@phdthesis{Heydenreich2013,
  author    = {Heydenreich, Nadine},
  title     = {Studies on the contact-kinin system and macrophage activation in experimental focal cerebral ischemia},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-94534},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Traditionally, ischemic stroke has been regarded as the mere consequence of cessation of cerebral blood flow, e.g. due to the thromboembolic occlusion of a major brain supplying vessel. However, the simple restoration of blood flow via thrombolysis and/or mechanical recanalization alone often does not guarantee a good functional outcome. It appears that secondary detrimental processes are triggered by hypoxia and reoxygenation, which are referred to as ischemia/reperfusion (I/R) injury. During recent years it became evident that, beside thrombosis inflammation and edema formation are key players in the pathophysiology of cerebral ischemia. The contact-kinin system represents an interface between thrombotic, inflammatory and edematous circuits. It connects the intrinsic coagulation pathway with the plasma kallikrein-kinin system (KKS) via coagulation factor FXII. The serine protease inhibitor C1-inhibitor (C1-INH) has a wide spectrum of inhibitory activities and counteracts activation of the contact-kinin system at multiple levels. The first part of the thesis aimed to multimodally interfere with infarct development by C1-INH and to analyze modes of actions of human plasma derived C1-INH Berinert® P in a murine model of focal cerebral ischemia. It was shown that C57BL/6 mice following early application of 15.0 units (U) C1-INH, but not 7.5 U developed reduced brain infarctions by ~60\% and less neurological deficits in the model of transient occlusion of the middle cerebral artery (tMCAO). This protective effect was preserved at more advanced stages of infarction (day 7), without increasing the risk of intracerebral bleeding or affecting normal hemostasis. Less neurological deficits could also be observed with delayed C1-INH treatment, whereas no improvement was achieved in the model of permanent MCAO (pMCAO). Blood-brain-barrier (BBB) damage, inflammation and thrombosis were significantly improved following 15.0 U C1-INH application early after onset of ischemia. Based on its strong antiedematous, antiinflammatory and antithrombotic properties C1-INH constitutes a multifaceted therapeutic compound that protects from ischemic neurodegeneration in 'clinically meaningful' settings. The second part of the thesis addresses the still elusive functional role of macrophages in the early phase of stroke, especially the role of the macrophage-specific adhesion molecule sialoadhesin (Sn). For the first time, sialoadhesin null (Sn-/-) mice, homozygous deficient for Sn on macrophages were subjected to tMCAO to assess the clinical outcome. Neurological and motor function was significantly improved in Sn-/- mice on day 1 after ischemic stroke compared with wildtype (Sn+/+) animals. These clinical improvements were clearly detectable even on day 3 following tMCAO. Infarctions on day 1 were roughly the same size as in Sn+/+ mice and did not grow until day 3. No intracerebral bleeding could be detected at any time point of data acquisition. Twenty four hours after ischemia a strong induction of Sn was detectable in Sn+/+ mice, which was previously observed only on perivascular macrophages in the normal brain. Deletion of Sn on macrophages resulted in less disturbance of the BBB and a reduced number of CD11b+ (specific marker for macrophages/microglia) cells, which, however, was not associated with altered expression levels of inflammatory cytokines. To further analyze the function of macrophages following stroke this thesis took advantage of LysM-Cre+/-/IKK2-/- mice bearing a nuclear factor (NF)-ϰB activation defect in the myeloid lineage, including macrophages. Consequently, macrophages were not able to synthesize inflammatory cytokines under the control of NF-ϰB. Surprisingly, infarct sizes and neurological deficits upon tMCAO were roughly the same in conditional knockout mice and respective wildtype littermates. These findings provide evidence that macrophages do not contribute to tissue damage and neurological deficits, at least, not by release of inflammatory cytokines in the early phase of cerebral ischemia. In contrast, Sn which is initially expressed on perivascular macrophages and upregulated on macrophages/microglia within the parenchyma following stroke, influenced functional outcome.},
  subject      = {Blut-Hirn-Schranke},
  language  = {en}
}