Lipoxygenase: An Emerging Target for Stroke Therapy

Leyen, Klaus van

doi:10.2174/18715273112119990053

Cited by 40 publications

(32 citation statements)

References 124 publications

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“…[4][5][6] Inhibition of 12/15-LOX reduces infarct size, edema, and blood-brain barrier leakage, and is being investigated as a novel approach to stroke therapy. 3,[5][6][7][8] One of the key regulators of this redox homeostatic network, along with the hypoxia-inducible factors, is the Signal Transducers and Activators of Transcription (STAT) family of proteins. 9 Phosphorylation at specific tyrosine residues and subsequent dimerization is required for STAT activation; the dimers then translocate to the nucleus, where they bind to their target gene's promoter region.…”

Section: Introductionmentioning

confidence: 99%

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Jung

Karataş

Liu

et al. 2015

J Cereb Blood Flow Metab

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Oxidative stress is a major brain injury mechanism after ischemic stroke. 12/15-lipoxygenase (12/15-LOX) is a key mediator of oxidative stress, contributing to neuronal cell death and vascular leakage. Nonetheless, the mechanism leading to its upregulation is currently unknown. We show here that Signal Transducers and Activators of Transcription (STATs), specifically STAT6 and possibly STAT1, increase transcription of 12/15-LOX in neuronal cells. Both p-STAT6 and -1 bound to specific STAT binding sites in the mouse 12/15-LOX promoter. Small interfering RNA (siRNA) knockdown showed STAT6 to be the dominant regulator, reducing 12/15-LOX promoter activation and cell death in oxidatively stressed HT22 cells. STAT6 siRNA efficiently prevented the increase of 12/15-LOX in murine primary neurons, both after induction of oxidative stress and after oxygen-glucose deprivation. Early activation of STAT6 and STAT1 in mice was consistent with a role in regulating 12/15-LOX in focal ischemia. Brains of human stroke patients showed increased p-STAT6 and p-STAT1 in the peri-infarct region, along with 12/15-LOX and markers of apoptosis. These results link STAT6 and STAT1 to the 12/15-LOX damage pathway and suggest disregulation of STAT-dependent transcription as injury mechanism in stroke. Selectively targeting STATs may thus be a novel therapeutic approach to reducing brain injury after a stroke.

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Section: Introductionmentioning

confidence: 99%

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

Jung

Karataş

Liu

et al. 2015

J Cereb Blood Flow Metab

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“…The activity of m12/15-LOX is increased in the mouse brain following ischemic induction and m12/15-LOX co-localizes with a marker for oxidized lipids, MDA2. 4 In addition, a similar co-localization was detected in the brain of human stroke patients, as well as increased levels of apoptosis-inducing factor, AIF. 4,6 Finally, animal studies by van Leyen et al demonstrated a 40% reduction of infarct size in a m12/15-LOX knockout (K/O) mouse relative to wild-type (WT).…”

Section: 1 Introductionmentioning

confidence: 70%

“…4 In addition, a similar co-localization was detected in the brain of human stroke patients, as well as increased levels of apoptosis-inducing factor, AIF. 4,6 Finally, animal studies by van Leyen et al demonstrated a 40% reduction of infarct size in a m12/15-LOX knockout (K/O) mouse relative to wild-type (WT). 9 These data strongly suggest that h12/15-LOX is involved in stroke and might be an attractive therapeutic target.…”

Section: 1 Introductionmentioning

confidence: 70%

“…3 Human reticulocyte 12/15-LOX (h12/15-LOX and/or h15-LOX-1), encoded by the ALOX15 gene, preferentially reacts with free polyunsaturated fatty acids (PUFAs) but also can directly oxidize lipid membranes containing PUFAs. 3,4,5 These oxidized lipids within the lipid bilayer lead to the formation of hydrophilic pores, which affect the barrier function of the membrane and thus lead to cellular dysfunction, particularly in stroke. 6 …”

Section: 1 Introductionmentioning

confidence: 99%

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A potent and selective inhibitor targeting human and murine 12/15-LOX

Armstrong

Freedman

Jung

et al. 2016

Bioorganic & Medicinal Chemistry

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Human reticulocyte 12/15-Lipoxygenase (h12/15-LOX) is a lipid-oxidizing enzyme that can directly oxidize lipid membranes in the absence of a phospholipase, leading to a direct attack on organelles, such as the mitochondria. This cytotoxic activity of h12/15-LOX is up-regulated in neurons and endothelial cells after a stroke and thought to contribute to both neuronal cell death and blood-brain barrier leakage. The discovery of inhibitors that selectively target recombinant h12/15-LOX in vitro, as well as possessing activity against the murine ortholog ex vivo, could potentially support a novel therapeutic strategy for the treatment of stroke. Herein, we report a new family of inhibitors discovered in a High Throughput Screen (HTS) that are selective and potent against recombinant h12/15-LOX and cellular mouse 12/15-LOX (m12/15-LOX). MLS000099089 (compound 99089), the parent molecule, exhibits an IC50 potency of 3.4 ± 0.5 µM against h12/15-LOX in vitro and an ex vivo IC50 potency of approximately 10 µM in a mouse neuronal cell line, HT-22. Compound 99089 displays greater than 30-fold selectivity versus h5-LOX and COX-2, 15-fold versus h15-LOX-2 and 10-fold versus h12-LOX, when tested at 20 µM inhibitor concentration. Steady-state inhibition kinetics reveals that the mode of inhibition of 99089 against h12/15-LOX is that of a mixed inhibitor with a Kic of 1.0 ± 0.08 µM and a Kiu of 6.0 ± 3.3 µM. These data indicate that 99089 and related derivatives may serve as a starting point for the development of anti-stroke therapeutics due to their ability to selectively target h12/15-LOX in vitro and m12/15-LOX ex vivo.

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“…[10] Moreover, it has been shown that 15-LOX-1 is upregulated in mice following a stroke and the ensuing ischemia. [11] In addition, 15-LOX-1 has been linked to airway inflammation diseases[12–16] such as asthma, chronic obstructive pulmonary disease (COPD) and chronic bronchitis, and more recently in various CNS diseases[11,17–25] like Alzheimer’s and Parkinson’s diseases as well as stroke. Recent evidence shows that 15-LOX-1 plays conserved roles in the molecular mechanisms contributing to the pathophysiology of these diseases.…”

Section: Introductionmentioning

confidence: 99%

Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

Eleftheriadis

Poelman

Leus

et al. 2016

European Journal of Medicinal Chemistry

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The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented fragment Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.

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Lipoxygenase: An Emerging Target for Stroke Therapy

Cited by 40 publications

References 124 publications

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

STAT-Dependent Upregulation of 12/15-Lipoxygenase Contributes to Neuronal Injury after Stroke

A potent and selective inhibitor targeting human and murine 12/15-LOX

Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

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