics of neurodegeneration after controlled cortical impact in mice: more than a focal brain injury. J Neurotrauma 22:252-265.
66. Cutler SM, Cekic M, Miller DM, Wali B, Van Landingham JW, et al. (2007) Progesterone improves acute recovery after traumatic brain injury in the aged rat. J Neurotrauma 24:1475-1486.
67. Tamas A, Zsombok A, Farkas O, Reglodi D, Pal J, et al. (2006) Postinjury administration of pituitary adenylate cyclase activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats. J Neurotrauma 23:686-695.
68. Loane DJ, Faden AI (2010) Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends Pharmacol Sci 31:596-604.
69. Samson AL, Medcalf RL (2006) Tissue-type plasminogen activator: a multifaceted modulator of neurotransmission and synaptic plasticity. Neuron 50:673-678.
70. Minor K, Phillips J, Seeds NW (2009) Tissue plasminogen activator promotes axonal outgrowth on CNS myelin after conditioned injury. Journal of neurochemistry 109:706-715.
71. Goto H, Fujisawa H, Oka F, Nomura S, Kajiwara K, et al. (2007) Neurotoxic effects of exogenous recombinant tissue-type plasminogen activator on the normal rat brain. J Neurotrauma 24:745-752.
72. Sashindranath M, Sales E, Daglas M, Freeman R, Samson AL, et al. (2012) The tissue-type plasminogen activator-plasminogen activator inhibitor 1 complex promotes neurovascular injury in brain trauma: evidence from mice and humans. Brain 135:3251-3264.
73. Vivien D, Buisson A (2000) Serine protease inhibitors: novel therapeutic targets for stroke? J Cereb Blood Flow Metab 20:755-764.
74. Armstead WM, Bohman LE, Riley J, Yarovoi S, Higazi AA, et al. (2013) tPAS (481) A Prevents Impairment of Cerebrovascular Autoregulation by Endogenous tPA after Traumatic Brain Injury by Upregulating p38 MAPK and Inhibiting ET-1. J Neurotrauma 30:1898-1907.
75. Armstead WM, Riley J, Yarovoi S, Cines DB, Smith DH, et al. (2012) tPAS481A prevents neurotoxicity of endogenous tPA in traumatic brain injury. J Neurotrauma 29:1794-1802.
76. Mori T, Wang X, Kline AE, Siao CJ, Dixon CE, et al. (2001) Reduced cortical injury and edema in tissue plasminogen activator knockout mice after brain trauma. Neuroreport 12:4117-4120.
77. Armstead WM, Kiessling JW, Riley J, Cines DB, Higazi AA (2011) tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK. Neurol Res 33:726-733.
78. Xin H, Li Y, Shen LH, Liu X, Wang X, et al. (2010) Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS One 5:e9027.
79. Neafsey EJ, Bold EL, Haas G, Hurley-Gius KM, Quirk G, et al. (1986) The organization of the rat motor cortex: a microstimulation mapping study. Brain research 396:77-96.
80. Kartje-Tillotson G, Neafsey EJ, Castro AJ (1985) Electrophysiological analysis of motor cortical plasticity after cortical lesions in newborn rats. Brain research 332:103-111.
81. Zhao C, Deng W, Gage FH (2008) Mechanisms and functional implications of adult neurogenesis. Cell 132:645-660.
82. Lu D, Mahmood A, Zhang R, Copp M (2003) Upregulation of neurogenesis and reduction in functional deficits following administration of DEtA/NONOate, a nitric oxide donor, after traumatic brain injury in rats. J Neurosurg 99:351-361.
83. Zheng W, Zhuge Q, Zhong M, Chen G, Shao B, et al. (2013) Neurogenesis in adult human brain after traumatic brain injury. J Neurotrauma 30:1872-1880.
84. Sun D, Colello RJ, Daugherty WP, Kwon TH, McGinn MJ, et al. (2005) Cell proliferation and neuronal differentiation in the dentate gyrus in juvenile and adult rats following traumatic brain injury. J Neurotrauma 22:95-105.
85. Toni N, Teng EM, Bushong EA, Aimone JB, Zhao C, et al. (2007) Synapse formation on neurons born in the adult hippocampus. Nat Neurosci 10:727-734.
86. Zhao C, Teng EM, Summers RG Jr, Ming GL, Gage FH (2006) Distinct morphological stages of dentate granule neuron maturation in the adult mouse hippocampus. J Neurosci 26:3-11.
87. Vivar C, van Praag H (2013) Functional circuits of new neurons in the dentate gyrus. Front Neural Circuits 7:15.
88. Obiang P, Maubert E, Bardou I, Nicole O, Launay S, et al. (2011) Enriched housing reverses age-associated impairment of cognitive functions and tPAdependent maturation of BDNF. Neurobiol Learn Mem 96:121-129.
89. Barnes P, Thomas KL (2008) Proteolysis of proBDNF is a key regulator in the formation of memory. PLoS One 3:e3248.
90. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, et al. (1995) Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci U S A 92:8856-8860.
91. Figurov A, Pozzo-Miller LD, Olafsson P, Wang T, Lu B (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706-709.
92. Gao X, Chen J (2009) Conditional knockout of brain-derived neurotrophic factor in the hippocampus increases death of adult-born immature neurons following traumatic brain injury. J Neurotrauma 26:1325-1335.
93. Lu B, Pang PT, Woo NH (2005) The yin and yang of neurotrophin action. Nat Rev Neurosci 6:603-614.
94. Mast TG, Fadool DA (2012) Mature and precursor brain-derived neurotrophic factor have individual roles in the mouse olfactory bulb. PLoS One 7:e31978.
95. Yang J, Harte-Hargrove LC, Siao CJ, Marinic T, Clarke R, et al. (2014) proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep 7:796-806.
96. Kaplan GB, Vasterling JJ, Vedak PC (2010) Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder, and their comorbid conditions: role in pathogenesis and treatment. Behav Pharmacol 21:427-437.
97. Zhang Y, Pardridge WM (2006) Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Res 1111:227-229.
98. Griesbach GS, Hovda DA, Molteni R, Wu A, Gomez-Pinilla F (2004) Voluntary exercise following traumatic brain injury: brain-derived neurotrophic factor upregulation and recovery of function. Neuroscience 125:129-139.
99. Yi JH, Katagiri Y, Susarla B, Figge D, Symes AJ, et al. (2012) Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice. J Comp Neurol 520:3295-3313.
100. Wu YP, Siao CJ, Lu W, Sung TC, Frohman MA, et al. (2000) The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate. J Cell Biol 148:1295-1304.
101. Bukhari N, Torres L, Robinson JK, Tsirka SE (2011) Axonal regrowth after spinal cord injury via chondroitinase and the tissue plasminogen activator (tPA)/plasmin system. J Neurosci 31:14931-14943.
102. Rodier M, Prigent-Tessier A, Bejot Y, Jacquin A, Mossiat C, et al. (2014) Exogenous t-PA Administration Increases Hippocampal Mature BDNF Levels. Plasmin- or NMDA-Dependent Mechanism? PLoS One 9:e92416.
103. Cho E, Lee KJ, Seo JW, Byun CJ, Chung SJ, et al. (2012) Neuroprotection by urokinase plasminogen activator in the hippocampus. Neurobiol Dis 46:215-224.