Therapeutisches Potenzial und Langzeiteffekt der TLR4-Inhibition bei der fokalen zerebralen Ischämie

Therapeutic potential and long term effect of TLR4 inhibition in focal cerebral ischemia

by Lena Andresen
Doctoral thesis
Date of Examination:2016-05-11
Date of issue:2016-04-11
Advisor:Prof. Dr. George Trendelenburg
Referee:Prof. Dr. George Trendelenburg
Referee:Prof. Dr. Thomas A. Bayer
Persistent Address: http://dx.doi.org/10.53846/goediss-5608

 

 

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Abstract

English

Ischemic stroke is known to be one of the leading causes of death worldwide. As therapeutic options especially for treatment beyond 4,5 to 6 hours after the beginning of symptoms are limited, recent studies have focussed on the therapeutic protection of the penumbra, where the brain tissue is damaged by post-ischemic process. In this doctoral thesis the effect of antibody-induced inhibition of the toll-like receptor 4 (TLR4), a receptor being involved in the post-ischemic immune response, has been investigated in a murine model of cerebral ischemia. Since neuroprotective effects of TLR4 inhibition have already been shown in recent studies after 48 hours of post-ischemic reperfusion, this work concentrates on the effect of TLR4 inhibition 14 days after mild cerebral ischemia (15 minutes of middle cerebral artery occlusion). The anti-TLR4/MD2-antibody MTS510 or PBS has been applied intraarterially shortly before MCAO. Analysis was based on neurological tests, infarct volumes as well as cell quantification based on immunohistochemical staining. Neither of these parameters showed any significant difference among the mice that received the antibody and those being part of the control group. As comparable long term studies with transgene mouse models did show neuroprotective effects of TLR4 inhibition and a high mortality occurred in both groups despite modifications of the experimental set-up, further studies are needed before clinical investigation.
Keywords: stroke; experimental stroke; focal cerebral ischemia; MCAO; TLR4; neuroprotection
Schlagwörter: Schlaganfall; fokale zerebrale Ischämie; experimenteller Schlaganfall; MCAO; TLR4; Neuroprotektion
 
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