Rand Askalan1, Nadia Gabarin2, Edward A Armstrong3, Yuan Fang Liu2, Deema Couchman2, Jerome Y Yager3. 1. Neuroscience and Mental Health Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada. Electronic address: r.askalan@utoronto.ca. 2. Neuroscience and Mental Health Program, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada. 3. Section of Pediatric Neurosciences, Stollery Children׳s Hospital, University of Alberta, Edmonton, AB, Canada.
Abstract
PURPOSE: Apoptosis is implicated in mild-moderate ischemic injury. Cell death pathways in the severely ischemic brain are not characterized. We sought to determine the role of apoptosis in the severely ischemic immature brain. METHODS: Seven-day old rats were randomly assigned to mild-moderate or severe cerebral hypoxia-ischemia (HI) group. After ligating the right common carotid artery, animals were subjected to hypoxia for 90min in the mild-moderate HI or 180min in the severe HI. The core and peri-infarct area were measured in H&E stained brain sections using NIS Elements software. Brain sections were processed for caspase-3, AIF and RIP3 immuno-staining. Number of positive cells were counted and compared between the two groups. RESULTS: The core constituted a significantly higher proportion of the ischemic lesion in the severely compared to the moderately injured brain (P<0.04) up to 7 days post-injury. Apoptotic cell death was significantly higher (P<0.05) in the core than the peri-infarct of the severe HI brain. In the peri-infarct area of severe HI, AIF-induced cell death increased over time and caspase-3 and AIF equally mediated neuronal death. Necroptosis was significantly higher (P=0.02) in the peri-infarct of the severe HI lesion compared to the moderate HI lesion. In males, but not in females, apoptosis was higher in moderate compared to severe HI. CONCLUSIONS: Caspase-independent cell death plays an important role in severe ischemic injury. Injury severity, timing of intervention post-injury and sex of the animal are important determinants in designing neuroprotective intervention for the severely ischemic immature brain.
PURPOSE: Apoptosis is implicated in mild-moderate ischemic injury. Cell death pathways in the severely ischemic brain are not characterized. We sought to determine the role of apoptosis in the severely ischemic immature brain. METHODS: Seven-day old rats were randomly assigned to mild-moderate or severe cerebral hypoxia-ischemia (HI) group. After ligating the right common carotid artery, animals were subjected to hypoxia for 90min in the mild-moderate HI or 180min in the severe HI. The core and peri-infarct area were measured in H&E stained brain sections using NIS Elements software. Brain sections were processed for caspase-3, AIF and RIP3 immuno-staining. Number of positive cells were counted and compared between the two groups. RESULTS: The core constituted a significantly higher proportion of the ischemic lesion in the severely compared to the moderately injured brain (P<0.04) up to 7 days post-injury. Apoptotic cell death was significantly higher (P<0.05) in the core than the peri-infarct of the severe HI brain. In the peri-infarct area of severe HI, AIF-induced cell death increased over time and caspase-3 and AIF equally mediated neuronal death. Necroptosis was significantly higher (P=0.02) in the peri-infarct of the severe HI lesion compared to the moderate HI lesion. In males, but not in females, apoptosis was higher in moderate compared to severe HI. CONCLUSIONS: Caspase-independent cell death plays an important role in severe ischemic injury. Injury severity, timing of intervention post-injury and sex of the animal are important determinants in designing neuroprotective intervention for the severely ischemic immature brain.
Authors: Burak Ozaydin; Ela Bicki; Onur E Taparli; Temour Z Sheikh; Danielle K Schmidt; Sefer Yapici; Margarett B Hackett; Nida Karahan-Keles; Jens C Eickhoff; Karson Corcoran; Claudia Lagoa-Miguel; Jose Guerrero Gonzalez; Douglas C Dean Iii; Andre M M Sousa; Peter A Ferrazzano; Jon E Levine; Pelin Cengiz Journal: Dev Neurosci Date: 2022-05-25 Impact factor: 3.421
Authors: Brandon J Dixon; Di Chen; Yang Zhang; Jerry Flores; Jay Malaguit; Derek Nowrangi; John H Zhang; Jiping Tang Journal: ASN Neuro Date: 2016-09-28 Impact factor: 4.146