11926
2014
eng
269
8
article
1
2015-09-29
--
--
C1-Inhibitor protects from focal brain trauma in a cortical cryolesion mice model by reducing thrombo-inflammation
Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.
Frontiers in Cellular Neuroscience
10.3389/fncel.2014.00269
1662-5102
25249935
urn:nbn:de:bvb:20-opus-119263
Frontiers in Cellular Neuroscience 8:269. doi: 10.3389/fncel.2014.00269
Christiane Albert-Weissenberger
Stine Mencl
Michael K. Schuhmann
Irmak Salur
Eva Göb
Friederike Langhauser
Sarah Hopp
Nelli Hennig
Sven G. Meuth
Marc W. Nolte
Anna-Leena Sirén
Christoph Kleinschnitz
eng
uncontrolled
thrombosis
eng
uncontrolled
traumatic brain injury
eng
uncontrolled
C1-inhibitor
eng
uncontrolled
blood-brain barrier
eng
uncontrolled
contact-kinin system
eng
uncontrolled
edema
eng
uncontrolled
inflammation
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/11926/025_Albert_Weissenberger_Frontiers_in_Ceööuöar_Neuroscience.pdf
13188
2013
eng
16
5
article
1
2016-04-12
--
--
Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?
Background
Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing \(I_h\), stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts.
Methods
In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays.
Results
After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups.
Conclusions
Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.
Experimental & Translational Stroke Medicine
10.1186/2040-7378-5-16
urn:nbn:de:bvb:20-opus-131887
Experimental & Translational Stroke Medicine 2013, 5:16. doi:10.1186/2040-7378-5-16
Petra Ehling
Eva Göb
Stefan Bittner
Thomas Budde
Andreas Ludwig
Christoph Kleinschnitz
Sven G. Meuth
eng
uncontrolled
ischemia
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/13188/038_Ehling_Ischemia-induced.pdf
12924
2013
eng
16
5
article
1
2016-03-10
--
--
Ischemia-induced cell depolarization: does the hyperpolarization-activated cation channel HCN2 affect the outcome after stroke in mice?
Background
Brain ischemia is known to include neuronal cell death and persisting neurological deficits. A lack of oxygen and glucose are considered to be key mediators of ischemic neurodegeneration while the exact mechanisms are yet unclear. In former studies the expression of two different two-pore domain potassium \((K_{2P})\) channels (TASK1, TREK1) were shown to ameliorate neuronal damage due to cerebral ischemia. In neurons, TASK channels carrying hyperpolarizing \(K^+\) leak currents, and the pacemaker channel HCN2, carrying depolarizing Ih, stabilize the membrane potential by a mutual functional interaction. It is assumed that this ionic interplay between TASK and HCN2 channels enhances the resistance of neurons to insults accompanied by extracellular pH shifts.
Methods
In C57Bl/6 (wildtype, WT), \(hcn2^{+/+}\) and \(hcn2^{-/-}\) mice we used an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of HCN2 in stroke formation. Subsequent analyses comprise behavioural tests and hcn2 gene expression assays.
Results
After 60 min of tMCAO induction in WT mice, we collected tissue samples at 6, 12, and 24 h after reperfusion. In the infarcted neocortex, hcn2 expression analyses revealed a nominal peak of hcn2 expression 6 h after reperfusion with a tendency towards lower expression levels with longer reperfusion times. Hcn2 gene expression levels in infarcted basal ganglia did not change after 6 h and 12 h. Only at 24 h after reperfusion, hcn2 expression significantly decreases by ~55%. However, 30 min of tMCAO in hcn2-/- as well as hcn2+/+ littermates induced similar infarct volumes. Behavioural tests for global neurological function (Bederson score) and motor function/coordination (grip test) were performed at day 1 after surgery. Again, we found no differences between the groups.
Conclusions
Here, we hypothesized that the absence of HCN2, an important functional counter player of TASK channels, affects neuronal survival during stroke-induced tissue damage. However, together with a former study on TASK3 these results implicate that both TASK3 and HCN2 which were supposed to be neuroprotective due to their pH-dependency, do not influence ischemic neurodegeneration during stroke in the tMCAO model.
Experimental & Translational Stroke Medicine
10.1186/2040-7378-5-16
urn:nbn:de:bvb:20-opus-129240
Experimental & Translational Stroke Medicine 2013 5:16. doi:10.1186/2040-7378-5-16
Petra Ehling
Eva Göb
Stefan Bittner
Thomas Budde
Andreas Ludwig
Christoph Kleinschnitz
Sven G. Meuth
eng
uncontrolled
neurology
Medizin und Gesundheit
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12924/131_Ehling_Exp_Transl_Stroke_Med.pdf
9705
2013
eng
article
1
--
--
--
Early microvascular dysfunction in cerebral small vessel disease is not detectable on 3.0 Tesla magnetic resonance imaging: a longitudinal study in spontaneously hypertensive stroke-prone rats
Background
Human cerebral small vessel disease (CSVD) has distinct histopathologic and imaging findings in its advanced stages. In spontaneously hypertensive stroke-prone rats (SHRSP), a well-established animal model of CSVD, we recently demonstrated that cerebral microangiopathy is initiated by early microvascular dysfunction leading to the breakdown of the blood–brain barrier and an activated coagulatory state resulting in capillary and arteriolar erythrocyte accumulations (stases). In the present study, we investigated whether initial microvascular dysfunction and other stages of the pathologic CSVD cascade can be detected by serial magnetic resonance imaging (MRI).
Findings
Fourteen SHRSP and three control (Wistar) rats (aged 26–44 weeks) were investigated biweekly by 3.0 Tesla (3 T) MRI. After perfusion, brains were stained with hematoxylin–eosin and histology was correlated with MRI data. Three SHRSP developed terminal CSVD stages including cortical, hippocampal, and striatal infarcts and macrohemorrhages, which could be detected consistently by MRI. Corresponding histology showed small vessel thromboses and increased numbers of small perivascular bleeds in the infarcted areas. However, 3 T MRI failed to visualize intravascular erythrocyte accumulations, even in those brain regions with the highest densities of affected vessels and the largest vessels affected by stases, as well as failing to detect small perivascular bleeds.
Conclusion
Serial MRI at a field strength of 3 T failed to detect the initial microvascular dysfunction and subsequent small perivascular bleeds in SHRSP; only terminal stages of cerebral microangiopathy were reliably detected. Further investigations at higher magnetic field strengths (7 T) using blood- and flow-sensitive sequences are currently underway.
Experimental & Translational Stroke Medicine
10.1186/2040-7378-5-8
http://www.etsmjournal.com/content/5/1/8
urn:nbn:de:bvb:20-opus-97056
In: Experimental & Translational Stroke Medicine (2013) 5: 8, doi:10.1186/2040-7378-5-8
Christoph Kleinschnitz
Stine Mencl
Cornelia Garz
Solveig Niklass
Holger Braun
Eva Göb
György Homola
Hans-Jochen Heinze
Klaus G. Reymann
Stefanie Schreiber
eng
uncontrolled
Cerebral small vessel disease
eng
uncontrolled
SHRSP
eng
uncontrolled
MRI
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Strahlentherapie
Neurologische Klinik und Poliklinik
Förderzeitraum 2013
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/9705/Kleinschnitz_2040-7378-5-8.pdf
15140
2015
eng
13428
5
article
1
2017-07-12
--
--
A combined pre-clinical meta-analysis and randomized confirmatory trial approach to improve data validity for therapeutic target validation
Biomedical research suffers from a dramatically poor translational success. For example, in ischemic stroke, a condition with a high medical need, over a thousand experimental drug targets were unsuccessful. Here, we adopt methods from clinical research for a late-stage pre-clinical meta-analysis (MA) and randomized confirmatory trial (pRCT) approach. A profound body of literature suggests NOX\(_{2}\) to be a major therapeutic target in stroke. Systematic review and MA of all available NOX\(_{2}\)\(^{-/y}\) studies revealed a positive publication bias and lack of statistical power to detect a relevant reduction in infarct size. A fully powered multi-center pRCT rejects NOX\(_{2}\) as a target to improve neurofunctional outcomes or achieve a translationally relevant infarct size reduction. Thus stringent statistical thresholds, reporting negative data and a MA-pRCT approach can ensure biomedical data validity and overcome risks of bias.
Scientific Reports
10.1038/srep13428
urn:nbn:de:bvb:20-opus-151401
Scientific Reports 5, 13428 (2015). DOI: 10.1038/srep13428
294683
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Pamela W. M. Kleikers
Carlijn Hooijmans
Eva Göb
Friederike Langhauser
Sarah S. J. Rewell
Kim Radermacher
Merel Ritskes-Hoitinga
David W. Howells
Christoph Kleinschnitz
Harald H. H. W. Schmidt
eng
uncontrolled
focal cerebral ischemia
eng
uncontrolled
darbepoetin alpha
eng
uncontrolled
mice
eng
uncontrolled
translational stroke research
eng
uncontrolled
colony-stimulating factor
eng
uncontrolled
NADPH oxidase inhibitors
eng
uncontrolled
chronic kidney disease
eng
uncontrolled
diabetes mellitus
eng
uncontrolled
oxidative stress
eng
uncontrolled
search filter
Krankheiten
open_access
Neurologische Klinik und Poliklinik
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/15140/006_Kleikers_SCIENTIFIC_REPORTS.pdf