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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

Analysis of platelet derived growth factor-CC (PDGF-CC) in human TBI cerebrospinal fluid (CSF) samples. Human CSF Samples obtained from patients within the first 24 h after TBI were immunoblotted for PDGF-CC. (A) Immunoblots from 17 TBI patients and nine controls are shown. As a control for PDGF-CC a sample of releasate from human platelets is shown in the last lane of the first blot. The extended glasgow outcome scale (GOSE) score of each patient is shown at the top of each lane (GOSE 1–8) and the position of molecular mass size markers are indicated at the left of each blot. (B) The relative amount of PDGF-CC in each sample was estimated from the intensity of the PDGF-CC, assigned a value from 0 to 10 and the average for each GOSE score was plotted against the GOSE score. The filled circles are the TBI samples and the open square represents the non-TBI samples. Each point is the mean ± SEM and the line is a linear regression fit of the TBI samples, a Spearman’s correlation analysis of these data yields a one tailed p = 0.0292.
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Figure 7: Analysis of platelet derived growth factor-CC (PDGF-CC) in human TBI cerebrospinal fluid (CSF) samples. Human CSF Samples obtained from patients within the first 24 h after TBI were immunoblotted for PDGF-CC. (A) Immunoblots from 17 TBI patients and nine controls are shown. As a control for PDGF-CC a sample of releasate from human platelets is shown in the last lane of the first blot. The extended glasgow outcome scale (GOSE) score of each patient is shown at the top of each lane (GOSE 1–8) and the position of molecular mass size markers are indicated at the left of each blot. (B) The relative amount of PDGF-CC in each sample was estimated from the intensity of the PDGF-CC, assigned a value from 0 to 10 and the average for each GOSE score was plotted against the GOSE score. The filled circles are the TBI samples and the open square represents the non-TBI samples. Each point is the mean ± SEM and the line is a linear regression fit of the TBI samples, a Spearman’s correlation analysis of these data yields a one tailed p = 0.0292.

Mentions: Although our data suggest that the BBB leakage, controlled by PDGF signaling in the NVU, may contribute to TBI progression in animal models, it is not known if PDGF-CC protein levels are altered in human TBI. Therefore, we examined PDGF-CC levels in the CSF of human TBI patients and in control non-TBI patients by immunoblotting. For these studies we obtained CSF from 17 TBI patients and 9 non-TBI patients. The TBI patients had GOSE ranging from 1 to 8, where 1 is the most severe, indicating that the patient died of their injuries, and 8 is the mildest injury and the patients have a good recovery (Lu et al., 2010). Immunoblot analysis of these samples is shown in Figure 7 along with a platelet releasate sample as a positive control for PDGF-CC. Note that the lanes with the strongest PDGF-CC signal are all from TBI patients with the lowest (most severe) GOSE scores. The relative intensity of the PDGF-CC staining in each lane was ranked from 0 to 10 for both the TBI patients and non-TBI patients with 0 being undetectable and 10 representing the most intense PDGF-CC staining, and these data were then plotted against the GOSE score (Figure 7B). This semi-quantitative analysis suggests that there may be a correlation between TBI severity and the presence of PDGF-CC in the CSF. These data are also similar to a positive correlation reported between PDGF-CC levels in plasma and worse outcomes in ischemic stroke patients (Rodríguez-González et al., 2013), and with our previous study showing elevated tPA-inhibitor complexes in the CSF of the most severe TBI patients (Sashindranath et al., 2012).


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)

Analysis of platelet derived growth factor-CC (PDGF-CC) in human TBI cerebrospinal fluid (CSF) samples. Human CSF Samples obtained from patients within the first 24 h after TBI were immunoblotted for PDGF-CC. (A) Immunoblots from 17 TBI patients and nine controls are shown. As a control for PDGF-CC a sample of releasate from human platelets is shown in the last lane of the first blot. The extended glasgow outcome scale (GOSE) score of each patient is shown at the top of each lane (GOSE 1–8) and the position of molecular mass size markers are indicated at the left of each blot. (B) The relative amount of PDGF-CC in each sample was estimated from the intensity of the PDGF-CC, assigned a value from 0 to 10 and the average for each GOSE score was plotted against the GOSE score. The filled circles are the TBI samples and the open square represents the non-TBI samples. Each point is the mean ± SEM and the line is a linear regression fit of the TBI samples, a Spearman’s correlation analysis of these data yields a one tailed p = 0.0292.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 7: Analysis of platelet derived growth factor-CC (PDGF-CC) in human TBI cerebrospinal fluid (CSF) samples. Human CSF Samples obtained from patients within the first 24 h after TBI were immunoblotted for PDGF-CC. (A) Immunoblots from 17 TBI patients and nine controls are shown. As a control for PDGF-CC a sample of releasate from human platelets is shown in the last lane of the first blot. The extended glasgow outcome scale (GOSE) score of each patient is shown at the top of each lane (GOSE 1–8) and the position of molecular mass size markers are indicated at the left of each blot. (B) The relative amount of PDGF-CC in each sample was estimated from the intensity of the PDGF-CC, assigned a value from 0 to 10 and the average for each GOSE score was plotted against the GOSE score. The filled circles are the TBI samples and the open square represents the non-TBI samples. Each point is the mean ± SEM and the line is a linear regression fit of the TBI samples, a Spearman’s correlation analysis of these data yields a one tailed p = 0.0292.
Mentions: Although our data suggest that the BBB leakage, controlled by PDGF signaling in the NVU, may contribute to TBI progression in animal models, it is not known if PDGF-CC protein levels are altered in human TBI. Therefore, we examined PDGF-CC levels in the CSF of human TBI patients and in control non-TBI patients by immunoblotting. For these studies we obtained CSF from 17 TBI patients and 9 non-TBI patients. The TBI patients had GOSE ranging from 1 to 8, where 1 is the most severe, indicating that the patient died of their injuries, and 8 is the mildest injury and the patients have a good recovery (Lu et al., 2010). Immunoblot analysis of these samples is shown in Figure 7 along with a platelet releasate sample as a positive control for PDGF-CC. Note that the lanes with the strongest PDGF-CC signal are all from TBI patients with the lowest (most severe) GOSE scores. The relative intensity of the PDGF-CC staining in each lane was ranked from 0 to 10 for both the TBI patients and non-TBI patients with 0 being undetectable and 10 representing the most intense PDGF-CC staining, and these data were then plotted against the GOSE score (Figure 7B). This semi-quantitative analysis suggests that there may be a correlation between TBI severity and the presence of PDGF-CC in the CSF. These data are also similar to a positive correlation reported between PDGF-CC levels in plasma and worse outcomes in ischemic stroke patients (Rodríguez-González et al., 2013), and with our previous study showing elevated tPA-inhibitor complexes in the CSF of the most severe TBI patients (Sashindranath et al., 2012).

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