Abstract
Central nervous system (CNS) disorders such as ischemic stroke, multiple sclerosis (MS) or Alzheimers disease are characterized by the loss of blood-brain barrier (BBB) integrity. Here we demonstrate that the small tyrosine kinase inhibitor imatinib enhances BBB integrity in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). Treatment was accompanied by decreased CNS inflammation and demyelination and especially reduced T-cell recruitment. This was supported by downregulation of the chemokine receptor (CCR) 2 in CNS and lymph nodes, and by modulation of the peripheral immune response towards an anti-inflammatory phenotype. Interestingly, imatinib ameliorated neuroinflammation, even when the treatment was initiated after the clinical manifestation of the disease. We have previously shown that imatinib reduces BBB disruption and stroke volume after experimentally induced ischemic stroke by targeting platelet-derived growth factor receptor -α (PDGFR-α) signaling. Here we demonstrate that PDGFR-α signaling is a central regulator of BBB integrity during neuroinflammation and therefore imatinib should be considered as a potentially effective treatment for MS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzamides / administration & dosage*
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / metabolism*
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Brain / immunology
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Brain / pathology
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Central Nervous System / drug effects
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Central Nervous System / metabolism
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Central Nervous System / pathology
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Disease Models, Animal
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / drug therapy*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Gene Expression Regulation
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Imatinib Mesylate
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Inflammation / drug therapy*
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Inflammation / immunology
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Inflammation / metabolism
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Multiple Sclerosis / genetics*
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Multiple Sclerosis / metabolism
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Multiple Sclerosis / pathology
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Neurons / drug effects
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Neurons / immunology
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Neurons / pathology
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Peptides / administration & dosage
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Peptides / toxicity
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Piperazines / administration & dosage*
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Pyrimidines / administration & dosage*
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Rats
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Receptor, Platelet-Derived Growth Factor alpha / genetics
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Receptor, Platelet-Derived Growth Factor alpha / metabolism*
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Receptors, CCR2 / metabolism
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Signal Transduction
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Spinal Cord / immunology
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Spinal Cord / pathology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
Substances
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Benzamides
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Ccr2 protein, rat
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Peptides
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Piperazines
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Pyrimidines
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Receptors, CCR2
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Imatinib Mesylate
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Receptor, Platelet-Derived Growth Factor alpha
Grants and funding
This study was supported by the NHR Foundation (MZA, MZ), Wenner-Gren Fellowship (MZ), Soderberg’s Foundation (TO), AFA Foundation (TO), Knut and Alice Wallenberg’s Foundation (TO), Swedish Research Council (TO, UE, IN), LeDucq Foundation (UE), Swedish Brain Foundation and Hållsten’s Research Foundation (UE), the Swedish Agency for Innovation Systems (VINNOVA) (UE), the Swedish Cancer Foundation (UE), Swedish Stroke Foundation (IN), Royal Swedish Agency (IN), Magnus Bergwall’s Foundation (IN) and Karolinska Institute (IN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.