Auswirkung der TLR4-Inhibition bei verschiedenen Applikationswegen im Modell des ischämischen Schlaganfalls

Impact of TLR4 inhibition on different routes of application in a model of ischemic stroke

von Konstantina Theodorou
Dissertation
Datum der mündl. Prüfung:2020-11-16
Erschienen:2020-11-10
Betreuer:Prof. Dr. George Trendelenburg
Gutachter:Prof. Dr. Thomas A. Bayer
Gutachter:Prof. Dr. Holger Reichardt
Gutachter:Prof. Dr. Rainer Mausberg
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-8307

 

 

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Zusammenfassung

Englisch

Stroke is one of the most common diseases today and one of the leading causes for physical and psychological disability. Except of the recanalisation therapies that have been established there are no other therapeutical methods to tread stroke and prevent neurological damage successfully. Treatments modificating the postischemic inflammatory reaction after stroke, known to lead in extended tissue damage and neuronal degeneration, could be one approach to reach a better neurological outcome. In recent studies the Toll-like-Receptor 4 (TLR4) was identified as one of the central sensors for inflammatory response after stroke, leading to production of proinflammatory cytokines causing cell damage. The TLR4 is highly expressed in the CNS on different cells like microglia and neurons. This thesis aims to investigate whether TLR4 inhibition could be used to treat stroke in a standard model of focal cerebral ischemia, the middle cerebral artery occlusion model (MCAO). In order to block the TLR4 an anti-TLR4/MD2 antibody (clone MTS510), was injected intraperitoneal or intravenous after 45 min MCAO in adult male C57Bl/6 wild-type mice and the effects of stroke outcome have been studied after the reperfusion time of 48 hours. PBS was used for control group. Significant reduction of direct infarct volume as well as brain edema could be observed on mice treated intravenous after 45 min of MCAO. No disparity was showed in the neurological scoring and the histological cell counts of activated macrophages/ microglia and neurons between the treated and untreated mice. Conducted cell counts via flow cytometry analysis of immun cells revealed no significant effect on the number of macrophages, microglia or B-cells but a significant rise in the number of T-cells in the ipsilateral brain side of antibody treated mice, suggesting an altered immune answer. Further studies are needed in order to investigate the exact pathophysiology of blocking the TLR4 before clinical use could be envisaged.
Keywords: Cerebral ischemia; Mouse model; MCAO; Toll-like receptor 4; MTS510; Stroke; Ischemic; Neurology
 
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