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Erschienen in: Translational Stroke Research 1/2015

01.02.2015 | Original Article

Longitudinal Assessment of Imatinib’s Effect on the Blood–Brain Barrier After Ischemia/Reperfusion Injury with Permeability MRI

verfasst von: Zamir Merali, Jackie Leung, D. Mikulis, F. Silver, Andrea Kassner

Erschienen in: Translational Stroke Research | Ausgabe 1/2015

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Abstract

Acute ischemic stroke (AIS) often results in degeneration of the blood–brain barrier (BBB), which can lead to vasogenic edema and an increased risk of intracerebral hemorrhage. Imatinib is an agent that may be able to protect the BBB and reduce the risk of the harmful consequences of BBB degeneration. We sought to measure the effect of Imatinib on the BBB after experimental stroke longitudinally in vivo with permeability dynamic contrast-enhanced MRI. Ischemia/reperfusion injury was induced with a transient middle cerebral artery occlusion surgery. Rats were given Imatinib at 2 and 20 h after stroke onset. Post-assessment included neurologic functioning, MR imaging, Evans Blue extravasation, Western blot, and immunohistology assay. Imatinib protected the BBB by 24 h but failed to decrease BBB permeability at an earlier time-point. Imatinib also reduced infarct volume, edema, and improved neurologic functioning by 24 h. Rats treated with Imatinib also had a higher expression of the BBB structural protein Zona ocludens-1 and a reduction in nuclear factor-kappa beta (NF-κβ) activation. Imatinib is a promising agent to protect the BBB after AIS, but its effect on the BBB may not become prominent until 24 h after the onset of ischemia. This finding may help elucidate Imatinib’s role in the clinical management of AIS and influence future study designs.
Literatur
1.
Zurück zum Zitat The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109–18.CrossRef The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997;28(11):2109–18.CrossRef
4.
Zurück zum Zitat Kassner A, Roberts T, Taylor K, Silver F, Mikulis D. Prediction of hemorrhage in acute ischemic stroke using permeability MR imaging. Am J Neuroradiol. 2005;26(9):2213–7.PubMed Kassner A, Roberts T, Taylor K, Silver F, Mikulis D. Prediction of hemorrhage in acute ischemic stroke using permeability MR imaging. Am J Neuroradiol. 2005;26(9):2213–7.PubMed
5.
Zurück zum Zitat Kassner A, Thornhill R. Measuring the integrity of the human blood–brain barrier using magnetic resonance imaging. Methods Mol Biol. 2011;686:229–45.PubMedCrossRef Kassner A, Thornhill R. Measuring the integrity of the human blood–brain barrier using magnetic resonance imaging. Methods Mol Biol. 2011;686:229–45.PubMedCrossRef
6.
Zurück zum Zitat Armstead WM, Nassar T, Akkawi S, Smith DH, Xiao-Han C, Cines DB, et al. Neutralizing the neurotoxic effects of exogenous and endogenous tPA. Nat Neurosci. 2006;9(9):1150–5.PubMedCrossRef Armstead WM, Nassar T, Akkawi S, Smith DH, Xiao-Han C, Cines DB, et al. Neutralizing the neurotoxic effects of exogenous and endogenous tPA. Nat Neurosci. 2006;9(9):1150–5.PubMedCrossRef
7.
Zurück zum Zitat Sandoval KE, Witt KA. Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 2008;32(2):200–19.PubMedCrossRef Sandoval KE, Witt KA. Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 2008;32(2):200–19.PubMedCrossRef
8.
Zurück zum Zitat Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39(4):1121–6.PubMedCrossRef Rosell A, Cuadrado E, Ortega-Aznar A, Hernandez-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood–brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39(4):1121–6.PubMedCrossRef
9.
Zurück zum Zitat Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke. 2008;39(8):2249–56.PubMedCrossRef Paciaroni M, Agnelli G, Corea F, Ageno W, Alberti A, Lanari A, et al. Early hemorrhagic transformation of brain infarction: rate, predictive factors, and influence on clinical outcome: results of a prospective multicenter study. Stroke. 2008;39(8):2249–56.PubMedCrossRef
10.
Zurück zum Zitat Abbruscato TJ, Lopez SP, Mark KS, Hawkins BT, Davis TP. Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells. J Pharm Sci. 2002;91(12):2525–38.PubMedCrossRef Abbruscato TJ, Lopez SP, Mark KS, Hawkins BT, Davis TP. Nicotine and cotinine modulate cerebral microvascular permeability and protein expression of ZO-1 through nicotinic acetylcholine receptors expressed on brain endothelial cells. J Pharm Sci. 2002;91(12):2525–38.PubMedCrossRef
11.
Zurück zum Zitat Jiao H, Wang Z, Liu Y, Wang P, Xue Y. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J Mol Neurosci. 2011;44(2):130––9. Jun 2011.PubMedCrossRef Jiao H, Wang Z, Liu Y, Wang P, Xue Y. Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J Mol Neurosci. 2011;44(2):130––9. Jun 2011.PubMedCrossRef
12.
Zurück zum Zitat Abrams MB, Nilsson I, Lewandowski SA, Kjell J, Codeluppi S, Olson L, et al. Imatinib enhances functional outcome after spinal cord injury. PLoS One. 2012;7(6):e38760.PubMedCentralPubMedCrossRef Abrams MB, Nilsson I, Lewandowski SA, Kjell J, Codeluppi S, Olson L, et al. Imatinib enhances functional outcome after spinal cord injury. PLoS One. 2012;7(6):e38760.PubMedCentralPubMedCrossRef
13.
Zurück zum Zitat Su E, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood–brain barrier integrity during ischemic stroke. Nat Med. 2008;14:731.PubMedCentralPubMedCrossRef Su E, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, et al. Activation of PDGF-CC by tissue plasminogen activator impairs blood–brain barrier integrity during ischemic stroke. Nat Med. 2008;14:731.PubMedCentralPubMedCrossRef
14.
Zurück zum Zitat Ma Q, Huang B, Khatibi N, Rolland 2nd W, Suzuki H, Zhang JH, et al. PDGFR-alpha inhibition preserves blood–brain barrier after intracerebral hemorrhage. Ann Neurol. 2011;70(6):920–31.PubMedCentralPubMedCrossRef Ma Q, Huang B, Khatibi N, Rolland 2nd W, Suzuki H, Zhang JH, et al. PDGFR-alpha inhibition preserves blood–brain barrier after intracerebral hemorrhage. Ann Neurol. 2011;70(6):920–31.PubMedCentralPubMedCrossRef
15.
Zurück zum Zitat Adzemovic MZ, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood–brain barrier integrity and by modulating the peripheral immune response. PLoS One. 2013;8(2):e56586.PubMedCrossRef Adzemovic MZ, Zeitelhofer M, Eriksson U, Olsson T, Nilsson I. Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood–brain barrier integrity and by modulating the peripheral immune response. PLoS One. 2013;8(2):e56586.PubMedCrossRef
16.
Zurück zum Zitat Deli MA, Ábrahám CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol. 2005;25(1):59–127.PubMedCrossRef Deli MA, Ábrahám CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood–brain barrier models: physiology, pathology, and pharmacology. Cell Mol Neurobiol. 2005;25(1):59–127.PubMedCrossRef
17.
Zurück zum Zitat Hoffmann A, Bredno J, Wendland MF, Derugin N, Hom J, Schuster T, et al. Validation of in vivo magnetic resonance imaging blood–brain barrier permeability measurements by comparison with gold standard histology. Stroke. 2011;42(7):2054–60.PubMedCentralPubMedCrossRef Hoffmann A, Bredno J, Wendland MF, Derugin N, Hom J, Schuster T, et al. Validation of in vivo magnetic resonance imaging blood–brain barrier permeability measurements by comparison with gold standard histology. Stroke. 2011;42(7):2054–60.PubMedCentralPubMedCrossRef
18.
Zurück zum Zitat Durukan A, Tatlisumak T. Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol, Biochem Behav. 2007;87(1):179–97.CrossRef Durukan A, Tatlisumak T. Acute ischemic stroke: Overview of major experimental rodent models, pathophysiology, and therapy of focal cerebral ischemia. Pharmacol, Biochem Behav. 2007;87(1):179–97.CrossRef
19.
Zurück zum Zitat Liu S, Zhen G, Meloni BP, Campbell K, Winn HR. Rodent stroke model guidelines for preclinical stroke trials (1st edition). J Exp Stroke Transl Med. 2009;2(2):2–27.PubMedCentralPubMedCrossRef Liu S, Zhen G, Meloni BP, Campbell K, Winn HR. Rodent stroke model guidelines for preclinical stroke trials (1st edition). J Exp Stroke Transl Med. 2009;2(2):2–27.PubMedCentralPubMedCrossRef
20.
Zurück zum Zitat Kriz J. Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol. 2006;18(1–2):145–57.PubMedCrossRef Kriz J. Inflammation in ischemic brain injury: timing is important. Crit Rev Neurobiol. 2006;18(1–2):145–57.PubMedCrossRef
21.
Zurück zum Zitat Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022–8.PubMedCrossRef Larson RA, Druker BJ, Guilhot F, O'Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022–8.PubMedCrossRef
22.
Zurück zum Zitat Uluç K, Miranpuri A, Kujoth GC, Aktüre E, Başkaya MK. Focal cerebral ischemia model by endovascular suture occlusion of the middle cerebral artery in the rat. J Vis Exp. 2011;05((48):e1978. Uluç K, Miranpuri A, Kujoth GC, Aktüre E, Başkaya MK. Focal cerebral ischemia model by endovascular suture occlusion of the middle cerebral artery in the rat. J Vis Exp. 2011;05((48):e1978.
23.
Zurück zum Zitat Takano K, Tatlisumak T, Bergmann AG, Gibson III DG, Fisher M. Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats. J Neurol Sci. 1997;153(1):8–11.PubMedCrossRef Takano K, Tatlisumak T, Bergmann AG, Gibson III DG, Fisher M. Reproducibility and reliability of middle cerebral artery occlusion using a silicone-coated suture (Koizumi) in rats. J Neurol Sci. 1997;153(1):8–11.PubMedCrossRef
24.
Zurück zum Zitat Vidarsson L, Thornhill RE, Liu F, Mikulis DJ, Kassner A. Quantitative permeability magnetic resonance imaging in acute ischemic stroke: how long do we need to scan? Magn Reson Imaging. 2009;27(9):1216–22.PubMedCrossRef Vidarsson L, Thornhill RE, Liu F, Mikulis DJ, Kassner A. Quantitative permeability magnetic resonance imaging in acute ischemic stroke: how long do we need to scan? Magn Reson Imaging. 2009;27(9):1216–22.PubMedCrossRef
25.
Zurück zum Zitat Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3(1):1–7.PubMedCrossRef Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. J Cereb Blood Flow Metab. 1983;3(1):1–7.PubMedCrossRef
26.
Zurück zum Zitat Gerriets T, Stolz E, Walberer M, Müller C, Kluge A, Bachmann A, et al. Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke. 2004;35(2):566–71.PubMedCrossRef Gerriets T, Stolz E, Walberer M, Müller C, Kluge A, Bachmann A, et al. Noninvasive quantification of brain edema and the space-occupying effect in rat stroke models using magnetic resonance imaging. Stroke. 2004;35(2):566–71.PubMedCrossRef
27.
Zurück zum Zitat Radu M, Chernoff J. An in vivo assay to test blood vessel permeability. J Vis Exp. 2013;73:e50062.PubMed Radu M, Chernoff J. An in vivo assay to test blood vessel permeability. J Vis Exp. 2013;73:e50062.PubMed
28.
Zurück zum Zitat Garcia JH, Wagner S, Liu K, Hu X. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke. 1995;26(4):627–35.PubMedCrossRef Garcia JH, Wagner S, Liu K, Hu X. Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats: statistical validation. Stroke. 1995;26(4):627–35.PubMedCrossRef
29.
Zurück zum Zitat Ciarcia R, Vitiello MT, Galdiero M, Pacilio C, Iovane V, d'Angelo D, et al. Imatinib treatment inhibit IL-6, IL-8, NF-KB and AP-1 production and modulate intracellular calcium in CML patients. J Cell Physiol. 2012;227(6):2798–803.PubMedCrossRef Ciarcia R, Vitiello MT, Galdiero M, Pacilio C, Iovane V, d'Angelo D, et al. Imatinib treatment inhibit IL-6, IL-8, NF-KB and AP-1 production and modulate intracellular calcium in CML patients. J Cell Physiol. 2012;227(6):2798–803.PubMedCrossRef
30.
Zurück zum Zitat Watson PM, Anderson JM, Vanltallie CM, Doctrow SR. The tight-junction-specific protein ZO-l is a component of the human and rat blood–brain barriers. Neurosci Lett. 1991;129(1). Watson PM, Anderson JM, Vanltallie CM, Doctrow SR. The tight-junction-specific protein ZO-l is a component of the human and rat blood–brain barriers. Neurosci Lett. 1991;129(1).
31.
Zurück zum Zitat Neumann-Haefelin T, Kastrup A, de Crespigny A, Yenari MA, Ringer T, Sun GH, et al. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood–brain barrier damage, and edema formation. Stroke. 2000;31(8):1965–73.PubMedCrossRef Neumann-Haefelin T, Kastrup A, de Crespigny A, Yenari MA, Ringer T, Sun GH, et al. Serial MRI after transient focal cerebral ischemia in rats: dynamics of tissue injury, blood–brain barrier damage, and edema formation. Stroke. 2000;31(8):1965–73.PubMedCrossRef
32.
Zurück zum Zitat Xi G, Keep RF, Hua Y, Xiang J, Hoff JT. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke. 1999;30(6):1247–55.PubMedCrossRef Xi G, Keep RF, Hua Y, Xiang J, Hoff JT. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke. 1999;30(6):1247–55.PubMedCrossRef
33.
Zurück zum Zitat Berti R, Williams AJ, Moffett JR, Hale SL, Velarde LC, Elliott PJ, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia–reperfusion brain injury. J Cereb Blood Flow Metab. 2002;22(9):1068–79.PubMedCrossRef Berti R, Williams AJ, Moffett JR, Hale SL, Velarde LC, Elliott PJ, et al. Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia–reperfusion brain injury. J Cereb Blood Flow Metab. 2002;22(9):1068–79.PubMedCrossRef
34.
Zurück zum Zitat Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, et al. Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke. 2004;35(4):987–91.PubMedCrossRef Nurmi A, Lindsberg PJ, Koistinaho M, Zhang W, Juettler E, Karjalainen-Lindsberg ML, et al. Nuclear factor-kappaB contributes to infarction after permanent focal ischemia. Stroke. 2004;35(4):987–91.PubMedCrossRef
35.
Zurück zum Zitat Carroll JE, Hess DC, Howard EF, Hill WD. Is nuclear factor-kappaB a good treatment target in brain ischemia/reperfusion injury? Neuroreport. 2000;11(9):R1–4.PubMed Carroll JE, Hess DC, Howard EF, Hill WD. Is nuclear factor-kappaB a good treatment target in brain ischemia/reperfusion injury? Neuroreport. 2000;11(9):R1–4.PubMed
36.
Zurück zum Zitat Zhang L, Zhang ZG, Zhang RL, Lu M, Adams J, Elliott PJ, et al. Postischemic (6-Hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke. 2001;32(12):2926–31.PubMedCrossRef Zhang L, Zhang ZG, Zhang RL, Lu M, Adams J, Elliott PJ, et al. Postischemic (6-Hour) treatment with recombinant human tissue plasminogen activator and proteasome inhibitor PS-519 reduces infarction in a rat model of embolic focal cerebral ischemia. Stroke. 2001;32(12):2926–31.PubMedCrossRef
37.
Zurück zum Zitat Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull. 2001;55(3):375–86.PubMedCrossRef Hill WD, Hess DC, Carroll JE, Wakade CG, Howard EF, Chen Q, et al. The NF-kappaB inhibitor diethyldithiocarbamate (DDTC) increases brain cell death in a transient middle cerebral artery occlusion model of ischemia. Brain Res Bull. 2001;55(3):375–86.PubMedCrossRef
38.
Zurück zum Zitat Kim E, Matsuse M, Saenko V, Suzuki K, Ohtsuru A, Mitsutake N, et al. Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-kappaB activation in anaplastic thyroid carcinoma cells. Thyroid. 2012;22(7):717–24.PubMedCentralPubMedCrossRef Kim E, Matsuse M, Saenko V, Suzuki K, Ohtsuru A, Mitsutake N, et al. Imatinib enhances docetaxel-induced apoptosis through inhibition of nuclear factor-kappaB activation in anaplastic thyroid carcinoma cells. Thyroid. 2012;22(7):717–24.PubMedCentralPubMedCrossRef
39.
Zurück zum Zitat Schofield ZV, Woodruff TM, Halai R, Wu MC, Cooper MA. Neutrophils — a key component of ischemia reperfusion injury. Shock. 2013 Oct 1. Schofield ZV, Woodruff TM, Halai R, Wu MC, Cooper MA. Neutrophils — a key component of ischemia reperfusion injury. Shock. 2013 Oct 1.
40.
Zurück zum Zitat Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19(8):819–34.PubMedCrossRef Barone FC, Feuerstein GZ. Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab. 1999;19(8):819–34.PubMedCrossRef
41.
Zurück zum Zitat Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 2000;10(1):113–26.PubMedCrossRef Stanimirovic D, Satoh K. Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol. 2000;10(1):113–26.PubMedCrossRef
Metadaten
Titel
Longitudinal Assessment of Imatinib’s Effect on the Blood–Brain Barrier After Ischemia/Reperfusion Injury with Permeability MRI
verfasst von
Zamir Merali
Jackie Leung
D. Mikulis
F. Silver
Andrea Kassner
Publikationsdatum
01.02.2015
Verlag
Springer US
Erschienen in
Translational Stroke Research / Ausgabe 1/2015
Print ISSN: 1868-4483
Elektronische ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-014-0358-6

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