title: Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation.
abstract: The only approved pharmacological treatment for ischemic stroke is intravenous administration of plasminogen activator (tPA) to re-canalize the occluded cerebral vessel. Not only reperfusion but also tPA itself can induce an inflammatory response. Microglia are the innate immune cells of the central nervous system and the first immune cells to become activated in stroke. Neuroserpin, an endogenous inhibitor of tPA, is up-regulated following cerebral ischemia. To examine neuroserpin-dependent mechanisms of neuroprotection in stroke, we studied neuroserpin deficient (Ns(-/-))mice in an animal model of temporal focal ischemic stroke. Infarct size and neurological outcome were worse in neuroserpin deficient mice even though the fibrinolytic activity in the ischemic brain was increased. The increased infarct size was paralleled by a selective increase in proinflammatory microglia activation in Ns(-/-) mice. Our results show excessive microglial activation in Ns(-/-) mice mediated by an increased activity of tPA. This activation results in a worse outcome further underscoring the potential detrimental proinflammatory effects of tPA.
authors: Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Mathias
authors: M
authors: Gelderblom
authors: Melanie
authors: M
authors: Neumann
authors: Peter
authors: P
authors: Ludewig
authors: Christian
authors: C
authors: Bernreuther
authors: Susanne
authors: S
authors: Krasemann
authors: Priyadharshini
authors: P
authors: Arunachalam
authors: Christian
authors: C
authors: Gerloff
authors: Markus
authors: M
authors: Glatzel
authors: Tim
authors: T
authors: Magnus
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007249:Inflammation; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000473:pathology*; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics*; D020556:Neutrophil Infiltration; D015843:Serpins / Q000172:deficiency / Q000235:genetics*; D020521:Stroke / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D015843:Serpins; D010959:Tissue Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha; D000097522:Neuroserpin
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