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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 lesion volume and edema 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 and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after bilateral CCI. (A) Representative T2-weighted MRI images. (B) Quantitative analysis of the lesion volume determined from theT2-weighted hyper-intense signal. (C) The relative extent of cerebral edema in both hemispheres was determined by calculating the ADC values from DWI scans. Data are expressed as mean ± SEM (n = 4–5), the single asterisk indicates p < 0.05, and the dotted line indicates the normal ADC value of 736 × 10−3 mm2/s reported for age matched mice (Rau et al., 2006).
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Figure 4: Imatinib reduces lesion volume and edema 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 and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after bilateral CCI. (A) Representative T2-weighted MRI images. (B) Quantitative analysis of the lesion volume determined from theT2-weighted hyper-intense signal. (C) The relative extent of cerebral edema in both hemispheres was determined by calculating the ADC values from DWI scans. Data are expressed as mean ± SEM (n = 4–5), the single asterisk indicates p < 0.05, and the dotted line indicates the normal ADC value of 736 × 10−3 mm2/s reported for age matched mice (Rau et al., 2006).

Mentions: To characterize the extent of injury in the midline CCI model and to examine the potential efficacy of Imatinib in a more severe model of TBI we performed midline CCI followed by Imatinib treatment and analyses as above. Briefly, mice were gavaged 45 min after TBI and then twice a day for 5 days following injury with either vehicle or 200 mg/kg of Imatinib. T2 and DWI MRI scans were obtained at 24 h and 7 days post-injury. Lesion volumes were calculated from the T2 scans (Figures 4A,B). As expected, the midline CCI resulted in a bilateral injury that was nearly twice as large as the unilateral injury at 24 h after CCI (39.8 ± 5.6 mm3 vs. 22.7 ± 2.9 mm3) and remained larger 7 days after injury (18.9 ± 3.2 mm3 vs. 12.5 ± 2.4 mm3) (compare Figure 2B with Figure 4B). Imatinib treatment was also effective at reducing lesion size in the midline CCI model, producing a non-significant trend toward a smaller lesion at 24 h but a significant decrease in lesion volume by 7 days post injury (18.9 ± 3.2 mm3 vs. 8.0 ± 3.2 mm3).


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 lesion volume and edema 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 and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after bilateral CCI. (A) Representative T2-weighted MRI images. (B) Quantitative analysis of the lesion volume determined from theT2-weighted hyper-intense signal. (C) The relative extent of cerebral edema in both hemispheres was determined by calculating the ADC values from DWI scans. Data are expressed as mean ± SEM (n = 4–5), the single asterisk indicates p < 0.05, and the dotted line indicates the normal ADC value of 736 × 10−3 mm2/s reported for age matched mice (Rau et al., 2006).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
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Figure 4: Imatinib reduces lesion volume and edema 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 and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after bilateral CCI. (A) Representative T2-weighted MRI images. (B) Quantitative analysis of the lesion volume determined from theT2-weighted hyper-intense signal. (C) The relative extent of cerebral edema in both hemispheres was determined by calculating the ADC values from DWI scans. Data are expressed as mean ± SEM (n = 4–5), the single asterisk indicates p < 0.05, and the dotted line indicates the normal ADC value of 736 × 10−3 mm2/s reported for age matched mice (Rau et al., 2006).
Mentions: To characterize the extent of injury in the midline CCI model and to examine the potential efficacy of Imatinib in a more severe model of TBI we performed midline CCI followed by Imatinib treatment and analyses as above. Briefly, mice were gavaged 45 min after TBI and then twice a day for 5 days following injury with either vehicle or 200 mg/kg of Imatinib. T2 and DWI MRI scans were obtained at 24 h and 7 days post-injury. Lesion volumes were calculated from the T2 scans (Figures 4A,B). As expected, the midline CCI resulted in a bilateral injury that was nearly twice as large as the unilateral injury at 24 h after CCI (39.8 ± 5.6 mm3 vs. 22.7 ± 2.9 mm3) and remained larger 7 days after injury (18.9 ± 3.2 mm3 vs. 12.5 ± 2.4 mm3) (compare Figure 2B with Figure 4B). Imatinib treatment was also effective at reducing lesion size in the midline CCI model, producing a non-significant trend toward a smaller lesion at 24 h but a significant decrease in lesion volume by 7 days post injury (18.9 ± 3.2 mm3 vs. 8.0 ± 3.2 mm3).

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