TY - JOUR A1 - Schuhmann, Michael K. A1 - Bittner, Stefan A1 - Meuth, Sven G. A1 - Kleinschnitz, Christoph A1 - Fluri, Felix T1 - Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model JF - International Journal of Molecular Sciences N2 - Breakdown of the blood-brain barrier (BBB) is an early hallmark of multiple sclerosis (MS), a progressive inflammatory disease of the central nervous system. Cell adhesion in the BBB is modulated by sphingosine-1-phosphate (S1P), a signaling protein, via S1P receptors (S1P\(_1\)). Fingolimod phosphate (FTY720-P) a functional S1P\(_1\) antagonist has been shown to improve the relapse rate in relapsing-remitting MS by preventing the egress of lymphocytes from lymph nodes. However, its role in modulating BBB permeabilityin particular, on the tight junction proteins occludin, claudin 5 and ZO-1has not been well elucidated to date. In the present study, FTY720-P did not change the transendothelial electrical resistance in a rat brain microvascular endothelial cell (RBMEC) culture exposed to inflammatory conditions and thus did not decrease endothelial barrier permeability. In contrast, occludin was reduced in RBMEC culture after adding FTY720-P. Additionally, FTY720-P did not alter the amount of endothelial matrix metalloproteinase (MMP)-9 and MMP-2 in RBMEC cultures. Taken together, our observations support the assumption that S1P\(_1\) plays a dual role in vascular permeability, depending on its ligand. Thus, S1P\(_1\) provides a mechanistic basis for FTY720-P-associated disruption of endothelial barrierssuch as the blood-retinal barrierwhich might result in macular edema. KW - randomized controlled trial KW - Sphingosine 1-Phosphate KW - vascular permeability KW - rat brain microvascular endothelial cell culture KW - tight junctions KW - FTY720-P KW - blood-brain barrier KW - inflammation KW - novo renal transplantation KW - endothelial cells KW - experimental autoimmune encephalomyelitis KW - relapsing multiple sclerosis KW - Zonula Occludens-1 KW - matrix metalloproteinases Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-145047 VL - 16 ER - TY - JOUR A1 - Schrewe, L. A1 - Lill, C. M. A1 - Liu, T. A1 - Salmen, A. A1 - Gerdes, L. A. A1 - Guillot-Noel, L. A1 - Akkad, D. A. A1 - Blaschke, P. A1 - Graetz, C. A1 - Hoffjan, S. A1 - Kroner, A. A1 - Demir, S. A1 - Böhme, A. A1 - Rieckmann, P. A1 - El Ali, A. A1 - Hagemann, N. A1 - Hermann, D. M. A1 - Cournu-Rebeix, I. A1 - Zipp, F. A1 - Kümpfel, T. A1 - Buttmann, M. A1 - Zettl, U. K. A1 - Fontaine, B. A1 - Bertram, L. A1 - Gold, R. A1 - Chan, A. T1 - Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS JF - Journal of Neuroinflammation N2 - Background: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. Methods: MOG\(_{35-55}\) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. Results: EAE disease course was slightly attenuated in male apoE-deficient (apoE\(^{-/-}\)) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE\(^{-/-}\) mice compared to wildtype mice (cumulative median score: apoE\(^{-/-}\) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naive animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. Conclusions: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease. KW - immune KW - apoE KW - gender KW - inflammation KW - association studies in genetics KW - apoe KW - CNS disease KW - system KW - multiple sclerosis KW - MSSS KW - experimental autoimmune encephalomyelitis KW - disease severity KW - cognitive function KW - Alzheimer disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136252 VL - 12 IS - 234 ER - TY - JOUR A1 - Rottlaender, Andrea A1 - Kuerten, Stefanie T1 - Stepchild or prodigy? Neuroprotection in multiple sclerosis (MS) research JF - International Journal of Molecular Sciences N2 - Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS) and characterized by the infiltration of immune cells, demyelination and axonal loss. Loss of axons and nerve fiber pathology are widely accepted as correlates of neurological disability. Hence, it is surprising that the development of neuroprotective therapies has been neglected for a long time. A reason for this could be the diversity of the underlying mechanisms, complex changes in nerve fiber pathology and the absence of biomarkers and tools to quantify neuroregenerative processes. Present therapeutic strategies are aimed at modulating or suppressing the immune response, but do not primarily attenuate axonal pathology. Yet, target-oriented neuroprotective strategies are essential for the treatment of MS, especially as severe damage of nerve fibers mostly occurs in the course of disease progression and cannot be impeded by immune modulatory drugs. This review shall depict the need for neuroprotective strategies and elucidate difficulties and opportunities. KW - experimental autoimmune encephalomyelitis KW - white matter KW - lesions KW - remyelination KW - multiple sclerosis KW - regeneration KW - neuroprotection KW - degeneration KW - axonal damage KW - neurodegeneration KW - pathology KW - sodium channels KW - axonal injury KW - central nervous system Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148416 VL - 16 ER -