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.

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

“…HI encephalopathy affects mainly preterm infants due to their underdeveloped cerebral circulation resulting in long term disabilities and still remains the leading cause of perinatal brain injury (Li et al, 2015b; Shenoda, 2015; Suzuki, 2015). Based on this several HI injury models have been developed in rodent models to mimic this injury and give us opportunity to study different therapeutic approaches.…”

Growth Hormone Neuroprotection Against Kainate Excitotoxicity in the Retina is Mediated by Notch/PTEN/Akt Signaling

“…On the one hand, Notch signaling inhibition results in neuroprotection and improved cognitive function in rats with craniocerebral injury and experimental stroke. 61,62 Notch activation is thought to have deleterious effects after ischemic stroke where it increases cell death in hippocampal cells, disrupts glial function, promotes aberrant proliferation, and causes additional damage. 19,63,64 Notch may promote cell death after neural injury through the disruption of Müller cell function, which supports the neural microenvironment.…”

Pericytes in Brain Injury and Repair After Ischemic Stroke

“…However, the phenomenon of reperfusion-no-reflow in microvasculature is common. Therefore, angiogenesis, which opens new pathways of blood flow to the hypoperfusion area, is crucial for tissue preservation and restoration [80]. Angiogenesis includes proliferation of vessel composing cells, recruitment of pericytes, coverage of endothelial tube by pericytes, and maturation of neo-vessels.…”