title: Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia.
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.
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 149 13th St., R. 2401, Charlestown, MA, 02129, USA.|Neurosurgery Clinic, Polatli Government Hospital, Ankara, Turkey.
authors.forename: Kazim
authors.initials: K
authors.lastname: Yigitkanli
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 149 13th St., R. 2401, Charlestown, MA, 02129, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 149 13th St., R. 2401, Charlestown, MA, 02129, USA.|Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research Germany, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany.
authors.forename: Anton
authors.initials: A
authors.lastname: Pekcec
authors.affiliation: Neuroprotection Research Laboratory, Department of Radiology, Harvard Medical School, Massachusetts General Hospital, 149 13th St., R. 2401, Charlestown, MA, 02129, USA.
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.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.
authors.forename: Klaus
authors.initials: K
authors.lastname: van Leyen
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism; D003342:Corpus Striatum / Q000293:injuries / Q000378:metabolism; D006624:Hippocampus / Q000293:injuries / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: Apoptosis; Cardiac arrest; Cortex; Global cerebral ischemia; Hippocampus; Lipoxygenase