Impact of Oxidized Phospholipids on Outcomes from Cerebral Ischemia and Reperfusion Injury

TL;DR

This study shows that oxidized phospholipids contribute to brain damage after stroke and suggests targeting them could help treat stroke.

Contribution

The study identifies oxidized phospholipids as key players in stroke-induced brain injury and proposes them as novel therapeutic targets.

Findings

Oxidized phospholipids increase during cerebral ischemia and reperfusion injury in both cells and mice.

The E06 antibody protects against neuronal cell death and reduces inflammation by targeting oxidized phospholipids.

Nrf2-deficient mice show worse stroke outcomes, but E06 antibody mitigates these effects.

Abstract

Background/Objectives: The mechanisms leading to oxidative stress and cellular dysfunction during stroke are not well understood. Methods: We tested if transient cerebral artery occlusion (MCAo) in mice results in the generation of oxidized phospholipids (OxPLs) that contribute to neuronal cell death and glial activation. Results: Both in vitro and in vivo cerebral ischemia and reperfusion injury (IRI) resulted in the elevation of specific OxPLs. Neuronal cell death was determined in the presence of OxPLs and the natural OxPL E06 antibody (antioxidized phospholipid antibody) protected the cells from the toxic effects. IRI in mice gave rise to increased immunoreactivity of OxPLs in the brain. E06 reduced inflammatory markers in the brain following IRI, including iba-1, GFAP and inflammatory cytokines. In addition, OxPLs gave rise to M1 and Mox microglial phenotypes which was reversed in the presence of E06 and elicited a more M2 phenotype. Nrf2-deficient mice showed increased infarct volumes and microglia from Nrf2−/− mice showed a reduction in Mox gene expression, and E06 protects both mice and cells from the Nrf2-deficit. Finally, AB1-2 Ab which recognizes the E06 Ab, ameliorates the impact of E06 Ab on infarct volume in the mouse model. Conclusions: Taken together, the data indicate that OxPLs play an important role in inflammation and neuronal cell loss in cerebral IRI and inactivation of OxPLs may provide novel targets for potential drug targets in the treatment of stroke.

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