Abstract
Apolipoprotein E (Apoe) genetic polymorphisms have been implicated in the long term outcome of subarachnoid haemorrhage (SAH), but little is known about the effect of Apoe on the early brain injury (EBI) after SAH. This study investigated the potential role of APOE in EBI post-SAH. Multiple techniques were used to determine the early BBB disruption in EBI post-SAH in a murine model using wild-type (WT) and Apoe−/− (KO) mice. Progressive BBB disruption (Evans blue extravasation and T2 hyperintensity in magnetic resonance imaging) was observed before the peak of endogenous APOE expression elevation at 48h after SAH. Moreover, Apoe−/− mice exhibited more severe BBB disruption charcteristics after SAH than WT mice, including higher levels of Evans blue and IgG extravasation, T2 hyperintensity in magnetic resonance imaging, tight junction proteins degradation and endothelial cells death. Mechanistically, we found that APOE restores the BBB integrity in the acute stage after SAH via the cyclophilin A (CypA)-NF-κB-proinflammatory cytokines-MMP-9 signalling pathway. Consequently, although early BBB disruption causes neurological dysfunctions after SAH, we capture a different aspect of the effects of APOE on EBI after SAH that previous studies had overlooked and open up the idea of BBB disruption as a target of APOE-based therapy for EBI amelioration research in the future.
Highlights
Despite intense clinical efforts including surgical clipping and interventional embolization, subarachnoid haemorrhage (SAH) remains a devastating condition with case fatality rates of approximately 50% and one third of survivors requiring lifelong care [1]
We defined a therapeutic target for Early brain injury (EBI) inhibition to restrict neurological dysfunctions in experimental SAH
This approach is based on our results showing that: (1) endogenous APOE is significantly elevated at early times after SAH, (2) APOE elevation is associated with EBI inhibition through a mechanism that includes blood-brain barrier (BBB)-dependent changes
Summary
Despite intense clinical efforts including surgical clipping and interventional embolization, subarachnoid haemorrhage (SAH) remains a devastating condition with case fatality rates of approximately 50% and one third of survivors requiring lifelong care [1]. Considering no interventions for the prevention of SAH currently exist [5], pharmacotherapy has an accepted role in reducing the secondary brain injuries post-SAH. The results of most pharmacologic interventions focused on the prevention and/or alleviation of CVS failed in the outcome improvement of SAH patients or www.impactjournals.com/oncotarget just inconclusive [5]. Brain injury (EBI) associated with SAH presents pathological brain changes including blood-brain barrier (BBB) disruption and others that arise within the first 72h following bleeding. These changes are being recognized as the predominant determination of mortality and disability after SAH in humans [7].
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