@article{FluriSchuhmannKleinschnitz2015,
  author    = {Fluri, Felix and Schuhmann, Michael K and Kleinschnitz, Christoph},
  title     = {Animal models of ischemic stroke and their application in clinical research},
  series = {Drug Design, Development and Therapy},
  volume    = {9},
  journal   = {Drug Design, Development and Therapy},
  doi       = {10.2147/DDDT.S56071},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149157},
  pages     = {3445-3454},
  year      = {2015},
  abstract  = {This review outlines the most frequently used rodent stroke models and discusses their strengths and shortcomings. Mimicking all aspects of human stroke in one animal model is not feasible because ischemic stroke in humans is a heterogeneous disorder with a complex pathophysiology. The transient or permanent middle cerebral artery occlusion (MCAo) model is one of the models that most closely simulate human ischemic stroke. Furthermore, this model is characterized by reliable and well-reproducible infarcts. Therefore, the MCAo model has been involved in the majority of studies that address pathophysiological processes or neuroprotective agents. Another model uses thromboembolic clots and thus is more convenient for investigating thrombolytic agents and pathophysiological processes after thrombolysis. However, for many reasons, preclinical stroke research has a low translational success rate. One factor might be the choice of stroke model. Whereas the therapeutic responsiveness of permanent focal stroke in humans declines significantly within 3 hours after stroke onset, the therapeutic window in animal models with prompt reperfusion is up to 12 hours, resulting in a much longer action time of the investigated agent. Another major problem of animal stroke models is that studies are mostly conducted in young animals without any comorbidity. These models differ from human stroke, which particularly affects elderly people who have various cerebrovascular risk factors. Choosing the most appropriate stroke model and optimizing the study design of preclinical trials might increase the translational potential of animal stroke models.},
  language  = {en}
}
@article{FluriFleischerKleinschnitz2015,
  author    = {Fluri, Felix and Fleischer, Michael and Kleinschnitz, Christoph},
  title     = {Accidental Thrombolysis in a Stroke Patient Receiving Apixaban},
  series = {Cerebrovascular Diseases Extra},
  volume    = {5},
  journal   = {Cerebrovascular Diseases Extra},
  doi       = {10.1159/000375181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126326},
  pages     = {55-56},
  year      = {2015},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{FluriHeinenKleinschnitz2013,
  author    = {Fluri, Felix and Heinen, Florian and Kleinschnitz, Christoph},
  title     = {Intravenous Thrombolysis in a Stroke Patient Receiving Rivaroxaban},
  series = {Cerebrovascular Disease Extra},
  volume    = {2013},
  journal   = {Cerebrovascular Disease Extra},
  number    = {3},
  doi       = {10.1159/000355839},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128816},
  pages     = {153-155},
  year      = {2013},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{SchuhmannStollPappetal.2019,
  author    = {Schuhmann, Michael K. and Stoll, Guido and Papp, Lena and Bohr, Arne and Volkmann, Jens and Fluri, Felix},
  title     = {Electrical stimulation of the mesencephalic locomotor region has no impact on blood-brain barrier alterations after cerebral photothrombosis in rats},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {16},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20164036},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201284},
  year      = {2019},
  abstract  = {Blood-brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.},
  language  = {en}
}
@article{SchuhmannBittnerMeuthetal.2015,
  author    = {Schuhmann, Michael K. and Bittner, Stefan and Meuth, Sven G. and Kleinschnitz, Christoph and Fluri, Felix},
  title     = {Fingolimod (FTY720-P) does not stabilize the blood-brain barrier under inflammatory conditions in an in vitro model},
  series = {International Journal of Molecular Sciences},
  volume    = {16},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms161226177},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-145047},
  pages     = {29454-29466},
  year      = {2015},
  abstract  = {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.},
  language  = {en}
}
@article{SchuhmannPappStolletal.2021,
  author    = {Schuhmann, Michael K. and Papp, Lena and Stoll, Guido and Blum, Robert and Volkmann, Jens and Fluri, Felix},
  title     = {Mesencephalic electrical stimulation reduces neuroinflammation after photothrombotic stroke in rats by targeting the cholinergic anti-inflammatory pathway},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {3},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22031254},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259099},
  year      = {2021},
  abstract  = {Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.},
  language  = {en}
}
@article{SchuhmannStollBohretal.2019,
  author    = {Schuhmann, Michael K. and Stoll, Guido and Bohr, Arne and Volkmann, Jens and Fluri, Felix},
  title     = {Electrical stimulation of the mesencephalic locomotor region attenuates neuronal loss and cytokine expression in the perifocal region of photothrombotic stroke in rats},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20092341},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201355},
  year      = {2019},
  abstract  = {Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson's disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.},
  language  = {en}
}
@article{SchuhmannFluri2017,
  author    = {Schuhmann, Michael K. and Fluri, Felix},
  title     = {Effects of fullerenols on mouse brain microvascular endothelial cells},
  series = {International Journal of Molecular Sciences},
  volume    = {18},
  journal   = {International Journal of Molecular Sciences},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms18081783},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158072},
  year      = {2017},
  abstract  = {Fullerenols, water-soluble C60-fullerene derivatives, have been shown to exert neuroprotective effects in vitro and in vivo, most likely due to their capability to scavenge free radicals. However, little is known about the effects of fullerenols on the blood-brain barrier (BBB), especially on cerebral endothelial cells under inflammatory conditions. Here, we investigated whether the treatment of primary mouse brain microvascular endothelial cells with fullerenols impacts basal and inflammatory blood-brain barrier (BBB) properties in vitro. While fullerenols (1, 10, and 100 µg/mL) did not change transendothelial electrical resistance under basal and inflammatory conditions, 100 µg/mL of fullerenol significantly reduced erk1/2 activation and resulted in an activation of NFκB in an inflammatory milieu. Our findings suggest that fullerenols might counteract oxidative stress via the erk1/2 and NFκB pathways, and thus are able to protect microvascular endothelial cells under inflammatory conditions.},
  language  = {en}
}
@article{ElhfnawyVolkmannSchliesseretal.2019,
  author    = {Elhfnawy, Ahmed Mohamed and Volkmann, Jens and Schliesser, Mira and Fluri, Felix},
  title     = {Are cerebral white matter lesions related to the presence of bilateral internal carotid artery stenosis or to the length of stenosis among patients with ischemic cerebrovascular events?},
  series = {Frontiers in Neurology},
  volume    = {10},
  journal   = {Frontiers in Neurology},
  number    = {919},
  doi       = {10.3389/fneur.2019.00919},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201241},
  year      = {2019},
  abstract  = {Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL). Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values. Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95\% CI 1.12-11.18, p = 0.03), female sex (OR 3.11, 95\% CI 1.19-8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95\% CI 1.16-6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95\% CI 0.93-5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs. Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.},
  language  = {en}
}
@article{ElhfnawyElsalamawyAbdelraoufetal.2020,
  author    = {Elhfnawy, Ahmed Mohamed and Elsalamawy, Doaa and Abdelraouf, Mervat and Schliesser, Mira and Volkmann, Jens and Fluri, Felix},
  title     = {Red flags for a concomitant giant cell arteritis in patients with vertebrobasilar stroke: a cross-sectional study and systematic review},
  series = {Acta Neurologica Belgica},
  volume    = {120},
  journal   = {Acta Neurologica Belgica},
  number    = {6},
  issn      = {0300-9009},
  doi       = {10.1007/s13760-020-01344-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-315610},
  pages     = {1389-1398},
  year      = {2020},
  abstract  = {Giant cell arteritis (GCA) may affect the brain-supplying arteries, resulting in ischemic stroke, whereby the vertebrobasilar territory is most often involved. Since etiology is unknown in 25\% of stroke patients and GCA is hardly considered as a cause, we examined in a pilot study, whether screening for GCA after vertebrobasilar stroke might unmask an otherwise missed disease. Consecutive patients with vertebrobasilar stroke were prospectively screened for GCA using erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, and halo sign of the temporal and vertebral artery on ultrasound. Furthermore, we conducted a systematic literature review for relevant studies. Sixty-five patients were included, and two patients (3.1\%) were diagnosed with GCA. Patients with GCA were older in age (median 85 versus 69 years, p = 0.02). ESR and CRP were significantly increased and hemoglobin was significantly lower in GCA patients compared to non-GCA patients (median, 75 versus 11 mm in 1 h, p = 0.001; 3.84 versus 0.25 mg/dl, p = 0.01, 10.4 versus 14.6 mg/dl, p = 0.003, respectively). Multiple stenoses/occlusions in the vertebrobasilar territory affected our two GCA patients (100\%), but only five (7.9\%) non-GCA patients (p = 0.01). Our literature review identified 13 articles with 136 stroke patients with concomitant GCA. Those were old in age. Headache, increased inflammatory markers, and anemia were frequently reported. Multiple stenoses/occlusions in the vertebrobasilar territory affected around 70\% of stroke patients with GCA. Increased inflammatory markers, older age, anemia, and multiple stenoses/occlusions in the vertebrobasilar territory may be regarded as red flags for GCA among patients with vertebrobasilar stroke.},
  language  = {en}
}