title: Acute Blockage of Notch Signaling by DAPT Induces Neuroprotection and Neurogenesis in the Neonatal Rat Brain After Stroke.
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.
authors.affiliation: Department of Laboratory, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Zhongxia
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Rehabilitation, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Jiangping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Laboratory, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Congying
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Laboratory, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Keming
authors.initials: K
authors.lastname: Ren
authors.affiliation: Department of Neurology, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Zhezhi
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Neonatology, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China.
authors.forename: Huimin
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Laboratory, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China. jiangkw_zju@163.com.|Department of Neurology, The Children's Hospital Zhejiang University School of Medicine, 3333 Binsheng Road, Hangzhou, 310003, China. jiangkw_zju@163.com.
authors.forename: Kewen
authors.initials: K
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D003959:Diamines / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: C000612000:24-diamino-5-phenylthiazole; D003959:Diamines; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D051880:Receptors, Notch; D013844:Thiazoles
keywords: Angiogenesis; Ischemia; N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester; Neurogenesis; Neuroprotection; Notch signaling