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Imatinib treatment reduces brain injury in a murine model of traumatic brain injury.

Su EJ, Fredriksson L, Kanzawa M, Moore S, Folestad E, Stevenson TK, Nilsson I, Sashindranath M, Schielke GP, Warnock M, Ragsdale M, Mann K, Lawrence AL, Medcalf RL, Eriksson U, Murphy GG, Lawrence DA - Front Cell Neurosci (2015)

Bottom Line: Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction.This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function.Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
Current therapies for Traumatic brain injury (TBI) focus on stabilizing individuals and on preventing further damage from the secondary consequences of TBI. A major complication of TBI is cerebral edema, which can be caused by the loss of blood brain barrier (BBB) integrity. Recent studies in several CNS pathologies have shown that activation of latent platelet derived growth factor-CC (PDGF-CC) within the brain can promote BBB permeability through PDGF receptor α (PDGFRα) signaling, and that blocking this pathway improves outcomes. In this study we examine the efficacy for the treatment of TBI of an FDA approved antagonist of the PDGFRα, Imatinib. Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction. This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function. Finally, analysis of cerebrospinal fluid (CSF) from human TBI patients suggests a possible correlation between high PDGF-CC levels and increased injury severity. Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα.

No MeSH data available.


Related in: MedlinePlus

Imatinib reduces tissue loss after Bi-lateral TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after bilateral CCI. Twenty one days later, animals underwent MRI T2 scan and then were perfused and fixed in paraformaldehyde and stained with H&E. (A,B) Representative photomicrographs of coronal sections near bregma −1.5 (10× objective) from vehicle-treated (A) and Imatinib-treated (B) mice. (C,D) Representative T2-weighted MRI images from vehicle-treated (C) and Imatinib-treated mice (D). (E) Quantification of volumetric loss of tissue determined from the T2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.
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Figure 5: Imatinib reduces tissue loss after Bi-lateral TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after bilateral CCI. Twenty one days later, animals underwent MRI T2 scan and then were perfused and fixed in paraformaldehyde and stained with H&E. (A,B) Representative photomicrographs of coronal sections near bregma −1.5 (10× objective) from vehicle-treated (A) and Imatinib-treated (B) mice. (C,D) Representative T2-weighted MRI images from vehicle-treated (C) and Imatinib-treated mice (D). (E) Quantification of volumetric loss of tissue determined from the T2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.

Mentions: Mice subjected to midline CCI were also analyzed for long term loss of neuronal tissue due to cavitation 21 days after injury. These data are shown in Figure 5 and indicate that unlike the differences in initial lesion size, that were nearly 2-fold at 24 h after injury (39.8 ± 5.6 mm3 vs. 22.7 ± 2.9 mm3), the final difference in tissue loss due to cavitation was only ~9% between the two models (3.9 ± 0.3 mm3 vs. 3.6 ± 0.3 mm3, compare Figures 3E, 5E). Nonetheless, H&E staining of brain sections showed that there was much more hippocampal loss and remodeling in the bilateral TBI model compared to the unilateral model, where the left hippocampus remained largely intact (compare Figures 3A–5A). Similar to the results in lesion size, and edema, Imatinib treatment significantly reduced cavitations in the bilateral TBI model (Figures 5D,E) and appeared to preserve hippocampal structure (Figure 5B). This suggests that even in a severe model of TBI early intervention with Imatinib may have long term benefit in TBI.


Imatinib treatment reduces brain injury in a murine model of traumatic brain injury.

Su EJ, Fredriksson L, Kanzawa M, Moore S, Folestad E, Stevenson TK, Nilsson I, Sashindranath M, Schielke GP, Warnock M, Ragsdale M, Mann K, Lawrence AL, Medcalf RL, Eriksson U, Murphy GG, Lawrence DA - Front Cell Neurosci (2015)

Imatinib reduces tissue loss after Bi-lateral TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after bilateral CCI. Twenty one days later, animals underwent MRI T2 scan and then were perfused and fixed in paraformaldehyde and stained with H&E. (A,B) Representative photomicrographs of coronal sections near bregma −1.5 (10× objective) from vehicle-treated (A) and Imatinib-treated (B) mice. (C,D) Representative T2-weighted MRI images from vehicle-treated (C) and Imatinib-treated mice (D). (E) Quantification of volumetric loss of tissue determined from the T2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4596067&req=5

Figure 5: Imatinib reduces tissue loss after Bi-lateral TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after bilateral CCI. Twenty one days later, animals underwent MRI T2 scan and then were perfused and fixed in paraformaldehyde and stained with H&E. (A,B) Representative photomicrographs of coronal sections near bregma −1.5 (10× objective) from vehicle-treated (A) and Imatinib-treated (B) mice. (C,D) Representative T2-weighted MRI images from vehicle-treated (C) and Imatinib-treated mice (D). (E) Quantification of volumetric loss of tissue determined from the T2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.
Mentions: Mice subjected to midline CCI were also analyzed for long term loss of neuronal tissue due to cavitation 21 days after injury. These data are shown in Figure 5 and indicate that unlike the differences in initial lesion size, that were nearly 2-fold at 24 h after injury (39.8 ± 5.6 mm3 vs. 22.7 ± 2.9 mm3), the final difference in tissue loss due to cavitation was only ~9% between the two models (3.9 ± 0.3 mm3 vs. 3.6 ± 0.3 mm3, compare Figures 3E, 5E). Nonetheless, H&E staining of brain sections showed that there was much more hippocampal loss and remodeling in the bilateral TBI model compared to the unilateral model, where the left hippocampus remained largely intact (compare Figures 3A–5A). Similar to the results in lesion size, and edema, Imatinib treatment significantly reduced cavitations in the bilateral TBI model (Figures 5D,E) and appeared to preserve hippocampal structure (Figure 5B). This suggests that even in a severe model of TBI early intervention with Imatinib may have long term benefit in TBI.

Bottom Line: Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction.This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function.Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.

ABSTRACT
Current therapies for Traumatic brain injury (TBI) focus on stabilizing individuals and on preventing further damage from the secondary consequences of TBI. A major complication of TBI is cerebral edema, which can be caused by the loss of blood brain barrier (BBB) integrity. Recent studies in several CNS pathologies have shown that activation of latent platelet derived growth factor-CC (PDGF-CC) within the brain can promote BBB permeability through PDGF receptor α (PDGFRα) signaling, and that blocking this pathway improves outcomes. In this study we examine the efficacy for the treatment of TBI of an FDA approved antagonist of the PDGFRα, Imatinib. Using a murine model we show that Imatinib treatment, begun 45 min after TBI and given twice daily for 5 days, significantly reduces BBB dysfunction. This is associated with significantly reduced lesion size 24 h, 7 days, and 21 days after TBI, reduced cerebral edema, determined from apparent diffusion co-efficient (ADC) measurements, and with the preservation of cognitive function. Finally, analysis of cerebrospinal fluid (CSF) from human TBI patients suggests a possible correlation between high PDGF-CC levels and increased injury severity. Thus, our data suggests a novel strategy for the treatment of TBI with an existing FDA approved antagonist of the PDGFRα.

No MeSH data available.


Related in: MedlinePlus