The Cystine/Glutamate Antiporter, System xc–, Contributes to Cortical Infarction After Moderate but Not Severe Focal Cerebral Ischemia in Mice

Abstract

Understanding the mechanisms underlying ischemic brain injury is of importance to the goal of devising novel therapeutics for protection and/or recovery. Previous work in our laboratory and in others has shown that activation of cystine/glutamate antiporter, system xc– (Sxc–), facilitates neuronal injury in several in vitro models of energy deprivation. However, studies on the contribution of this antiporter to ischemic brain damage in vivo are more limited. Since embolic or thrombotic transient or permanent occlusion of a cerebral blood vessel eventually leads to brain infarction in most stroke cases, we evaluated the contribution of Sxc– to cerebral ischemic damage by comparing brain infarction between mice naturally null for SLC7a11 (SLC7a11sut/sut mice). The gene the encodes for the substrate specific light chain for system xcc– — with their wild type (SLC7a11 + ⁣/ +)littermates following photothrombotic ischemic stroke of the middle cerebral artery (PTI) and permanent middle cerebral artery occlusion (pMCAo) rendered by cauterization. In the PTI model, we found a time-dependent reduction in cerebral blood flow that reached 50% from baseline in both genotypes 47–48 h post-illumination. Despite this, a remarkable reduction in incidence and total infarct volume of SLC7a11sut/sut mice was revealed 48 h following PTI as compared to SLC7a11+/+ mice. No difference in injury markers and/or infarct volume was measured between genotypes when occlusion of the MCA was permanent, however. Present data demonstrate a model-dependent differential role for Sxc– in focal cerebral ischemic damage, further highlighting that ischemic severity activates heterogeneous biochemical events that lead to damage engendered by stroke.

Mechanism of ferroptosis regulating ischemic stroke and pharmacologically inhibiting ferroptosis in treatment of ischemic stroke

“…182 However, studies have found that system Xc − activity rapidly increased after transient middle cerebral artery occlusion (tMCAO) in the rat brain, 183 and xCT protein levels in microglia/ macrophages, neurons, and astrocytes were elevated. 184,185 Hewett et al 186 compared infarcts in mice naturally null for SLC7a11 (SLC7a11 sut/sut mice) with wild type (SLC7a11 +/+ ) after middle cerebral artery photothrombotic ischemic stroke (PTI) and permanent middle cerebral artery occlusion (pMCAO). They found that the infarct volume in SLC7a11 sut/sut mice decreased significantly 48 h after PTI, but no difference between the two groups when MCA was permanently occluded, suggesting that system Xc − aggravated the damage in mice with non-severe ischemic stroke.…”

“…However, studies have found that system Xc − activity rapidly increased after transient middle cerebral artery occlusion (tMCAO) in the rat brain, 183 and xCT protein levels in microglia/macrophages, neurons, and astrocytes were elevated 184,185 . Hewett et al 186 . compared infarcts in mice naturally null for SLC7a11 (SLC7a11 sut/sut mice) with wild type (SLC7a11 +/+ ) after middle cerebral artery photothrombotic ischemic stroke (PTI) and permanent middle cerebral artery occlusion (pMCAO).…”

Glutamatergic system components as potential biomarkers and therapeutic targets in cancer in non-neural organs

“…System xCT (Sx c - ) is a cystine/glutamate Na + -dependent antiporter that mediates the exchange of extracellular L-cystine and intracellular L-glutamate at a 1:1 ratio across the cellular plasma membrane, that is involved in neural protection against cerebral degeneration or damage ( 158 – 160 ). This system is a member of the heteromeric amino acid transporter family (glycoprotein‐associated amino acid exchangers) consisting of a heterodimer formed by the transporter subunit or light chain xCT (SLC7A11) and a regulatory subunit or heavy chain 4F2hc (4F2 cell-surface antigen heavy chain, acronyms: CD98, rBAT, FRP1, slc3 family SLC3A2) covalently linked through a disulfide bond to xCT ( 161 ).…”