18880
2016
eng
970-982
6
79
article
1
2019-10-15
--
--
Targeting coagulation factor XII as a novel therapeutic option in brain trauma
Objective:
Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury.
Methods:
We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury.
Results:
Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage.
Interpretation:
The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies.
Annals of Neurology
10.1002/ana.24655
urn:nbn:de:bvb:20-opus-188800
Annals of Neurology (2016) 79:6, 970-982. https://doi.org/10.1002/ana.24655
291840
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Sarah Hopp
Christiane Albert-Weissenberger
Stine Mencl
Michael Bieber
Michael K. Schuhmann
Christian Stetter
Bernhard Nieswandt
Peter M. Schmidt
Camelia-Maria Monoranu
Irina Alafuzoff
Niklas Marklund
Marc W. Nolte
Anna-Leena Sirén
Christoph Kleinschnitz
eng
uncontrolled
Molecular-weight heparin
eng
uncontrolled
Thrombus formation
eng
uncontrolled
Cerebral-ischemia
eng
uncontrolled
in-vivo
eng
uncontrolled
Intravascular coagulation
eng
uncontrolled
Hemodynamic depression
eng
uncontrolled
Head-injury
eng
uncontrolled
Rats
eng
uncontrolled
Model
eng
uncontrolled
Mice
Biowissenschaften; Biologie
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Neurologische Klinik und Poliklinik
Rudolf-Virchow-Zentrum
OpenAIRE
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/18880/Hopp_AnnalsOfNeurology_2016.pdf
14660
2016
eng
140
13
article
1
2017-03-31
--
--
Combined [\(^{18}\)F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice
Background
Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry.
Methods
A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1.
Results
Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging.
Conclusions
[\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI.
Journal of Neuroinflammation
10.1186/s12974-016-0604-9
urn:nbn:de:bvb:20-opus-146606
Journal of Neuroinflammation (2016) 13:140 DOI 10.1186/s12974-016-0604-9
680966
Ina Israel
Andrea Ohsiek
Ehab Al-Momani
Christiane Albert-Weissenberger
Christian Stetter
Stine Mencl
Andreas K. Buck
Christoph Kleinschnitz
Samuel Samnick
Anna-Leena Sirén
eng
uncontrolled
neuroinflammation
eng
uncontrolled
TBI
eng
uncontrolled
immunohistochemistry
eng
uncontrolled
weight drop
eng
uncontrolled
PET
eng
uncontrolled
diffuse
eng
uncontrolled
focal
eng
uncontrolled
TSPO
eng
uncontrolled
autoradiography
eng
uncontrolled
IBA-1
Medizin und Gesundheit
open_access
Neurochirurgische Klinik und Poliklinik
Klinik und Poliklinik für Nuklearmedizin
Physiologisches Institut
Neurologische Klinik und Poliklinik
OpenAIRE
Förderzeitraum 2016
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/14660/Israel_10.1186_s12974-016-0604-9.pdf