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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 improves neurological outcome in Morris Water Maze (MWM) after TBI. Imatinib ameliorates TBI associated impairments in spatial learning and memory. (A) Cumulative proximity scores are plotted across 4 days of training for TBI (n = 7) and Sham (n = 9) treated mice. (B) Cumulative proximity scores are plotted across 4 days of training for TBI mice treated with vehicle or Imatinib. (C) Average proximity during the probe trial which was completed 24 h after the last training trial plotted for Sham and TBI treated mice. (D) Average proximity during the probe trial which was completed 24 h after the last training trial is plotted for mice subjected to TBI and then treated with Imatinib (n = 8) or Vehicle (n = 7). (E) Cumulative proximity measured during the visible platform version of the water maze is plotted for Sham and TBI treated mice. Data represent the average of 6 trials. (F) Cumulative proximity measured during the visible platform version of the water maze is plotted for mice subjected to TBI and then treated with Imatinib or vehicle. (G) Swim speed measured during the probe trial in Sham and TBI treated mice. (H) Probe trial swim speed of mice subjected to TBI and then treated with Imatinib or vehicle. Data are presented as mean ± SEM. Single asterisk in (A,B) indicates p < 0.05 for main effect of treatment evaluated using a two-way repeated measures ANOVA with treatment and training days as factors. Single asterisk in (C–H) indicates p < 0.05, two tailed unpaired t-test.
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Figure 6: Imatinib improves neurological outcome in Morris Water Maze (MWM) after TBI. Imatinib ameliorates TBI associated impairments in spatial learning and memory. (A) Cumulative proximity scores are plotted across 4 days of training for TBI (n = 7) and Sham (n = 9) treated mice. (B) Cumulative proximity scores are plotted across 4 days of training for TBI mice treated with vehicle or Imatinib. (C) Average proximity during the probe trial which was completed 24 h after the last training trial plotted for Sham and TBI treated mice. (D) Average proximity during the probe trial which was completed 24 h after the last training trial is plotted for mice subjected to TBI and then treated with Imatinib (n = 8) or Vehicle (n = 7). (E) Cumulative proximity measured during the visible platform version of the water maze is plotted for Sham and TBI treated mice. Data represent the average of 6 trials. (F) Cumulative proximity measured during the visible platform version of the water maze is plotted for mice subjected to TBI and then treated with Imatinib or vehicle. (G) Swim speed measured during the probe trial in Sham and TBI treated mice. (H) Probe trial swim speed of mice subjected to TBI and then treated with Imatinib or vehicle. Data are presented as mean ± SEM. Single asterisk in (A,B) indicates p < 0.05 for main effect of treatment evaluated using a two-way repeated measures ANOVA with treatment and training days as factors. Single asterisk in (C–H) indicates p < 0.05, two tailed unpaired t-test.

Mentions: Cognitive function in mice exposed to midline CCI was assessed by examining spatial learning and memory in the MWM. Data comparing mice with bilateral CCI to Sham treated mice are presented in Figures 6A,C,E,G. Data comparing injured mice treated with Imatinib or vehicle are presented in Figures 6B,D,F,H. All data are presented in terms of proximity which is a measure of “search error” and therefore lower scores indicate a more selective search strategy. Mice in the Sham group exhibited typical performance across the four days of training (Figure 6A) during which time their cumulative proximity scores significantly decreased. Conversely, the performance of mice in the TBI group did not improve over time and was significantly worse compared to the Sham group (p < 0.001). To assess long-term memory, a probe trial was conducted 24 h after the last training trial was completed on day 4. Similar to the cumulative proximity, the average proximity measure is a search error measure which is independent of swim speed. The duration of the probe trial is fixed at 60 s; therefore an average measure is made (c.f. cumulative for the variable length training trials). Again, a lower number indicated a more selective search strategy. Injured mice in the TBI group were significantly impaired when compared to the mice in the Sham treated group. In addition, the injured mice in the TBI group performed significantly worse even when the platform was clearly marked (Figure 6E) and exhibited slower swim speeds during the probe trial (Figure 6G). In a separate experiment, mice were exposed to bilateral CCI 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 prior to the start of the water maze. Across the 4 days of training (Figure 6B) injured mice that were treated with Imatinib exhibited significantly better performance when compared to the vehicle treated mice (p < 0.01). Similarly, mice treated with Imatinib outperformed vehicle treated mice during the probe trial (Figure 6D). Treatment with Imatinib did not alter performance on the visible platform version of the water maze (Figure 6F) or swim speed (Figure 6H).


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 improves neurological outcome in Morris Water Maze (MWM) after TBI. Imatinib ameliorates TBI associated impairments in spatial learning and memory. (A) Cumulative proximity scores are plotted across 4 days of training for TBI (n = 7) and Sham (n = 9) treated mice. (B) Cumulative proximity scores are plotted across 4 days of training for TBI mice treated with vehicle or Imatinib. (C) Average proximity during the probe trial which was completed 24 h after the last training trial plotted for Sham and TBI treated mice. (D) Average proximity during the probe trial which was completed 24 h after the last training trial is plotted for mice subjected to TBI and then treated with Imatinib (n = 8) or Vehicle (n = 7). (E) Cumulative proximity measured during the visible platform version of the water maze is plotted for Sham and TBI treated mice. Data represent the average of 6 trials. (F) Cumulative proximity measured during the visible platform version of the water maze is plotted for mice subjected to TBI and then treated with Imatinib or vehicle. (G) Swim speed measured during the probe trial in Sham and TBI treated mice. (H) Probe trial swim speed of mice subjected to TBI and then treated with Imatinib or vehicle. Data are presented as mean ± SEM. Single asterisk in (A,B) indicates p < 0.05 for main effect of treatment evaluated using a two-way repeated measures ANOVA with treatment and training days as factors. Single asterisk in (C–H) indicates p < 0.05, two tailed unpaired t-test.
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Figure 6: Imatinib improves neurological outcome in Morris Water Maze (MWM) after TBI. Imatinib ameliorates TBI associated impairments in spatial learning and memory. (A) Cumulative proximity scores are plotted across 4 days of training for TBI (n = 7) and Sham (n = 9) treated mice. (B) Cumulative proximity scores are plotted across 4 days of training for TBI mice treated with vehicle or Imatinib. (C) Average proximity during the probe trial which was completed 24 h after the last training trial plotted for Sham and TBI treated mice. (D) Average proximity during the probe trial which was completed 24 h after the last training trial is plotted for mice subjected to TBI and then treated with Imatinib (n = 8) or Vehicle (n = 7). (E) Cumulative proximity measured during the visible platform version of the water maze is plotted for Sham and TBI treated mice. Data represent the average of 6 trials. (F) Cumulative proximity measured during the visible platform version of the water maze is plotted for mice subjected to TBI and then treated with Imatinib or vehicle. (G) Swim speed measured during the probe trial in Sham and TBI treated mice. (H) Probe trial swim speed of mice subjected to TBI and then treated with Imatinib or vehicle. Data are presented as mean ± SEM. Single asterisk in (A,B) indicates p < 0.05 for main effect of treatment evaluated using a two-way repeated measures ANOVA with treatment and training days as factors. Single asterisk in (C–H) indicates p < 0.05, two tailed unpaired t-test.
Mentions: Cognitive function in mice exposed to midline CCI was assessed by examining spatial learning and memory in the MWM. Data comparing mice with bilateral CCI to Sham treated mice are presented in Figures 6A,C,E,G. Data comparing injured mice treated with Imatinib or vehicle are presented in Figures 6B,D,F,H. All data are presented in terms of proximity which is a measure of “search error” and therefore lower scores indicate a more selective search strategy. Mice in the Sham group exhibited typical performance across the four days of training (Figure 6A) during which time their cumulative proximity scores significantly decreased. Conversely, the performance of mice in the TBI group did not improve over time and was significantly worse compared to the Sham group (p < 0.001). To assess long-term memory, a probe trial was conducted 24 h after the last training trial was completed on day 4. Similar to the cumulative proximity, the average proximity measure is a search error measure which is independent of swim speed. The duration of the probe trial is fixed at 60 s; therefore an average measure is made (c.f. cumulative for the variable length training trials). Again, a lower number indicated a more selective search strategy. Injured mice in the TBI group were significantly impaired when compared to the mice in the Sham treated group. In addition, the injured mice in the TBI group performed significantly worse even when the platform was clearly marked (Figure 6E) and exhibited slower swim speeds during the probe trial (Figure 6G). In a separate experiment, mice were exposed to bilateral CCI 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 prior to the start of the water maze. Across the 4 days of training (Figure 6B) injured mice that were treated with Imatinib exhibited significantly better performance when compared to the vehicle treated mice (p < 0.01). Similarly, mice treated with Imatinib outperformed vehicle treated mice during the probe trial (Figure 6D). Treatment with Imatinib did not alter performance on the visible platform version of the water maze (Figure 6F) or swim speed (Figure 6H).

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