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Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia

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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.

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Acknowledgements

Support through grants from the US National Institutes of Health (NIH R01NS049430, R01NS069939, and R21NS087165 to K.v.L.) is gratefully acknowledged.

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Author notes

  1. Kazim Yigitkanli

    Present address: Neurosurgery Clinic, Polatli Government Hospital, Ankara, Turkey

  2. Anton Pekcec

    Present address: Boehringer Ingelheim Pharma GmbH & Co. KG, Div. Research Germany, Birkendorfer Strasse 65, 88397, Biberach an der Riss, Germany

Authors and Affiliations

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

    Kazim Yigitkanli, Yi Zheng, Anton Pekcec, Eng H. Lo & Klaus van Leyen

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  1. Kazim Yigitkanli
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Correspondence to Klaus van Leyen.

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Yigitkanli, K., Zheng, Y., Pekcec, A. et al. Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia. Transl. Stroke Res. 8, 194–202 (2017). https://doi.org/10.1007/s12975-016-0509-z

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  • DOI: https://doi.org/10.1007/s12975-016-0509-z

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