Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation
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Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation. / Gelderblom, Mathias; Neumann, Melanie; Ludewig, Peter; Bernreuther, Christian; Krasemann, Susanne; Arunachalam, Priyadharshini; Gerloff, Christian; Glatzel, Markus; Magnus, Tim.
in: PLOS ONE, Jahrgang 8, Nr. 5, 01.01.2013, S. e63118.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Deficiency in serine protease inhibitor neuroserpin exacerbates ischemic brain injury by increased postischemic inflammation
AU - Gelderblom, Mathias
AU - Neumann, Melanie
AU - Ludewig, Peter
AU - Bernreuther, Christian
AU - Krasemann, Susanne
AU - Arunachalam, Priyadharshini
AU - Gerloff, Christian
AU - Glatzel, Markus
AU - Magnus, Tim
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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.
AB - 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.
KW - Animals
KW - Brain Ischemia
KW - Disease Models, Animal
KW - Gene Expression Regulation
KW - Inflammation
KW - Mice
KW - Mice, Knockout
KW - Microglia
KW - Neuropeptides
KW - Neutrophil Infiltration
KW - Serpins
KW - Stroke
KW - Tissue Plasminogen Activator
KW - Tumor Necrosis Factor-alpha
U2 - 10.1371/journal.pone.0063118
DO - 10.1371/journal.pone.0063118
M3 - SCORING: Journal article
C2 - 23658802
VL - 8
SP - e63118
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 5
ER -
