Imatinib treatment reduces brain injury in a murine model of traumatic brain injury.
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.
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Enming J
EJ
Su
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA ; Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet Stockholm, Sweden.
Linda
L
Fredriksson
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Mia
M
Kanzawa
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, MI, USA.
Shannon
S
Moore
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet Stockholm, Sweden.
Erika
E
Folestad
Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, MI, USA.
Tamara K
TK
Stevenson
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet Stockholm, Sweden.
Ingrid
I
Nilsson
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University Melbourne, VIC, Australia.
Maithili
M
Sashindranath
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Gerald P
GP
Schielke
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Mark
M
Warnock
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Margaret
M
Ragsdale
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Kris
K
Mann
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA.
Anna-Lisa E
AL
Lawrence
Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Monash University Melbourne, VIC, Australia.
Robert L
RL
Medcalf
Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institutet Stockholm, Sweden.
Ulf
U
Eriksson
Molecular and Behavioral Neuroscience Institute, University of Michigan Medical School Ann Arbor, MI, USA ; Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, MI, USA.
Geoffrey G
GG
Murphy
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School Ann Arbor, MI, USA ; Department of Molecular and Integrative Physiology, University of Michigan Medical School Ann Arbor, MI, USA.
Daniel A
DA
Lawrence
Imatinib; Morris water maze; TBI outcome; blood brain barrier; cerebral edema; platelet derived growth factor receptor α; platelet derived growth factor-CC; traumatic brain injury