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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 blood brain barrier (BBB) leakage after Traumatic brain injury (TBI). Mice were treated with vehicle or Imatinib (200 mg/kg, daily p.o. for 1 day) starting 45 min after unilateral controlled cortical impact (CCI). Twenty three hours after unilateral CCI, Evans blue (EB) dye was injected intravenously as a bolus and animals were perfused with phosphate buffered saline (PBS) 1 h later. (A) Representative brains from vehicle and Imatinib treated animals are shown. (B,C) Quantitative analysis of EB leakage in the ipsilateral (B) and contralateral (C) hemispheres. Data are expressed as mean ± SEM (n = 10) and double asterisks indicate p < 0.01.
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Figure 1: Imatinib reduces blood brain barrier (BBB) leakage after Traumatic brain injury (TBI). Mice were treated with vehicle or Imatinib (200 mg/kg, daily p.o. for 1 day) starting 45 min after unilateral controlled cortical impact (CCI). Twenty three hours after unilateral CCI, Evans blue (EB) dye was injected intravenously as a bolus and animals were perfused with phosphate buffered saline (PBS) 1 h later. (A) Representative brains from vehicle and Imatinib treated animals are shown. (B,C) Quantitative analysis of EB leakage in the ipsilateral (B) and contralateral (C) hemispheres. Data are expressed as mean ± SEM (n = 10) and double asterisks indicate p < 0.01.

Mentions: Since both TBI and ischemic stroke share the common pathophysiologic mechanisms of loss of BBB control and the development of cerebral edema (Bouma et al., 1991; Marion et al., 1991; Zauner et al., 1996; Bramlett and Dietrich, 2004; Lescot et al., 2010), we hypothesized that, as is the case with ischemic stroke, PDGFRα signaling might also play a role in TBI. To test this hypothesis we investigated if blocking PDGFRα signaling after TBI could reduce BBB leakage. For these studies we examined the efficacy of treatment with the PDGFRα antagonist Imatinib in mice subjected to CCI in the right parietotemporal cortex. The mice were treated with either vehicle or 200 mg/kg of Imatinib by gavage 45 min after CCI and again 22 h after injury. The mice were then analyzed for BBB integrity by EB extravasation 24 h after TBI. We predicted that if PDGFRα signaling contributes to loss of BBB integrity after TBI then Imatinib treatment should result in less BBB leakage 24 h after TBI. Consistent with our hypothesis, we found that compared to vehicle-treated controls, Imatinib treatment significantly reduced EB leakage in the ipsilateral hemisphere 24 h after TBI (Figures 1A,B >70%). We also found that the injury resulted in BBB leakage in the contralateral hemisphere, but at levels that were nearly 8-fold lower than in the ipsilateral hemisphere (3.4 ± 0.6 ipsi vs. 0.43 ± 0.08 contra). Similar to the effects observed in the ipsilateral hemisphere Imatinib treatment was also effective at reducing BBB leakage in the contralateral hemisphere (Figure 1C >75%). These results demonstrate that like its effects in stroke, spinal cord injury and MS (Su et al., 2008; Ma et al., 2011; Abrams et al., 2012; Adzemovic et al., 2013), Imatinib treatment preserves BBB integrity following 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 blood brain barrier (BBB) leakage after Traumatic brain injury (TBI). Mice were treated with vehicle or Imatinib (200 mg/kg, daily p.o. for 1 day) starting 45 min after unilateral controlled cortical impact (CCI). Twenty three hours after unilateral CCI, Evans blue (EB) dye was injected intravenously as a bolus and animals were perfused with phosphate buffered saline (PBS) 1 h later. (A) Representative brains from vehicle and Imatinib treated animals are shown. (B,C) Quantitative analysis of EB leakage in the ipsilateral (B) and contralateral (C) hemispheres. Data are expressed as mean ± SEM (n = 10) and double asterisks indicate p < 0.01.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Imatinib reduces blood brain barrier (BBB) leakage after Traumatic brain injury (TBI). Mice were treated with vehicle or Imatinib (200 mg/kg, daily p.o. for 1 day) starting 45 min after unilateral controlled cortical impact (CCI). Twenty three hours after unilateral CCI, Evans blue (EB) dye was injected intravenously as a bolus and animals were perfused with phosphate buffered saline (PBS) 1 h later. (A) Representative brains from vehicle and Imatinib treated animals are shown. (B,C) Quantitative analysis of EB leakage in the ipsilateral (B) and contralateral (C) hemispheres. Data are expressed as mean ± SEM (n = 10) and double asterisks indicate p < 0.01.
Mentions: Since both TBI and ischemic stroke share the common pathophysiologic mechanisms of loss of BBB control and the development of cerebral edema (Bouma et al., 1991; Marion et al., 1991; Zauner et al., 1996; Bramlett and Dietrich, 2004; Lescot et al., 2010), we hypothesized that, as is the case with ischemic stroke, PDGFRα signaling might also play a role in TBI. To test this hypothesis we investigated if blocking PDGFRα signaling after TBI could reduce BBB leakage. For these studies we examined the efficacy of treatment with the PDGFRα antagonist Imatinib in mice subjected to CCI in the right parietotemporal cortex. The mice were treated with either vehicle or 200 mg/kg of Imatinib by gavage 45 min after CCI and again 22 h after injury. The mice were then analyzed for BBB integrity by EB extravasation 24 h after TBI. We predicted that if PDGFRα signaling contributes to loss of BBB integrity after TBI then Imatinib treatment should result in less BBB leakage 24 h after TBI. Consistent with our hypothesis, we found that compared to vehicle-treated controls, Imatinib treatment significantly reduced EB leakage in the ipsilateral hemisphere 24 h after TBI (Figures 1A,B >70%). We also found that the injury resulted in BBB leakage in the contralateral hemisphere, but at levels that were nearly 8-fold lower than in the ipsilateral hemisphere (3.4 ± 0.6 ipsi vs. 0.43 ± 0.08 contra). Similar to the effects observed in the ipsilateral hemisphere Imatinib treatment was also effective at reducing BBB leakage in the contralateral hemisphere (Figure 1C >75%). These results demonstrate that like its effects in stroke, spinal cord injury and MS (Su et al., 2008; Ma et al., 2011; Abrams et al., 2012; Adzemovic et al., 2013), Imatinib treatment preserves BBB integrity following 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