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Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke

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Abstract

Notch signaling is critically involved in various biological events. Notch undergoes cleavage by the γ-secretase enzyme to release Notch intracellular domain that will translocate into nucleus to result in expression of target gene. γ-Secretase inhibitors have been developed as potential treatments for neurological degenerative diseases, but its effects against ischemic injury remain relatively uncertain. In the present study, we demonstrated that N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor not only rescued the cerebral hypoperfusion or ischemia neonatal rats from death, reduced apoptosis in penumbra, but also reduced brain infarct size. Furthermore, DAPT elicited some morphologic hallmarks such as neurogenesis and angiogenesis that related to the brain repair and functional recovery after stroke: increased accumulations of newborn cells in the peri-infarct region with a higher fraction of them adopting immature neuronal and glial markers instead of microglial markers on 5 days, enhanced vascular densities in penumbra at 14 days, and evident regulations of the gene profiles associated with neurogenesis in penumbral tissues. The current results suggest that DAPT is a potential neuroprotectants against ischemic injury in immature brain, and future treatment strategies such as clinical trials using γ-secretase inhibitors would be an attractive therapy for perinatal ischemia.

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Authors and Affiliations

  1. Department of Laboratory, The Children’s Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China

    Zhongxia Li, Congying Zhao, Keming Ren & Kewen Jiang

  2. Department of Rehabilitation, The Children’s Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China

    Jiangping Wang

  3. Department of Neonatology, The Children’s Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China

    Huimin Yu

  4. Department of Neurology, The Children’s Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China

    Zhezhi Xia & Kewen Jiang

Authors
  1. Zhongxia Li
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  2. Jiangping Wang
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  3. Congying Zhao
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  4. Keming Ren
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  7. Kewen Jiang
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Corresponding author

Correspondence to Kewen Jiang.

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Funding

This study was funded by the National Natural Science Foundation of China (30471840 and 30570644) and by Zhejiang Provincial Natural Science Foundation of China (Y205127 and R2090266).

Conflict of Interest

The authors declare that they have no competing interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Figure S1

N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) regulated the gene profiles associated with neurogenesis in penumbra at 5 days after focal cerebral ischemia. The Oligo GEArray DNA Microarray Rat Neurogenesis and Neural Stem Cell Gene Array containing 263 known genes were used in the experiments. Microarray protocols were as shown in Fig. 1b. a Representative gene arrays show the profiles of genes in non-stroke, stroke, or DAPT-treated stroke penumbral tissues. All clones with more than 1.5-fold estimated differences were considered for further evaluation. Red and blue circles indicate upregulated and downregulated genes, respectively, detected in microarrays under DAPT-treated conditions compared with genes under vehicle-treated ischemia condition in the penumbra. Real-time RT-PCR analysis of mRNA levels in the penumbra. Some upregulated and downregulated genes (b) detected in microarrays under DAPT-treated condition after stroke compared with levels in vehicle-treated stroke penumbra. Quantification of expression levels of upregulated and downregulated genes (c). Values are mean ± SEM; *P < 0.05, ANOVA, n = 4. (JPG 767 kb)

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Li, Z., Wang, J., Zhao, C. et al. Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke. Transl. Stroke Res. 7, 132–140 (2016). https://doi.org/10.1007/s12975-015-0441-7

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  • DOI: https://doi.org/10.1007/s12975-015-0441-7

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