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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 TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral 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 theT2-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 3: Imatinib reduces tissue loss 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. 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 theT2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.

Mentions: Since neuronal loss in the hippocampus has been linked to pathological outcomes of TBI in both humans (Tate and Bigler, 2000; Swartz et al., 2006) and in animal models of TBI (McIntosh et al., 1989; Dixon et al., 1991; Lowenstein et al., 1992; Hall et al., 2008), we next investigated whether intervention in the acute phase of TBI with 5 days of Imatinib treatment translated into long term tissue preservation. 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 CCI and then twice a day for 5 days following injury. Previous studies have demonstrated that hippocampal neurons undergo regional alterations and remodeling after TBI (Witgen et al., 2005; Cohen et al., 2007). Consistent with this, hematoxylin and eosin staining of brain sections showed that there was dramatic tissue loss and remodeling in the cortex and hippocampus 21 days after TBI, including large cavitations (Figure 3A). As with BBB permeability, lesion size, and vasogenic edema, Imatinib substantially reduced cavitations (Figure 3B). To quantify the extent of the cavitations, MRI T2 scans were performed 21 days after TBI. These scans confirmed the loss of tissue noted in the H&E stains, showing large areas of hyper-intense signals indicative of cavitation (Figures 3C,D). Quantification of the hyper-intense signals showed that Imatinib treatment significantly reduced tissue loss (vehicle 3.6 ± 0.3 mm3 vs, Imatinib 2.3 ± 0.4 mm3 Figure 3E). This suggests that early intervention with Imatinib may impact long term TBI progression.


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 TBI. Mice were treated with vehicle or Imatinib (200 mg/kg, twice daily p.o. for 5 days) starting 45 min after unilateral 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 theT2-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
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Figure 3: Imatinib reduces tissue loss 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. 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 theT2-weighted hyper-intense signal. Data are expressed as mean ± SEM (n = 5) and the single asterisk indicates p < 0.05.
Mentions: Since neuronal loss in the hippocampus has been linked to pathological outcomes of TBI in both humans (Tate and Bigler, 2000; Swartz et al., 2006) and in animal models of TBI (McIntosh et al., 1989; Dixon et al., 1991; Lowenstein et al., 1992; Hall et al., 2008), we next investigated whether intervention in the acute phase of TBI with 5 days of Imatinib treatment translated into long term tissue preservation. 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 CCI and then twice a day for 5 days following injury. Previous studies have demonstrated that hippocampal neurons undergo regional alterations and remodeling after TBI (Witgen et al., 2005; Cohen et al., 2007). Consistent with this, hematoxylin and eosin staining of brain sections showed that there was dramatic tissue loss and remodeling in the cortex and hippocampus 21 days after TBI, including large cavitations (Figure 3A). As with BBB permeability, lesion size, and vasogenic edema, Imatinib substantially reduced cavitations (Figure 3B). To quantify the extent of the cavitations, MRI T2 scans were performed 21 days after TBI. These scans confirmed the loss of tissue noted in the H&E stains, showing large areas of hyper-intense signals indicative of cavitation (Figures 3C,D). Quantification of the hyper-intense signals showed that Imatinib treatment significantly reduced tissue loss (vehicle 3.6 ± 0.3 mm3 vs, Imatinib 2.3 ± 0.4 mm3 Figure 3E). This suggests that early intervention with Imatinib may impact long term TBI progression.

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