@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{GabrielJirůHillmannKraftetal.2020,
  author    = {Gabriel, Katharina M. A. and J{\´i}rů-Hillmann, Steffi and Kraft, Peter and Selig, Udo and R{\"u}cker, Victoria and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Keidel, Matthias and Soda, Hassan and Rascher, Alexandra and Schneider, Rolf and Pfau, Mathias and Hoffmann, Roy and Stenzel, Joachim and Benghebrid, Mohamed and Goebel, Tobias and Doerck, Sebastian and Kramer, Daniela and Haeusler, Karl Georg and Volkmann, Jens and Heuschmann, Peter U. and Fluri, Felix},
  title     = {Two years' experience of implementing a comprehensive telemedical stroke network comprising in mainly rural region: the Transregional Network for Stroke Intervention with Telemedicine (TRANSIT-Stroke)},
  series = {BMC Neurology},
  volume    = {20},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-020-01676-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229214},
  year      = {2020},
  abstract  = {Background Telemedicine improves the quality of acute stroke care in rural regions with limited access to specialized stroke care. We report the first 2 years' experience of implementing a comprehensive telemedical stroke network comprising all levels of stroke care in a defined region. Methods The TRANSIT-Stroke network covers a mainly rural region in north-western Bavaria (Germany). All hospitals providing acute stroke care in this region participate in TRANSIT-Stroke, including four hospitals with a supra-regional certified stroke unit (SU) care (level III), three of those providing teleconsultation to two hospitals with a regional certified SU (level II) and five hospitals without specialized SU care (level I). For a two-year-period (01/2015 to 12/2016), data of eight of these hospitals were available; 13 evidence-based quality indicators (QIs) related to processes during hospitalisation were evaluated quarterly and compared according to predefined target values between level-I- and level-II/III-hospitals. Results Overall, 7881 patients were included (mean age 74.6 years +/- 12.8; 48.4\% female). In level-II/III-hospitals adherence of all QIs to predefined targets was high ab initio. In level-I-hospitals, three patterns of QI-development were observed: a) high adherence ab initio (31\%), mainly in secondary stroke prevention; b) improvement over time (44\%), predominantly related to stroke specific diagnosis and in-hospital organization; c) no clear time trends (25\%). Overall, 10 out of 13 QIs reached predefined target values of quality of care at the end of the observation period. Conclusion The implementation of the comprehensive TRANSIT-Stroke network resulted in an improvement of quality of care in level-I-hospitals.},
  language  = {en}
}
@article{ElhfnawyHeuschmannPhametal.2019,
  author    = {Elhfnawy, Ahmed Mohamed and Heuschmann, Peter U. and Pham, Mirko and Volkmann, Jens and Fluri, Felix},
  title     = {Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis},
  series = {Frontiers in Neurology},
  volume    = {10},
  journal   = {Frontiers in Neurology},
  number    = {317},
  issn      = {1664-2295},
  doi       = {10.3389/fneur.2019.00317},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196225},
  year      = {2019},
  abstract  = {Background and Purpose: Internal carotid artery stenosis (ICAS)≥70\% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70\% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70\% (Spearman correlation coefficient ρ = -0.57, p < 0.001, n = 51) but neither for sICAS<70\% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70\% and ≥70\% was 17 (15-20) and 15 (12-19) mm (p = 0.06), respectively, while that for sICAS<90\% and sICAS 90\% was 18 (15-21) and 13 (10-16) mm, respectively (p < 0.001). Among patients with ICAS <70\%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1\% and 51.1\%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6\%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70\% to be longer than that of sICAS≥70\%. Moreover, the ultrasound-measured length of sICAS<90\% was significantly longer than that of sICAS 90\%. Among patients with sICAS≥70\%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.},
  language  = {en}
}
@article{KraemerSchuhmannVolkmannetal.2022,
  author    = {Kr{\"a}mer, Stefanie D. and Schuhmann, Michael K. and Volkmann, Jens and Fluri, Felix},
  title     = {Deep brain stimulation in the subthalamic nucleus can improve skilled Forelimb movements and retune dynamics of striatal networks in a rat stroke model},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {24},
  doi       = {10.3390/ijms232415862},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312828},
  year      = {2022},
  abstract  = {Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[\(^{18}\)F]Fluoro-2-deoxyglucose-([\(^{18}\)F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [\(^{18}\)F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [\(^{18}\)F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network.},
  language  = {en}
}