Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood–brain barrier integrity and by modulating the peripheral immune response

Adzemovic, Milena Z.; Zeitelhofer, Manuel; Eriksson, Ulf; Olsson, Tomas; Nilsson, Ingrid

doi:10.1016/j.jneuroim.2014.08.087

Cited by 3 publications

(3 citation statements)

References 25 publications

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“…Subtle leakage across the BBB has been found in chronic non-active lesions, which may have a role in progressive MS [38][39][40]. Interestingly, it was recently shown that inhibition of PDGFR-a signaling using imatinib mesylate (Gleevec) enhanced BBB integrity, reduced CNS inflammation, and ameliorated experimental autoimmune encephalitis disease, suggesting a potential clinical application in MS [41]. Furthermore, brain tissue from mice stroke models displayed loss of PDGFRb 1 pericytes together with the appearance of a new perivascular PDGFRb 1 CD105 1 cell population [37].…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Iacobaeus¹,

Sugars²,

Andrén³

et al. 2017

Stem Cells Translational Medicine

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Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRb), CD73, CD271, alphasmooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146 1 PDGFRb 1 Ki67 1 cells and CD73 1 CD271 1 PDGFRb 1 Ki67 -cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146 1 PDGFRb 1 Ki67 1 and CD73 1 CD271 1 PDGFRb 1 Ki67 -MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146 1 PDGFRb 1 Ki67 1 MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73 1 CD271 1 adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS. STEM CELLS TRANSLATIONAL MEDICINE 2017;6:1840-1851 SIGNIFICANCE STATEMENTThis immunohistochemical study characterized vascular cells phenotypically similar to pericytes and mesenchymal stromal cells (MSCs) in brain tissue of multiple sclerosis (MS) and healthy persons. We found variations in phenotype, distribution, and proliferation of cells co-expressing markers for MSCs and pericytes that associated with inflammation and MS disease duration. Tissue from long standing MS presented with increased numbers of blood vessels that harbored expanded perivascular areas of cells staining positive for MSCs/pericyte markers. This is the first study to show involvement of MSC/pericyte phenotypic changes in MS pathology and highlights that vessel-targeted treatments may benefit late stage MS.

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Section: Discussionmentioning

confidence: 99%

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Iacobaeus¹,

Sugars²,

Andrén³

et al. 2017

Stem Cells Translational Medicine

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“…In the case of prostatitis, we believe that the high levels of CCL2 and CCL3 is part of the signaling cascade that ultimately lead to activation of microglia and inflammation in the spinal cord. Peripheral nerve injury has been shown to promote the deterioration of the bloodspinal cord barrier [39,40], allowing for the influx of immune cells as part of the proinflammatory environment that promotes neuropathic pain development [41]. It will be useful to determine if such is the case in mice with prostatitis.…”

Section: Discussionmentioning

confidence: 99%

Experimental autoimmune prostatitis induces microglial activation in the spinal cord

et al. 2014

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Background The pathogenesis of chronic prostatitis/chronic pelvic pain syndrome is unknown and factors including the host’s immune response and the nervous system have been attributed to the development of CP/CPPS. We previously demonstrated that mast cells and chemokines such as CCL2 and CCL3 play an important role in mediating prostatitis. Here, we examined the role of neuroinflammation and microglia in the CNS in the development of chronic pelvic pain. Methods Experimental autoimmune prostatitis (EAP) was induced using a subcutaneous injection of rat prostate antigen. Sacral spinal cord tissue (segments S4–S5) was isolated and utilized for immunofluorescence or QRT-PCR analysis. Tactile allodynia was measured at baseline and at various points during EAP using Von Frey fibers as a function for pelvic pain. EAP mice were treated with minocycline after 30 days of prostatitis to test the efficacy of microglial inhibition on pelvic pain. Results Prostatitis induced the expansion and activation of microglia and the development of inflammation in the spinal cord as determined by increased expression levels of CCL3, IL-1β, Iba1, and ERK1/2 phosphorylation. Microglial activation in mice with prostatitis resulted in increased expression of P2X4R and elevated levels of BDNF, two molecular markers associated with chronic pain. Pharmacological inhibition of microglia alleviated pain in mice with prostatitis and resulted in decreased expression of IL-1β, P2X4R, and BDNF. Conclusion Our data shows that prostatitis leads to inflammation in the spinal cord and the activation and expansion of microglia, mechanisms that may contribute to the development and maintenance of chronic pelvic pain.

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“…Neuroinflammation nearly participates in all kinds of neurological diseases in brain (Adzemovic et al, 2013). Neuroinflammation and BBB disruption have been identified as two critical mechanisms of ischemia stroke-induced brain injury (Zhu et al, 2018).…”

Section: Neuroinflammatory Factorsmentioning

confidence: 99%

The role of platelets in the blood-brain barrier during brain pathology

Lv,

Jiang,

Zhang

2024

Front. Cell. Neurosci.

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Platelets play critical roles in maintaining hemostasis. The blood brain barrier (BBB), a significant physical and metabolic barrier, helps maintain physiological stability by limiting transportations between the blood and neural tissues. When the brain undergoes inflammation, tumor, trauma, or bleeding, the platelet responses to help with maintaining BBB homeostasis. In the traditional point of view, activated platelets aggregate to form thrombi which cover the gaps of the blood vessels to protect BBB. However, increasing evidences indicate that platelets may harm BBB by enhancing vascular permeability. Hereby, we reviewed recently published articles with a special focus on the platelet-mediated damage of BBB. Factors released by platelets can induce BBB permeability, which involve platelet-activating factors (PAF), P-selectin, ADP, platelet-derived growth factors (PDGF) superfamily proteins, especially PDGF-AA and PDGF-CC, etc. Platelets can also secrete Amyloid-β (Aβ), which triggers neuroinflammation and downregulates the expression of tight junction molecules such as claudin-5 to damage BBB. Additionally, platelets can form aggregates with neutrophils to release reactive oxygen species (ROS), which can destroy the DNA, proteins, and lipids of endothelial cells (ECs). Moreover, platelets participate in neuroinflammation to affect BBB. Conversely, some of the platelet released factors such as PDGF-BB, protects BBB. In summary, platelets play dual roles in BBB integrity and the related mechanisms are reviewed.

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Imatinib ameliorates neuroinflammation in a rat model of multiple sclerosis by enhancing blood–brain barrier integrity and by modulating the peripheral immune response

Cited by 3 publications

References 25 publications

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Experimental autoimmune prostatitis induces microglial activation in the spinal cord

The role of platelets in the blood-brain barrier during brain pathology

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