Lipoxygenases and cyclooxygenases are among the oxidative enzymes that contribute to the generation of reactive oxygen species (ROS) after stroke. While the cyclooxygenases COX-1 and COX-2 have been and are continuing to be extensively studied, little data is available on the contribution of lipoxygenases to ischemic brain cell death. Our preliminary results have shown that levels of 12-LOX, the major lipoxygenase isoform in mouse and rat brain, are elevated in a mouse model of focal ischemia, predominantly in neuronal cells of the cortex. 12-LOX knockout mice show significantly reduced infarction sizes, a finding that seems to be mimicked by treatment of wild-type mice with a 12-LOX inhibitor. In both rat primary neurons and a murine hippocampal cell line, we have confirmed and extended the findings of others that 12-LOX mediates oxidative stress-induced cell death, and neurons prepared from the 12-LOX knockout mice show enhanced resistance to this form of oxidative stress. We thus propose the following Specific Aims: 1. To investigate 12-LOX upregulation and changes in activity in mouse brain after ischemia with various times of reoxyenation and to correlate increased 12-LOX levels with the extent of brain damage; 2. To study the mechanisms by which 12-LOX contributes to the death of cultured neuronal cells, and to elucidate the degradative machinery responsible for executing cell death downstream of 12-LOX action; 3. To determine the consequences of inactivating 12-LOX by either genetic or pharmacological means on brain damage after focal ischemia in the mouse. With the knowledge gained from these studies we seek to establish 12-LOX as a novel therapeutic target in the treatment of stroke. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS049430-03
Application #
7225210
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Golanov, Eugene V
Project Start
2005-04-01
Project End
2010-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
3
Fiscal Year
2007
Total Cost
$335,478
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Maher, Pamela; van Leyen, Klaus; Dey, Partha Narayan et al. (2018) The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium 70:47-55
Karatas, H; Eun Jung, Joo; Lo, E H et al. (2018) Inhibiting 12/15-lipoxygenase to treat acute stroke in permanent and tPA induced thrombolysis models. Brain Res 1678:123-128
Liu, Yu; Zheng, Yi; Karatas, Hulya et al. (2017) 12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke. Stroke 48:445-451
Yigitkanli, Kazim; Zheng, Yi; Pekcec, Anton et al. (2017) Increased 12/15-Lipoxygenase Leads to Widespread Brain Injury Following Global Cerebral Ischemia. Transl Stroke Res 8:194-202
Jung, Joo Eun; Karatas, Hulya; Liu, Yu et al. (2015) STAT-dependent upregulation of 12/15-lipoxygenase contributes to neuronal injury after stroke. J Cereb Blood Flow Metab 35:2043-51
Kuhn, Hartmut; Banthiya, Swathi; van Leyen, Klaus (2015) Mammalian lipoxygenases and their biological relevance. Biochim Biophys Acta 1851:308-30
van Leyen, Klaus; Holman, Theodore R; Maloney, David J (2014) The potential of 12/15-lipoxygenase inhibitors in stroke therapy. Future Med Chem 6:1853-5
Liu, Q; Qiu, J; Liang, M et al. (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5:e1084
Rai, Ganesha; Joshi, Netra; Jung, Joo Eun et al. (2014) Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies. J Med Chem 57:4035-48
Schaefer, Jan Hendrik; Leung, Wendy; Wu, Limin et al. (2014) Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation. J Cereb Blood Flow Metab 34:870-5

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