Abstract
Central nervous system (CNS) disorders such as ischemic stroke, multiple sclerosis (MS) or Alzheimeŕs 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.
Highlights
The Central nervous system (CNS) vasculature is specialized in keeping the CNS tissue in an immune-privileged environment
Visualization and quantification of spinal cord cross sections and whole-mount preparations demonstrated enhanced blood-brain barrier (BBB) integrity in the imatinib-treated rats compared to phosphate buffered saline (PBS) controls on both day 10 and 14 p.i. (Fig. 1 A–C)
We demonstrate that the small tyrosine kinase inhibitor imatinib ameliorates multiple sclerosis (MS)-like neuroinflammation by acting both on the peripheral immune response and the maintenance of the BBB
Summary
The CNS vasculature is specialized in keeping the CNS tissue in an immune-privileged environment. Cytokines produced by pathogenic T-cells, macrophages and resident brain microglia mediate upregulation of adhesion molecules in the BBB [2,3]. This leads to BBB activation and subsequent breakdown resulting in influx of immune cells into the CNS [4]. The BBB secretes chemokines and cytokines, thereby stimulating both proliferation and recruitment of inflammatory cells into the CNS [3] This selfsustaining vicious cycle of neuroinflammation could be well modulated and reduced by targeting the mechanisms regulating BBB function and integrity
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