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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 TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral CCI and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after unilateral 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 the ipsilateral hemisphere was determined by calculating the apparent diffusion co-efficient (ADC) values from diffusion weighted imaging (DWI) scans. Data are expressed as mean ± SEM (n = 6); single asterisk indicates p < 0.05, double asterisks indicate p < 0.01, 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 2: Imatinib reduces lesion volume and edema after TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral CCI and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after unilateral 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 the ipsilateral hemisphere was determined by calculating the apparent diffusion co-efficient (ADC) values from diffusion weighted imaging (DWI) scans. Data are expressed as mean ± SEM (n = 6); single asterisk indicates p < 0.05, double asterisks indicate p < 0.01, 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: Since brain edema is a common and serious consequence of TBI that contributes to lesion expansion and secondary brain damage (Dietrich et al., 1994; del Zoppo and Mabuchi, 2003) and since the rise in edema after TBI is thought to be due, at least in part, to the loss of the BBB control, we examined if Imatinib treatment also reduced lesion size and edema 24 h and 7 days after TBI. For these studies mice were subjected to CCI in the right parietotemporal cortex and then treated with either vehicle or 200 mg/kg of Imatinib by gavage 45 min after TBI and then twice a day for 5 days following injury. T2 and DWI MRI scans were obtained at 24 h and 7 days post-injury. The T2 scans were used to calculate the lesion volume and showed that by 24 h after CCI there was conspicuous tissue damage within the region surrounding the impact site (Figure 2A). The T2 scans also revealed that by 7 days post-injury there was extensive tissue loss and cavitation in the cortex of untreated mice that was significantly reduced in the Imatinib treated group (Figure 2A). Quantification of these data demonstrated that at 24 h after injury the mean T2 lesion volume was 22.7 ± 2.9 mm3 in the vehicle-treated group and 11.1 ± 1.2 mm3 in the Imatinib-treated group. By 7 days after injury, the T2 signal was reduced in both groups. However, the Imatinib-treated mice still showed a significant reduction in lesion size of approximately 50% compared to the vehicle-treated group (12.5 ± 2.4 mm3 vs. 6.0 ± 0.8 mm3, Figure 2B).


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 TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral CCI and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after unilateral 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 the ipsilateral hemisphere was determined by calculating the apparent diffusion co-efficient (ADC) values from diffusion weighted imaging (DWI) scans. Data are expressed as mean ± SEM (n = 6); single asterisk indicates p < 0.05, double asterisks indicate p < 0.01, 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 2: Imatinib reduces lesion volume and edema after TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral CCI and examined for lesion volume and cerebral edema by MRI 24 h and 7 days after unilateral 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 the ipsilateral hemisphere was determined by calculating the apparent diffusion co-efficient (ADC) values from diffusion weighted imaging (DWI) scans. Data are expressed as mean ± SEM (n = 6); single asterisk indicates p < 0.05, double asterisks indicate p < 0.01, 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: Since brain edema is a common and serious consequence of TBI that contributes to lesion expansion and secondary brain damage (Dietrich et al., 1994; del Zoppo and Mabuchi, 2003) and since the rise in edema after TBI is thought to be due, at least in part, to the loss of the BBB control, we examined if Imatinib treatment also reduced lesion size and edema 24 h and 7 days after TBI. For these studies mice were subjected to CCI in the right parietotemporal cortex and then treated with either vehicle or 200 mg/kg of Imatinib by gavage 45 min after TBI and then twice a day for 5 days following injury. T2 and DWI MRI scans were obtained at 24 h and 7 days post-injury. The T2 scans were used to calculate the lesion volume and showed that by 24 h after CCI there was conspicuous tissue damage within the region surrounding the impact site (Figure 2A). The T2 scans also revealed that by 7 days post-injury there was extensive tissue loss and cavitation in the cortex of untreated mice that was significantly reduced in the Imatinib treated group (Figure 2A). Quantification of these data demonstrated that at 24 h after injury the mean T2 lesion volume was 22.7 ± 2.9 mm3 in the vehicle-treated group and 11.1 ± 1.2 mm3 in the Imatinib-treated group. By 7 days after injury, the T2 signal was reduced in both groups. However, the Imatinib-treated mice still showed a significant reduction in lesion size of approximately 50% compared to the vehicle-treated group (12.5 ± 2.4 mm3 vs. 6.0 ± 0.8 mm3, Figure 2B).

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