Lipoxygenase: an emerging target for stroke therapy - PubMed (original) (raw)

Review

Lipoxygenase: an emerging target for stroke therapy

Klaus van Leyen. CNS Neurol Disord Drug Targets. 2013 Mar.

Abstract

Neuroprotection as approach to stroke therapy has recently seen a revival of sorts, fueled in part by the continuing necessity to improve acute stroke care, and in part by the identification of novel drug targets. 12/15- Lipoxygenase (12/15-LOX), one of the key enzymes of the arachidonic acid cascade, contributes to both neuronal cell death and vascular injury. Inhibition of 12/15-LOX may thus provide multifactorial protection against ischemic injury. Targeting 12/15-LOX and related eicosanoid pathways is the subject of this brief review.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest

Support from the National Institutes of Health (R01NS049430 and R01NS069939) is gratefully acknowledged. A patent on the use of LOXBlock inhibitors to treat stroke has been applied for (U.S. Patent Application No.: 12/671,567).

Figures

Figure 1. Model for activation of 12/15-LOX in the ischemic brain

Under ischemic conditions, cPLA2 is activated to release arachidonic acid from membrane phospholipids. This free arachidonic acid, together with a calcium influx from the extracellular milieu and the depletion of glutathione, leads to activation of 12/15-LOX, which starts binding to and oxidizing mitochondrial and ER membranes. This permeabilizes the organelles, leading to release of calcium from ER stores and generation of ROS by mitochondria, which further activates 12/15-LOX. Mitochondria release the pro-apoptotic proteins cytochrome c and AIF, which then translocates to the nucleus. Abbreviations: AA, arachidonic acid; Cyt., cytochrome; AIF, apoptosis-inducing factor; ROS, reactive oxygen species.

References

1. Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, Diener HC, Ashwood T, Wasiewski WW, Emeribe U. NXY-059 for the treatment of acute ischemic stroke. N Engl J Med. 2007;357:562–71. - PubMed
1. Moskowitz MA, Lo EH, Iadecola C. The science of stroke: mechanisms in search of treatments. Neuron. 2010;67:181–98. - PMC - PubMed
1. Zlokovic BV, Griffin JH. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci. 2011;34:198–209. - PMC - PubMed
1. Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron. 2011;71:406–24. - PubMed
1. Lau A, Tymianski M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch. 2010;460:525–42. - PubMed

Lipoxygenase: an emerging target for stroke therapy - PubMed (original) (raw)