The neuron-astrocyte-microglia triad in a rat model of chronic cerebral hypoperfusion: Protective effect of dipyridamole

Frontiers in Aging Neuroscience

Volumn 6, Issue NOV, 2014, Pages

  Lana, Daniele ^a   Melani, Alessia ^a   Pugliese, Anna Maria ^a   Cipriani, Sara ^b   Nosi, Daniele ^c   Pedata, Felicita ^a   Giovannini, Maria Grazia ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

^b INSERM   (France)

^c UNIVERSITY OF FLORENCE   (Italy)

Author keywords

Apoptosis; CA1; Confocal microscopy; Neuron astrocyte microglia triad; Phagocytosis

Indexed keywords

DIPYRIDAMOLE;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; ASTROCYTE; BRAIN ISCHEMIA; BRAIN NERVE CELL; CELL BODY; CELL INFILTRATION; CONTROLLED STUDY; IMMUNOFLUORESCENCE; MALE; MICROGLIA; NERVE DEGENERATION; NEUROPROTECTION; NONHUMAN; PATHOPHYSIOLOGY; PHAGOCYTOSIS; RAT; STRATUM RADIATUM; WISTAR RAT;

EID: 84921325168     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2014.00322     Document Type: Article

References (90)

1. Aktas, B., Utz, A., Hoenig-Liedl, P., Walter, U., and Geiger, J. (2003). Dipyridamole enhances NO/cGMP-mediated vasodilator-stimulated phosphoprotein phosphorylation and signaling in human platelets-in vitro and in vivo/ex vivo studies. Stroke 34, 764-769. doi: 10.1161/01.STR.0000056527.34434.59
2. Al Bahrani, A., Taha, S., Shaath, H., and Bakhiet, M. (2007). TNF-alpha and IL-8 in acute stroke and the modulation of these cytokines by antiplatelet agents. Curr. Neurovasc. Res. 4, 31-37. doi: 10.2174/156720207779940716
3. Allen, N. J., and Barres, B. A. (2009). Neuroscience: Glia-more than just brain glue. Nature 457, 675-677. doi: 10.1038/457675a
4. Barres, B. A. (2008). The mystery and magic of glia: a perspective on their roles in health and disease. Neuron 60, 430-440. doi: 10.1016/j.neuron.2008.10.013
5. Barreto, G. E., Gonzalez, J., Torres, Y., and Morales, L. (2011). Astrocytic-neuronal crosstalk: implications for neuroprotection from brain injury. Neurosci. Res. 71, 107-113. doi: 10.1016/j.neures.2011.06.004
6. Bennett, S. A., Tenniswood, M., Chen, J. H., Davidson, C. M., Keyes, M. T., Fortin, T., et al. (1998). Chronic cerebral hypoperfusion elicits neuronal apoptosis and behavioral impairment. Neuroreport 9, 161-1666. doi: 10.1097/00001756-199801050-00033
7. Bernabeu, R., and Sharp, F. R. (2000). NMDA and AMPA/kainate glutamate receptors modulate dentate neurogenesis and CA3 synapsin-I in normal and ischemic hippocampus. J. Cereb. Blood Flow Metab. 20, 1669-1680. doi: 10.1097/00004647-200012000-0000
8. Beynon, S. B., and Walker, F. R. (2012). Microglial activation in the injured and healthy brain: what are we really talking about? Practical and theoretical issues associated with the measurement of changes in microglial morphology. Neuroscience 225, 162-171. doi: 10.1016/j.neuroscience.2012.07.029
9. Blake, A. D. (2004). Dipyridamole is neuroprotective for cultured rat embryonic cortical neurons. Biochem. Biophys. Res. Commun. 314, 501-504. doi: 10.1016/j.bbrc.2003.12.115
10. Block, M. L., Zecca, L., and Hong, J. S. (2007). Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. doi: 10.1038/nrn2038
11. Bushong, E. A., Martone, M. E., Jones, Y. Z., and Ellisman, M. H. (2002). Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183-192.
12. Buus, C. L., Pourageaud, F., Fazzi, G. E., Janssen, G., Mulvany, M. J., and De Mey, J. G. R. (2001). Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circ. Res. 89, 180-186. doi: 10.1161/hh1401.093575
13. Carden, D. L., and Granger, D. N. (2000). Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 190, 255-266. doi: 10.1002/(SICI)1096-9896(200002)190:3<255
14. Cerbai, F., Lana, D., Nosi, D., Petkova-Kirova, P., Zecchi, S., Brothers, H. M., et al. (2012). The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus. PLoS ONE 7:e45250. doi: 10.1371/journal.pone.0045250
15. Chello, M., Mastroroberto, P., Malta, E., Cirillo, F., and Celi, V. (1999). Inhibition by dipyridamole of neutrophil adhesion to vascular endothelium during coronary bypass surgery. Ann. Thorac. Surg. 67, 1277-1282. doi: 10.1016/S0003-4975(99)00173-3
16. Chen, T. H., Kao, Y. C., Chen, B. C., Chen, C. H., Chan, P., and Lee, H. M. (2006). Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. Eur. J. Pharmacol. 541, 138-146. doi: 10.1016/j.ejphar.2006.05.002
17. Chmayssani, M., Festa, J. R., and Marshall, R. S. (2007). Chronic ischemia and neurocognition. Neuroimaging Clin. N. Am. 17, 313-324. doi: 10.1016/j.nic.2007.03.002
18. Choy, M., Ganesan, V., Thomas, D. L., Thornton, J. S., Proctor, E., King, M. D., et al. (2006). The chronic vascular and haemodynamic response after permanent bilateral common carotid occlusion in newborn and adult rats. J. Cereb. Blood Flow Metab. 26, 1066-1075. doi: 10.1038/sj.jcbfm.9600259
19. Cobos, I., Calcagnotto, M. E., Vilaythong, A. J., Thwin, M. T., Noebels, J. L., Baraban, S. C., et al. (2005). Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat. Neurosci. 8, 1059-1068. doi: 10.1038/nn1499
20. De Jong, G. I., Farkas, E., Stienstra, C. M., Plass, J. R., Keijser, J. N., de la Torre, J. C., et al. (1999). Cerebral hypoperfusion yields capillary damage in the hippocampal CA1 area that correlates with spatial memory impairment. Neuroscience 91, 203-210. doi: 10.1016/S0306-4522(98)00659-9
21. De Keyser, J., Mostert, J. P., and Koch, M. W. (2008). Dysfunctional astrocytes as key players in the pathogenesis of central nervous system disorders. J. Neurol. Sci. 267, 3-16. doi: 10.1016/j.jns.2007.08.044
22. Dirnagl, U. (2012). Pathobiology of injury after stroke: the neurovascular unit and beyond. Thrombolysis and Acute Stroke Treatment: Preparing for the Next Decade 1268, 21-25.
23. Eisert, W. (2002). "Dipyridamole," in Platelets, ed A. Michelson (London, UK: Academic Press), 803-815.
24. Elkeles, R. S., Hampton, J. R., Honour, A. J., Mitchell, J. R., and Prichard, J. S. (1968). Effect of a pyrimido-pyrimidine compound on platelet behaviour in vitro and in vivo. Lancet 2, 751-754. doi: 10.1016/S0140-6736(68)90952-5
25. Eltzschig, H. K., and Carmeliet, P. (2011). Hypoxia and Inflammation. N. Engl. J. Med. 364, 1977. doi: 10.1056/NEJMra0910283
26. Ernens, I., Leonard, F., Vausort, M., Rolland-Turner, M., Devaux, Y., and Wagner, D. R. (2010). Adenosine up-regulates vascular endothelial growth factor in human macrophages. Biochem. Biophys. Res. Commun. 392, 351-356. doi: 10.1016/j.bbrc.2010.01.023
27. Farkas, E., de Wilde, M. C., Kiliaan, A. J., and Luiten, P. G. M. (2002). Systemic effects of dietary n-3 PUFA supplementation accompany changes of CNS parameters in cerebral hypoperfusion. Ann. N.Y. Acad. Sci. 977, 77-86. doi: 10.1111/j.1749-6632.2002.tb04800.x
28. Farkas, E., Donka, G., De Vos, R. A. I., Mihaly, A., Bari, F., and Luiten, P. G. M. (2004). Experimental cerebral hypoperfusion induces white matter injury and microglial activation in the rat brain. Acta Neuropathol. 108, 57-64. doi: 10.1007/s00401-004-0864-9
29. Farkas, E., Institóris, á., Domoki, F., Mihály, A., and Bari, F. (2006). The effect of pre- and post-treatment with diazoxide on the early phase of chronic cerebral hypoperfusion in the rat. Brain Res. 1087, 168-174. doi: 10.1016/j.brainres.2006.02.134
30. Farkas, E., Luiten, P. G. M., and Bari, F. (2007). Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res. Rev. 54, 162-180. doi: 10.1016/j.brainresrev.2007.01.003
31. Faulkner, J. R., Herrmann, J. E., Woo, M. J., Tansey, K. E., Doan, N. B., and Sofroniew, M. V. (2004). Reactive astrocytes protect tissue and preserve function after spinal cord injury. J. Neurosci. 24, 2143-2155. doi: 10.1523/JNEUROSCI.3547-03.2004
32. Figueredo, V. M., Diamond, I., Zhou, H. Z., and Camacho, S. A. (1999). Chronic dipyridamole therapy produces sustained protection against cardiac ischemia-reperfusion injury. Am. J. Physiol. 277, H2091-H2097.
33. Gallagher, M., Landfield, P. W., McEwen, B., Meaney, M. J., Rapp, P. R., Sapolsky, R., et al. (1996). Hippocampal neurodegeneration in aging. Science 274, 484-485. doi: 10.1126/science.274.5287.484
34. Giovannini, M. G. (2002). Double-label confocal microscopy of phosphorylated protein kinases involved in long-term potentiation. Methods Enzymol. 345, 426-424. doi: 10.1016/S0076-6879(02)45035-5
35. Halkes, P. H. A., van Gijn, J., Kappelle, L. J., Koudstaal, P. J., and Algra, A. (2006). Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 367, 1665-1673. doi: 10.1136/jnnp.2008.143875
36. Hanisch, U. K., and Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat. Neurosci. 10, 1387-1394. doi: 10.1038/nn1997
37. Heptinstall, S., Fox, S., Crawford, J., and Hawkins, M. (1986). Inhibition of platelet-aggregation in whole-blood by dipyridamole and aspirin. Thromb. Res. 42, 215-223. doi: 10.1016/0049-3848(86)90297-5
38. Herber, D. L., Maloney, J. L., Roth, L. M., Freeman, M. J., Morgan, D., and Gordon, M. N. (2006). Diverse microglial responses after intrahippocampal administration of lipopolysaccharide. Glia 53, 382-391. doi: 10.1002/glia.20272
39. Hirono, N., Yamadori, A., and Komiyama, M. (1993). Dural arteriovenous fistula: a cause of hypoperfusion-induced intellectual impairment. Eur. Neurol. 33, 5-8. doi: 10.1159/000116889
40. Hsieh, M. S., Zhong, W. B., Yu, S. C., Lin, J. Y. C., Chi, W. M., and Lee, H. M. (2010). Dipyridamole suppresses high glucose-induced osteopontin secretion and mRNA expression in rat aortic smooth muscle cells. Circulation J. 74, 1242-1250. doi: 10.1253/circj. CJ-09-0561
41. Huizinga, R., van der Star, B. J., Kipp, M., Jong, R., Gerritsen, W., Clarner, T., et al. (2012). Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis. Glia 60, 422-431. doi: 10.1002/glia.22276
42. Iadecola, C., and Anrather, J. (2011). The immunology of stroke: from mechanisms to translation. Nat. Med. 7, 796-808. doi: 10.1038/nm.2399
43. Jones, L. F., Landas, S. K., and Johnson, A. K. (1994). Measurement of coronary blood-flow velocity in conscious rats. Am. J. Physiol. 266, H840-H845.
44. Kantor, O., Schmitz, C., Feiser, J., Brasnjevic, I., Korr, H., Busto, R., et al. (2007). Moderate loss of cerebellar purkinje cells after chronic bilateral common carotid artery occlusion in rats. Acta Neuropathol. 113, 549-558. doi: 10.1007/s00401-007-0204-y
45. Klausberger, T., and Somogyi, P. (2008). Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 21, 53-57. doi: 10.1126/science.1149381
46. Lauber, K., Blumenthal, S. G., Waibel, M., and Wesselborg, S. (2004). Clearance of apoptotic cells: getting rid of the corpses. Mol. Cell 14, 277-287. doi: 10.1016/S1097-2765(04)00237-0
47. Li, L., Lundkvist, A., Andersson, D., Wilhelmsson, U., Nagai, N., Pardo, A. C., et al. (2008). Protective role of reactive astrocytes in brain ischemia. J. Cereb. Blood Flow Metab. 28, 468-481. doi: 10.1038/sj.jcbfm.9600546
48. Liesz, A., Suri-Payer, E., Veltkamp, C., Doerr, H., Sommer, C., Rivest, S., et al. (2009). Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat. Med. 15, 192-199. doi: 10.1038/nm.1927
49. Liu, H. X., Zhang, J. J., Zheng, P., and Zhang, Y. (2005). Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Brain Res. Mol. Brain Res. 139, 169-177. doi: 10.1016/j.molbrainres.2005.05.014
50. Loufrani, L., Levy, B. I., and Henrion, D. (2002). Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin. Circ. Res. 91, 1183-1189. doi: 10.1161/01.RES.0000047505.11002.81
51. Maraula, G., Traini, C., Mello, T., Coppi, E., Galli, A., Pedata, F., et al. (2013). Effects of oxygen and glucose deprivation on synaptic transmission in rat dentate gyrus: role of A(2A) adenosine receptors. Neuropharmacology 67, 511-520. doi: 10.1016/j.neuropharm.2012.12.002
52. Melani, A., Cipriani, S., Corti, F., and Pedata, F. (2010). Effect of intravenous administration of dipyridamole in a rat model of chronic cerebral ischemia. Ann. N.Y. Acad. Sci. 1207, 89-96. doi: 10.1111/j.1749-6632.2010.05732.x
53. Miller, K. R., and Streit, W. J. (2007). The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol. 3, 245-253. doi: 10.1017/S1740925X08000136
54. Myer, D. J., Gurkoff, G. G., Lee, S. M., Hovda, D. A., and Sofroniew, M. V. (2006). Essential protective roles of reactive astrocytes in traumatic brain injury. Brain 129, 2761-2772. doi: 10.1093/brain/awl165
55. Naritomi, H. (1991). Experimental basis of multiinfarct dementia - memory impairments in rodent models of ischemia. Alzheimer Dis. Assoc. Disord. 5, 103-111. doi: 10.1097/00002093-199100520-00007
56. Nathan, C., and Ding, A. H. (2010). SnapShot: reactive oxygen intermediates (ROI). Cell 140, 951-951. doi: 10.1016/j.cell.2010.03.008
57. Nelson, P. T., Soma, L. A., and Lavi, E. (2002). Microglia in diseases of the central nervous system. Ann. Med. 34, 491-500. doi: 10.1080/078538902321117698
58. Nencini, P., Inzitari, D., Gibbs, J., and Mangiafico, S. (1993). Dementia with leukoaraiosis and dural arteriovenous malformation: clinical and PET case study. J. Neurol. Neurosurg. Psychiatry 56, 929-931. doi: 10.1136/jnnp.56.8.929
59. Newell, D. R., Oconnor, P. M., Calvert, A. H., and Harrap, K. R. (1986). The effect of the nucleoside transport inhibitor dipyridamole on the incorporation of [H-3] thymidine in the rat. Biochem. Pharmacol. 35, 3871-3877. doi: 10.1016/0006-2952(86)90678-7
60. Noda, M., Doi, Y., Liang, J., Kawanokuchi, J., Sonobe, Y., Takeuchi, H., et al. (2011). Fractalkine attenuates excito-neurotoxicity via microglial clearance of damaged neurons and antioxidant enzyme heme oxygenase-1 expression. J. Biol. Chem. 286, 2308-2319. doi: 10.1074/jbc. M110.169839
61. Ohtaki, H., Fujimoto, T., Sato, T., Kishimoto, K., Fujimoto, M., Moriya, M., et al. (2006). Progressive expression of vascular endothelial growth factor (VEGF) and angiogenesis after chronic ischemic hypoperfusion in rat. Acta Neurochir. Suppl. 96, 283-287. doi: 10.1007/3-211-30714-1_61
62. Otori, T., Katsumata, T., Muramatsu, H., Kashiwagi, F., Katayama, Y., and Terashi, A. (2003). Long-term measurement of cerebral blood flow and metabolism in a rat chronic hypoperfusion model. Clin. Exp. Pharmacol. Physiol. 30, 266-272. doi: 10.1046/j.1440-1681.2003.03825.x
63. Ozacmak, V. H., Sayan, H., Cetin, A., and Akyildiz-Igdem, A. (2007). AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem. Res. 32, 1314-1321. doi: 10.1007/s11064-007-9305-1
64. Pappas, B. A., de la Torre, J. C., Davidson, C. M., Keyes, M. T., and Fortin, T. (1996). Chronic reduction of cerebral blood flow in the adult rat: late-emerging CA1 cell loss and memory dysfunction. Brain Res. 708, 50-58. doi: 10.1016/0006-8993(95)01267-2
65. Pattillo, C. B., Bir, S. C., Branch, B. G., Grebe, E., Shen, X., Pardue, S., et al. (2011). Dipyridamole reverses peripheral ischemia and induces angiogenesis in the Db/Db diabetic mouse hind-limb model by decreasing oxidative stress. Free Radic. Biol. Med. 50, 262-269. doi: 10.1016/j.freeradbiomed.2010.10.714
66. Picano, E. (1989). Dipyridamole-echocardiography test: historical background and physiologic basis. Eur. Heart J. 10, 365-376.
67. Polazzi, E., and Monti, B. (2010). Microglia and neuroprotection: from in vitro studies to therapeutic applications. Prog. Neurobiol. 92, 293-315. doi: 10.1016/j.pneurobio.2010.06.009
68. Re, D. B., Le Verche, V., Yu, C., Amoroso, M. W., Politi, K. A., Phani, S., et al. (2014). Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81, 1001-1008. doi: 10.1016/j.neuron.2014.01.011
69. Rezaie, P., Trillo-Pazos, G., Greenwood, J., Everall, I. P., and Male, D. K. (2002). Motility and ramification of human fetal microglia in culture: an investigation using time-lapse video microscopy and image analysis. Exp. Cell Res. 274, 68-82. doi: 10.1006/excr.2001.5431
70. Ridet, J. L., Malhotra, S. K., Privat, A., and Gage, F. H. (1997). Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 20, 570-577. doi: 10.1016/S0166-2236(97)01139-9
71. Riksen, N. P., Oyen, W. J. G., Ramakers, B. P., van den Broek, P. H. H., Engbersen, R., Boerman, O. C., et al. (2005). Oral therapy with dipyridamole limits ischemia-reperfusion injury in humans. Clin. Pharmacol. Ther. 78, 52-59. doi: 10.1016/j.clpt.2005.03.003
72. Sarti, C., Pantoni, L., Bartolini, L., and Inzitari, D. (2002a). Persistent impairment of gait performances and working memory after bilateral common carotid artery occlusion in the adult Wistar rat. Behav. Brain Res. 136, 13-20. doi: 10.1016/S0166-4328(02)00090-6
73. Sarti, C., Pantoni, L., Bartolini, L., and Inzitari, D. (2002b). Cognitive impairment and chronic cerebral hypoperfusion: what can be learned from experimental models. J. Neurol. Sci. 203-204, 263-266. doi: 10.1016/S0022-510X(02)00302-7
74. Schmidt-Kastner, R., Aguirre-Chen, C., Saul, I., Yick, L., Hamasaki, D., Busto, R., et al. (2005). Astrocytes react to oligemia in the forebrain induced by chronic bilateral common carotid artery occlusion in rats. Brain Res. 1052, 28-39. doi: 10.1016/j.brainres.2005.06.018
75. Schmidt-Kastner, R., Truettner, J., Lin, B., Zhao, W., Saul, I., Busto, R., et al. (2001). Transient changes of brain-derived neurotrophic factor (BDNF) mRNA expression in hippocampus during moderate ischemia induced by chronic bilateral common carotid artery occlusion in the rat. Brain Res. Mol. Brain Res. 92, 157-166. doi: 10.1016/S0169-328X(01)00157-7
76. Serebruany, V. L., Sabaeva, E., Booze, C., Atar, O., and Hanley, D. (2009). Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation. Circulation 120, S1058. doi: 10.1160/TH09-03-0158
77. Shibata, M., Ohtani, R., Ihara, M., and Tomimoto, H. (2004). White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke 35, 2598-2603. doi: 10.1161/01.STR.0000143725.19053.60
78. Sofroniew, M. V. (2009). Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638-647. doi: 10.1016/j.tins.2009.08.002
79. Sofroniew, M. V., and Vinters, H. V. (2010). Astrocytes: biology and pathology. Acta Neuropathol. 119, 7-35. doi: 10.1007/s00401-009-0619-8
80. Spite, M., and Serhan, C. N. (2010). Novel lipid mediators promote resolution of acute inflammation impact of aspirin and statins. Circ. Res. 107, 1170-1184. doi: 10.1161/CIRCRESAHA.110.223883
81. Stence, N., Waite, M., and Dailey, M. E. (2001). Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33, 256-266. doi: 10.1002/1098-1136(200103)33:3<256::AID-GLIA1024>3.0.CO;2-J
82. Suen, D. F., Norris, K. L., and Youle, R. J. (2008). Mitochondrial dynamics and apoptosis. Genes Dev. 22, 1577-1590. doi: 10.1101/gad.1658508
83. Takahashi, K., Rochford, C. D. P., and Neumann, H. (2005). Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647-657. doi: 10.1084/jem.20041611
84. Tatemichi, T. K., Desmond, D. W., Prohovnik, I., and Eidelberg, D. (1995). Dementia associated with bilateral carotid occlusions: neuropsychological and haemodynamic course after extracranial to intracranial bypass surgery. J. Neurol. Neurosurg. Psychiatry 58, 633-636. doi: 10.1136/jnnp.58.5.633
85. Tomimoto, H., Ihara, M., Wakita, H., Ohtani, R., Lin, J. X., Akiguchi, I., et al. (2003). Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol. 106, 527-534. doi: 10.1007/s00401-003-0749-3
86. Tsuda, Y., Yamada, K., Hayakawa, T., Ayada, Y., Kawasaki, S., and Matsuo, H. (1994). Cortical blood flow and cognition after extracranial-intracranial bypass in a patient with severe carotid occlusive lesions. Acta Neurochir. 129, 198-204. doi: 10.1007/BF01406505
87. Venkatesh, P. K., Pattillo, C. B., Branch, B., Hood, J., Thoma, S., Illum, S., et al. (2010). Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway. Cardiovasc. Res. 85, 661-670. doi: 10.1093/cvr/cvq002
88. Weyrich, A. S., Denis, M. M., Kuhlmann-Eyre, J. R., Spencer, E. D., Dixon, D. A., Marathe, G. K., et al. (2005). Dipyridamole selectively inhibits inflammatory gene expression in platelet-monocyte aggregates. Circulation 111, 633-642. doi: 10.1161/01.CIR.0000154607.90506.45
89. Wilhelmsson, U., Bushong, E. A., Price, D. L., Smarr, B. L., Phung, V., Terada, M., et al. (2006). Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc. Natl. Acad. Sci. U.S.A. 103, 17513-17518. doi: 10.1073/pnas.0602841103
90. Yilmaz, G., and Granger, D. N. (2010). Leukocyte recruitment and ischemic brain injury. Neuromolecular Med. 12, 193-204. doi: 10.1007/s12017-009-8074-1