Title

Notch Activation Enhances The Microglia-Mediated Inflammatory Response Associated With Focal Cerebral Ischemia

Keywords

apoptosis; brain ischemia; focal ischemia; inflammation; neuroprotection; neuroregeneration

Abstract

Background and Purpose-Activation of Notch worsens ischemic brain damage as antisense knockdown or pharmacological inhibition of the Notch pathway reduces the infarct size and improves the functional outcome in a mouse model of stroke. We sought to determine whether Notch activation contributes to postischemic inflammation by directly modulating the microglial innate response. Methods-The microglial response and the attendant inflammatory reaction were evaluated in Notch1 antisense transgenic (Tg) and in nontransgenic (non-Tg) mice subjected to middle cerebral artery occlusion with or without treatment with a γ-secretase inhibitor (GSI). To investigate the impact of Notch on microglial effector functions, primary mouse microglia and murine BV-2 microglial cell line were exposed to oxygen glucose deprivation or lipopolysaccharide in the presence or absence of GSI. Immunofluorescence labeling, Western blotting, and reverse-transcription polymerase chain reaction were performed to measure microglial activation and production of inflammatory cytokines. The nuclear translocation of nuclear factor-κB in microglia was assessed by immunohistochemistry. The neurotoxic potential of microglia was determined in cocultures. Results-Notch1 antisense mice exhibit significantly lower numbers of activated microglia and reduced proinflammatory cytokine expression in the ipsilateral ischemic cortices compared to non-Tg mice. Microglial activation also was attenuated in Notch1 antisense cultures and in non-Tg cultures treated with GSI. GSI significantly reduced nuclear factor-κB activation and expression of proinflammatory mediators and markedly attenuated the neurotoxic activity of microglia in cocultures. Conclusions-These findings establish a role for Notch signaling in modulating the microglia innate response and suggest that inhibition of Notch might represent a complementary therapeutic approach to prevent reactive gliosis in stroke and neuroinflammation-related degenerative disorders. © 2011 American Heart Association. All rights reserved.

Publication Date

9-1-2011

Publication Title

Stroke

Volume

42

Issue

9

Number of Pages

2589-2594

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1161/STROKEAHA.111.614834

Socpus ID

80052424570 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/80052424570

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