Citation

Yigitkanli K, Zheng Y, Pekcec A, Lo EH, van Leyen K. Transl. Stroke Res. 2016; 8(2): 194-202.

Affiliation

Neuroprotection Research Laboratory, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 149 13th St., R. 2401, Charlestown, MA, 02129, USA. klaus_vanleyen@hms.harvard.edu.

Copyright

(Copyright © 2016, Holtzbrinck Springer Nature Publishing Group)

DOI

10.1007/s12975-016-0509-z

PMID

27838820

Abstract

Global ischemia following cardiac arrest is characterized by high mortality and significant neurological deficits in long-term survivors. Its mechanisms of neuronal cell death have only partially been elucidated. 12/15-lipoxygenase (12/15-LOX) is a major contributor to delayed neuronal cell death and vascular injury in experimental stroke, but a possible role in brain injury following global ischemia has to date not been investigated. Using a mouse bilateral occlusion model of transient global ischemia which produced surprisingly widespread injury to cortex, striatum, and hippocampus, we show here that 12/15-LOX is increased in a time-dependent manner in the vasculature and neurons of both cortex and hippocampus. Furthermore, 12/15-LOX co-localized with apoptosis-inducing factor (AIF), a mediator of non-caspase-related apoptosis in the cortex. In contrast, caspase-3 activation was more prevalent in the hippocampus. 12/15-lipoxygenase knockout mice were protected against global cerebral ischemia compared to wild-type mice, accompanied by reduced neurologic impairment. The lipoxygenase inhibitor LOXBlock-1 similarly reduced neuronal cell death both when pre-administered and when given at a therapeutically relevant time point 1 h after onset of ischemia. These findings suggest a pivotal role for 12/15-LOX in both caspase-dependent and caspase-independent apoptotic pathways following global cerebral ischemia and suggest a novel therapeutic approach to reduce brain injury following cardiac arrest.

Language: en