BID Mediates Oxygen-Glucose Deprivation-Induced Neuronal Injury in Organotypic Hippocampal Slice Cultures and Modulates Tissue Inflammation in a Transient Focal Cerebral Ischemia Model without Changing Lesion Volume.

Nellie Anne Martin,Gang Chen,Shona Pfeiffer,Kate Lykke Lambertsen,Beatrice D’Orsi,Hans Georg König,Helena Bonner,Maria Louise Elkjær,Martina Svensson,Tomas Deierborg,Jochen H Prehn

doi:10.3389/fncel.2016.00014

Abstract

The BH3 interacting-domain death agonist (BID) is a pro-apoptotic protein involved in death receptor-induced and mitochondria-mediated apoptosis. Recently, it has also been suggested that BID is involved in the regulation of inflammatory responses in the central nervous system. We found that BID deficiency protected organotypic hippocampal slice cultures in vitro from neuronal injury induced by oxygen-glucose deprivation. In vivo, BID-knockout (KO) mice and wild type (WT) mice were subjected to 60 min of transient middle cerebral artery occlusion (tMCAO) to induce focal cerebral ischemia, and allowed to recover for 24 h. Infarct volumes and functional outcome were assessed and the inflammatory response was evaluated using immunofluorescence, Western blotting, quantitative PCR (qPCR) and Mesoscale multiplex analysis. We observed no difference in the infarct volume or neurological outcome between BID-KO and WT mice. The inflammatory response was reduced by BID deficiency as indicated by a change in microglial/leukocyte response. In conclusion, our data suggest that BID deficiency is neuroprotective in an in vitro model and modulates the inflammatory response to focal cerebral ischemia in vivo. However, this is not translated into a robust neuroprotection in vivo.

Highlights

Within minutes following the incidence of an ischemic stroke, necrotic cell death is initiated in the core region of the infarct
organotypic hippocampal slice cultures (OHSC) derived from wild type (WT) and BH3 interacting-domain death agonist (BID)-KO mice were subjected to Oxygen–Glucose Deprivation (OGD) for 180 min in the presence or absence of the NMDA receptor antagonist, MK-801, a treatment that blocks the excitotoxic component of OGD-induced neuronal injury
The present study demonstrated a neuroprotective effect of BID deficiency against OGD-induced neuronal injury in vitro, yet we did not find a significant effect of BID deficiency on lesion volume or functional outcome in response to Transient Middle Cerebral Artery Occlusion (tMCAO) in vivo

Summary

Introduction

Within minutes following the incidence of an ischemic stroke, necrotic cell death is initiated in the core region of the infarct. The BH3 interacting-domain death agonist (BID) is a proapoptotic B-cell lymphoma-2 (BCL-2) family protein involved in death receptor-induced apoptosis. BID links death receptor signaling to the mitochondrial BCL-2 family-controlled apoptotic pathway (Wang et al, 1996; Engel et al, 2011). The involvement of BID in apoptosis is believed to be stimulated by cleavage of full length-BID in the cytosol to form truncated BID (tBID). This leads to translocation of tBID to the outer mitochondrial membrane resulting in cytochrome c release and thereby apoptosis (Broughton et al, 2009; Ren et al, 2010; Engel et al, 2011)

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Conclusion