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: Mathias Gelderblom, Melanie Neumann, Peter Ludewig, Christian Bernreuther, Susanne Krasemann, Priyadharshini Arunachalam, Christian Gerloff, Markus Glatzel, Tim Magnus
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e63118 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23658802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Neuropeptides
• Serpins
• Tumor Necrosis Factor-alpha
• neuroserpin
• Tissue Plasminogen Activator

Topics

• Animals
• Brain Ischemia (genetics, immunology, pathology)
• Disease Models, Animal
• Gene Expression Regulation
• Inflammation
• Mice
• Mice, Knockout
• Microglia (immunology, pathology)
• Neuropeptides (deficiency, genetics)
• Neutrophil Infiltration
• Serpins (deficiency, genetics)
• Stroke (genetics, immunology, pathology)
• Tissue Plasminogen Activator (genetics, immunology)
• Tumor Necrosis Factor-alpha (immunology, metabolism)