title: Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood-brain barrier integrity and by modulating the peripheral immune response.
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.
authors: Milena V
authors: MV
authors: Adzemovic
authors: Neuroimmunology Unit, Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors: Milena Z
authors: MZ
authors: Adzemovic
authors: Manuel
authors: M
authors: Zeitelhofer
authors: Ulf
authors: U
authors: Eriksson
authors: Tomas
authors: T
authors: Olsson
authors: Ingrid
authors: I
authors: Nilsson
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000276:immunology / Q000473:pathology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D005786:Gene Expression Regulation; D000068877:Imatinib Mesylate; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage / Q000633:toxicity; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D054390:Receptors, CCR2 / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D001549:Benzamides; C515336:Ccr2 protein, rat; D010455:Peptides; D010879:Piperazines; D011743:Pyrimidines; D054390:Receptors, CCR2; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha