Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland

ZHANG, Hongjian; Akbar, Mohammed; Kim, Hee‐Yong

doi:10.1042/0264-6021:3440487

Cited by 16 publications

(10 citation statements)

References 33 publications

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“…Interestingly, several compounds known to reduce edema in animal models of ischemia are also known lipoxygenase inhibitors: the enzyme glutathione peroxidase when overexpressed in mice26,27 as well as small molecule compounds like edaravone,28 melatonin,29,30 curcumin,31 AA-861,32,33 and green tea polyphenols like epigallocatechin gallate 34,35. Furthermore, some compounds may protect indirectly, in part by reducing lipid peroxidation, which prevents the activation of 12/15-LOX 36.…”

Section: Discussionmentioning

confidence: 99%

Protecting Against Cerebrovascular Injury

Jin

Arai

Murata

et al. 2008

Stroke

138

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Background and Purpose-The concept of the neurovascular unit suggests that effects on brain vasculature must be considered if neuroprotection is to be achieved in stroke. We previously reported that 12/15-lipoxygenase (12/15-LOX) is upregulated in the peri-infarct area after middle cerebral artery occlusion in mice, and 12/15-LOX contributes to brain damage after ischemia-reperfusion. The current study was designed to investigate 12/15-LOX involvement in vascular injury in the ischemic brain. Methods-In cell culture, a human brain microvascular endothelial cell line was subjected to either hypoxia or H 2 O 2 -induced oxidative stress with or without lipoxygenase inhibitors. For in vivo studies, mice were subjected to 90 minutes middle cerebral artery occlusion, and the effects of either 12/15-LOX gene knockout or treatment with lipoxygenase inhibitors were compared. Expression of 12/15-LOX and claudin-5 as well as extravasation of immunoglobulin G were detected by immunohistochemistry. Edema was measured as water content of brain hemispheres according to the wet-dry weight method. Results-Brain endothelial cells were protected against hypoxia and H 2 O 2 by the lipoxygenase inhibitor baicalein. After focal ischemia, 12/15-LOX was increased in neurons and endothelial cells. The vascular tight junction protein claudin-5 underwent extensive degradation in the peri-infarct area, which was partially prevented by the lipoxygenase inhibitor baicalein. Leakage of immunoglobulin G into the brain parenchyma was significantly reduced in 12/15-LOX knockout mice as well as wild-type mice treated with baicalein. Likewise, brain edema was significantly ameliorated. Conclusion-12/15-LOX may contribute to ischemic brain damage not just by causing neuronal cell death, but also by detrimental effects on the brain microvasculature. 12/15-LOX inhibitors may thus be effective as both neuroprotectants and vasculoprotectants.

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Section: Discussionmentioning

confidence: 99%

Protecting Against Cerebrovascular Injury

Jin

Arai

Murata

et al. 2008

Stroke

138

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“…This is not to deny the existence of LO in the capillary beds in the brain, because Moore et al (87) demonstrated 12-S-LO activity in a microvessel fraction. Also, Sawazaki et al (82) found a 12-LO product of AA and DHA in the rat pineal gland and Zhang et al (88) subsequently observed that the formation of these products is regulated by the light-dark cycle and melatonin through the modulation of both 12-LO (88) and cytosolic phopholipase A 2 expression (89). They also reported that n-3 fatty acid deficiency had profound effects not only on the pineal lipid profile but also on pineal biochemical activity, resulting in significantly fewer LO products (90).…”

Section: Mechanisms Of Action Of Dhamentioning

confidence: 99%

Mechanisms of action of docosahexaenoic acid in the nervous system

Salem

Litman

Kim

et al. 2001

Lipids

Self Cite

825

508

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This review describes (from both the animal and human literature) the biological consequences of losses in nervous system docosahexaenoate (DHA). It then concentrates on biological mechanisms that may serve to explain changes in brain and retinal function. Brief consideration is given to actions of DHA as a nonesterified fatty acid and as a docosanoid or other bioactive molecule. The role of DHA-phospholipids in regulating G-protein signaling is presented in the context of studies with rhodopsin. It is clear that the visual pigment responds to the degree of unsaturation of the membrane lipids. At the cell biological level, DHA is shown to have a protective role in a cell culture model of apoptosis in relation to its effects in increasing cellular phosphatidylserine (PS); also, the loss of DHA leads to a loss in PS. Thus, through its effects on PS, DHA may play an important role in the regulation of cell signaling and in cell proliferation. Finally, progress has been made recently in nuclear magnetic resonance studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation.Paper no. L8776 in Lipids 36, 945-959 (September 2001)

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“…It downregulates prooxidant enzymes, in particular 5- and 12-lipoxygenases [112,126-128] and NO synthases [9,34,77,108,112,129-134]. The widely observed attenuation of NO formation is particularly important in terms of limiting rise in the strongly prooxidant metabolite peroxynitrite and of the free radicals derived from this compound, namely, •NO 2 , carbonate (CO 3 • - ) and hydroxyl (•OH) radicals.…”

Section: Multiple Levels Of Antioxidative Protection By Melatoninmentioning

confidence: 99%

Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug

2005

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Melatonin, originally discovered as a hormone of the pineal gland, is also produced in other organs and represents, additionally, a normal food constituent found in yeast and plant material, which can influence the level in the circulation. Compared to the pineal, the gastrointestinal tract contains several hundred times more melatonin, which can be released into the blood in response to food intake and stimuli by nutrients, especially tryptophan. Apart from its use as a commercial food additive, supraphysiological doses have been applied in medical trials and pure preparations are well tolerated by patients. Owing to its amphiphilicity, melatonin can enter any body fluid, cell or cell compartment. Its properties as an antioxidant agent are based on several, highly diverse effects. Apart from direct radical scavenging, it plays a role in upregulation of antioxidant and downregulation of prooxidant enzymes, and damage by free radicals can be reduced by its antiexcitatory actions, and presumably by contributions to appropriate internal circadian phasing, and by its improvement of mitochondrial metabolism, in terms of avoiding electron leakage and enhancing complex I and complex IV activities. Melatonin was shown to potentiate effects of other antioxidants, such as ascorbate and Trolox. Under physiological conditions, direct radical scavenging may only contribute to a minor extent to overall radical detoxification, although melatonin can eliminate several of them in scavenger cascades and potentiates the efficacy of antioxidant vitamins. Melatonin oxidation seems rather important for the production of other biologically active metabolites such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), which have been shown to also dispose of protective properties. Thus, melatonin may be regarded as a prodrug, too. AMK interacts with reactive oxygen and nitrogen species, conveys protection to mitochondria, inhibits and downregulates cyclooxygenase 2.

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Melatonin: an endogenous negative modulator of 12-lipoxygenation in the rat pineal gland

Cited by 16 publications

References 33 publications

Protecting Against Cerebrovascular Injury

Protecting Against Cerebrovascular Injury

Mechanisms of action of docosahexaenoic acid in the nervous system

Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug

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