Abstract
EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB) disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.
Highlights
Ischemic stroke is the most prevalent neurological disease and the major cause of long-term disability in adults
To determine whether ischemia-induced neuronal death was aggravated by EAAC1 gene deletion, wild-type and EAAC1−/− female mice were subjected to bilateral common carotid artery occlusion for 30 min and neuronal death was assessed by Fluoro-Jade B staining at 3 days after ischemia
The present study demonstrates that EAAC1 gene deletion results in reduced neuronal GSH content, increased blood–brain barrier (BBB) disruption and increased neuronal death in female mice after transient cerebral ischemia
Summary
Ischemic stroke is the most prevalent neurological disease and the major cause of long-term disability in adults. A tight interplay between the brain and the peripheral immune system exists via the blood–brain barrier and this relationship leads to a vulnerability of the brain to immune response during and after stroke consisting of an early activation of peripheral immune cells with massive production of proinflammatory cytokines [1,2,3]. Ischemic stroke-induced neuronal death is mostly attributed to dysfunction in the homeostasis of glutamate. Increased extracellular glutamate levels promote activation of the NMDA receptor causing an influx of calcium, the production of reactive oxygen species (ROS), mitochondria dysfunction and the generation of reactive nitrogen species (RNS), all of which contribute to cell death [5,6]
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