At present, there is no effective treatment for intracerebral hemorrhage (ICH), a common and often fatal stroke subtype. Secondary brain injury after ICH is known to involve brain edema, disruption ofthe blood brain barrier (BBB), and neurological deficits. Platelet derived growth factor receptors (PDGFRs) are a subfamily of tyrosine kinase receptors including two members, PDGFR-a and PDGFR-p. PDGFRs are expressed in various cell-types in the brain and participate in smooth muscle phenotype changes. Our previous study has found that PDGFR suppression by Gleevec, a PDGFR inhibitor, reduces brain edema and BBB leakage in a mouse model of ICH. Others also reported that PDGFR is associated with BBB disruption in ischemic brain injury. However the mechanisms of PDGFR-associated BBB damage remain unclear and the role of smooth muscle phenotype changes in ICH injury has never been studied. Our preliminary data showed that Gleevec-induced BBB protection after ICH is associated with inhibition of p38 MAPK pathway. Our preliminary study also made a groundbreaking discovery that ICH results the loss of myogenic tone and the changes of smooth muscle phenotype proteins in the cerebral arteries near the hematoma;Gleevec treatment antagonizes these changes. Therefore, we hypothesize that PDGFR-suppression with Gleevec will reduce BBB disruption via protecting intercellular junctions and preventing smooth muscle phenotype changes thus improving neurological outcome after ICH. Gleevec treatment will also prevent neurovascular damage in other types of hemorrhagic brain injury including subarachnoid hemorrhage (SAH) and traumatic brain injury (TBI). The following studies are proposed to test our hypothesis:
Aim 1 will determine the neurovascular protective effect of Gleevec administration after ICH, including BBB integrity, smooth muscle phenotype changes and long-term neurological outcomes.
Aim 2 will investigate the role of PDGFR-p38- MAPK-MAPKAPK2-LIMK1 pathway in ICH-induced BBB disruption.
Aim 3 will determine the neurovascular protective effect of Gleevec treatment in SAH and TBI models. Our long-term goal is to explore the importance of PDGFR involved in neurovascular injury for future evaluation as a potential therapeutic target against hemorrhagic brain injury in patients

Public Health Relevance

No effective treatment strategies have yet been developed to reduce intracerebral hemorrhage (ICH)- induced brain injury. This project is to explore the effects and mechanism of Gleevec, a PDGFR inhibitor, in ICH model and also explore the effects of Gleevec in subarachnoid hemorrhage and traumatic brain injury models. Achieving our goal will lay the foundation for clinical evaluation of Gleevac treatment in patients with hemorrhagic brain injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Loma Linda University
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Guo, Zongduo; Hu, Qin; Xu, Liang et al. (2016) Lipoxin A4 Reduces Inflammation Through Formyl Peptide Receptor 2/p38 MAPK Signaling Pathway in Subarachnoid Hemorrhage Rats. Stroke 47:490-7
Jullienne, Amandine; Obenaus, Andre; Ichkova, Aleksandra et al. (2016) Chronic cerebrovascular dysfunction after traumatic brain injury. J Neurosci Res 94:609-22
Yang, Peng; Manaenko, Anatol; Xu, Feng et al. (2016) Role of PDGF-D and PDGFR-β in neuroinflammation in experimental ICH mice model. Exp Neurol 283:157-64
Flores, Jerry J; Klebe, Damon; Rolland, William B et al. (2016) PPARγ-induced upregulation of CD36 enhances hematoma resolution and attenuates long-term neurological deficits after germinal matrix hemorrhage in neonatal rats. Neurobiol Dis 87:124-33
Wu, Jiang; Zhang, Yang; Yang, Peng et al. (2016) Recombinant Osteopontin Stabilizes Smooth Muscle Cell Phenotype via Integrin Receptor/Integrin-Linked Kinase/Rac-1 Pathway After Subarachnoid Hemorrhage in Rats. Stroke 47:1319-27
Yang, Peng; Wu, Jiang; Miao, Liyan et al. (2016) Platelet-Derived Growth Factor Receptor-β Regulates Vascular Smooth Muscle Cell Phenotypic Transformation and Neuroinflammation After Intracerebral Hemorrhage in Mice. Crit Care Med 44:e390-402
Yin, Cheng; Huang, Guang-Fu; Sun, Xiao-Chuan et al. (2016) Tozasertib attenuates neuronal apoptosis via DLK/JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neuropharmacology 108:316-23
Wang, Yuechun; Reis, Cesar; Applegate 2nd, Richard et al. (2015) Ischemic conditioning-induced endogenous brain protection: Applications pre-, per- or post-stroke. Exp Neurol 272:26-40
Chen, Yujie; Zhang, Yang; Tang, Junjia et al. (2015) Norrin protected blood-brain barrier via frizzled-4/β-catenin pathway after subarachnoid hemorrhage in rats. Stroke 46:529-36
Huang, Lei; Sherchan, Prativa; Wang, Yuechun et al. (2015) Phosphoinositide 3-Kinase Gamma Contributes to Neuroinflammation in a Rat Model of Surgical Brain Injury. J Neurosci 35:10390-401

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