5-HPETE Is a Potent Inhibitor of Neuronal Na+, K+-ATPase Activity

Foley, Timothy D.

doi:10.1006/bbrc.1997.6790

Cited by 28 publications

(14 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…45 Indeed, LOX metabolites were found to be synthesized in both neurons and glial cells. 21,[46][47][48] Some of them, such as 5-and 12-hydroxyeicosatetraenoic acids, have been reported to exert various actions on neurons, including modulation of Na-K ATPase activity, 49 neurotransmitter release 50 or alteration of membrane potential. 51,52 LOXs also act as regulators of cell proliferation and death, and have been implied in the mediation of apoptosis induced by various physical or chemical agents such as UV light, oxidative stress or receptor ligands 25,26 In contrast, only a small number of studies investigated the involvement of LOXs in the various signaling pathways leading to neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

View full text Add to dashboard Cite

The cyclo-oxygenase (COX) and lipoxygenase (LOX) pathways belong to the eicosanoid synthesis pathway, a major component of the chronic inflammatory process occurring in Alzheimer's disease (AD). Clinical studies reported beneficial effects of COX inhibitors, but little is known about the involvement of LOXs in AD pathogenesis. b-amyloid peptide (Ab) accumulation contributes to neurodegeneration in AD, but mechanisms underlying Ab toxicity have not been fully elucidated yet. Here, using an antisense oligonucleotide-based strategy, we show that blockade of 12-LOX expression prevents both Ab-induced apoptosis and overexpression of c-Jun, a factor required for the apoptotic process, in cortical neurons. Conversely, the 12-LOX metabolite, 12(S)-HETE (12(S)-hydroxy-(5Z, 8Z, 10E, 14Z)-eicosatetraenoic acid), promoted c-Jun-dependent apoptosis. Specificity of the 12-LOX involvement was further supported by the observed lack of contribution of 5-LOX in this process. These data indicate that blockade of 12-LOX expression disrupts a c-Jun-dependent apoptosis pathway, and suggest that 12-LOX may represent a new target for the treatment of AD.

show abstract

Section: Discussionmentioning

confidence: 99%

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

et al. 2004

View full text Add to dashboard Cite

show abstract

“…5-LOX activity leads to conversion of arachidonic acid into 5-HPETE and leukotrienes, and MK-886 disrupts this process by inhibiting the 5-lipoxygenase-activating protein (FLAP) [9]. 5-HPETE is a potent inhibitor of neuronal Na + , K + -ATPase activity [10] and it remains to be clarified whether MK-886 treatment and/or 5-LOX gene disruption alter Na + , K + -ATPase activity in brain regions involved in antidepressant effects. On the other hand, leukotrienes act through specific leukotriene receptors, some of which are expressed in the brain [6,29].…”

Section: Nih Public Accessmentioning

confidence: 99%

Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice

Dimitrijević

Imbesi

et al. 2008

Neuroscience Letters

View full text Add to dashboard Cite

A common biological pathway may contribute to the comorbidity of atherosclerosis and depression. Increased activity of the enzymatic 5-lipoxygenase (5-LOX; 5LO) pathway is a contributing factor in atherosclerosis and a 5-LOX inhibitor, MK-886, is beneficial in animal models of atherosclerosis. In the brain, MK-886 increases phosphorylation of the glutamate receptor subunit GluR1, and the increased phosphorylation of this receptor has been associated with antidepressant treatment. In this work, we evaluated the behavioral effects of MK-886 in an automated assay of mouse forced swimming, which identifies antidepressant activity as increased climbing behavior and/or decreased rest time. Whereas a single injection of MK-886 (3 and 10 mg/kg) did not affect forced swimming behaviors assayed 30 min later, 6 daily injections of 3 mg/kg MK-886 slightly increased climbing and significantly reduced rest time in wild-type mice but not in 5-LOX-deficient mice. A diet delivery of MK-886, 4 μg per 100 mg body-weight per day, required three weeks to affect forced swimming; it increased climbing behavior. Climbing behavior was also increased in naive 5-LOX-deficient mice compared to naive wild-type controls. These results suggest that 5-LOX inhibition and deficiency may be associated with antidepressant activity. Increased climbing in a forced swimming assay is a typical outcome of antidepressants that increase noradrenergic and dopaminergic activity. Interestingly, 5-LOX deficiency and MK-886 treatment have been shown to be capable of increasing the behavioral effects of a noradrenaline/dopamine-potentiating drug, cocaine. Future research is needed to evaluate the clinical relevance of our findings.Keywords 5-lipoxygenase (5-LOX, 5LO); antidepressant; depression; atherosclerosis; GluR1 cardiovascular Recent studies pointed out an association between depressive symptoms and the progression of atherosclerosis [7,26]. It was proposed that a common biological mechanism contributes to triggering and/or maintenance of these two pathological conditions [19].A prominent role in the pathobiology of atherosclerosis is played by 5-lipoxygenase (5-LOX; 5LO), an enzyme involved in the metabolism of arachidonic acid in 5(S)-hydroperoxy-6-trans-8,11,14-cis-eicosatetraenoic acid (5-HPETE) and leukotrienes [16,25]. Whereas an Correspondence: Radmila Manev, MD, Department of Psychiatry, Heart and Mind Clinic, University of Illinois at Chicago, 1601 West Taylor Street, MC912, Chicago, IL 60612, USA, e-mail: Rmanev@psych.uic.edu; phone: 312-413-3970; fax: 312-413-4569. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the...

show abstract

“…In addition, there is a small literature on the neuroprotective and anti-inflammatory role of selected arachidonic acid metabolites. These include endocannabinoids (anandamide and 2-arachidonyl glycerol [24,60]), energy modulation (hydroperoxyeicosatetraenoic acid [31]), anti-inflammatory effects (11,12-epoxyeicosatrienoic acid [EET] [66]), lipoxygenasemediated analgesia (19,61), and circadian modulation (100). The formation of these metabolites may be favored when the COX2 pathway is blocked.…”

mentioning

confidence: 99%

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Gopez¹,

Yue²,

Vasudevan³

et al. 2005

Neurosurgery

104

View full text Add to dashboard Cite

OBJECTIVE-Increases in brain cyclooxygenase-2 (COX2) are associated with the central inflammatory response and with delayed neuronal death, events that cause secondary insults after traumatic brain injury. A growing literature supports the benefit of COX2-specific inhibitors in treating brain injuries. [5,5-dimethyl-3(3-fluorophenyl)-4(4-methylsulfonyl)phenyl-2( 5 H)-furanone] is a third-generation, highly specific COX2 enzyme inhibitor. DFU treatments (1 or 10 mg/kg intraperitoneally, twice daily for 3 d) were initiated either before or after traumatic brain injury in a lateral cortical contusion rat model. METHODS-DFU NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript RESULTS-DFU treatments initiated 10 minutes before injury or up to 6 hours after injury enhanced functional recovery at 3 days compared with vehicle-treated controls. Significant improvements in neurological reflexes and memory were observed. DFU initiated 10 minutes before injury improved histopathology and altered eicosanoid profiles in the brain. DFU 1 mg/kg reduced the rise in prostaglandin E 2 in the brain at 24 hours after injury. DFU 10 mg/kg attenuated injuryinduced COX2 immunoreactivity in the cortex (24 and 72 h) and hippocampus (6 and 72 h). This treatment also decreased the total number of activated caspase-3-immunoreactive cells in the injured cortex and hippocampus, significantly reducing the number of activated caspase-3-immunoreactive neurons at 72 hours after injury. DFU 1 mg/kg amplified potentially anti-inflammatory epoxyeicosatrienoic acid levels by more than fourfold in the injured brain. DFU 10 mg/kg protected the levels of 2-arachidonoyl glycerol, a neuro-protective endocannabinoid, in the injured brain.CONCLUSION-These improvements, particularly when treatment began up to 6 hours after injury, suggest exciting neuroprotective potential for COX2 inhibitors in the treatment of traumatic brain injury and support the consideration of Phase I/II clinical trials.Keywords 2-Arachidonoyl glycerol; Caspase-3; COX2 inhibitor; Eicosanoids; Endocannabinoid; Neuroinflammation; Rat behavior Traumatic brain injury (TBI) initiates a central inflammatory response that results in the increased production of prostaglandins and reactive oxygen species. These products may cause secondary insults to the brain (55,90,94). Cyclooxygenases catalyze the first step in the formation of prostaglandins from arachidonic acid, producing reactive oxygen species in the process. Cyclooxygenase-1 (COX1), present normally in most tissues, is thought to maintain essential physiological functions, such as gastric mucosal integrity, renal function, and platelet homeostasis (87,101). COX2, the inducible isoform, is expressed in the normal brain (30,87) but is rare or absent in most organs under normal conditions. As in the periphery (32,79), COX2 in the brain can be regulated by inflammatory cytokines (87), and prostaglandin production increases in response to pathological conditions of the central nervous system (3,70,72,89,107). ...

show abstract

5-HPETE Is a Potent Inhibitor of Neuronal Na+, K+-ATPase Activity

Cited by 28 publications

References 19 publications

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Blockade of 12-lipoxygenase expression protects cortical neurons from apoptosis induced by β-amyloid peptide

Effects of MK-886, a 5-lipoxygenase activating protein (FLAP) inhibitor, and 5-lipoxygenase deficiency on the forced swimming behavior of mice

Cyclooxygenase-2-specific Inhibitor Improves Functional Outcomes, Provides Neuroprotection, and Reduces Inflammation in a Rat Model of Traumatic Brain Injury

Contact Info

Product

Resources

About