Docosahexaenoic acid may act as a neuroprotector for methylmercury-induced neurotoxicity in primary neural cell cultures

Kaur, Parvinder; Heggland, Ingrid; Aschner, Michael; Syversen, Tore

doi:10.1016/j.neuro.2008.06.004

Cited by 41 publications

(23 citation statements)

References 87 publications

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“…Selenium and the omega-3 fatty acids, which are essential nutrients, have been shown to confer protection against MeHg toxicity (Kaur et al 2007, 2008; Nishikido et al 1987; Rice 2008; Strain et al 2008). However, selenium has no ability to reduce MeHg accumulation in the body (Newland et al 2006; Urano et al 1997).…”

Section: Discussionmentioning

confidence: 99%

“…However, selenium has no ability to reduce MeHg accumulation in the body (Newland et al 2006; Urano et al 1997). Docosahexaenoic acid, an omega-3 fatty acid, has also been shown to decrease MeHg accumulation in several cell lines; however, the precise mechanism of this effect is not known (Kaur et al 2007, 2008). In the present study, we demonstrated that ITCs such as 6-HITC and SFN are potentially useful chemopreventive agents for MeHg accumulation and toxicity and that they exert their action through an Nrf2-dependent mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Isothiocyanates Reduce Mercury Accumulation via an Nrf2-Dependent Mechanism during Exposure of Mice to Methylmercury

Toyama

Shinkai

Yasutake

et al. 2011

Environ Health Perspect

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Background: Methylmercury (MeHg) exhibits neurotoxicity through accumulation in the brain. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays an important role in reducing the cellular accumulation of MeHg.Objectives: We investigated the protective effect of isothiocyanates, which are known to activate Nrf2, on the accumulation of mercury after exposure to MeHg in vitro and in vivo.Methods: We used primary mouse hepatocytes in in vitro experiments and mice as an in vivo model. We used Western blotting, luciferase assays, atomic absorption spectrometry assays, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assays, and we identified toxicity in mice based on hind-limb flaccidity and mortality.Results: The isothiocyanates 6-methylsulfinylhexyl isothiocyanate (6-HITC) and sulforaphane (SFN) activated Nrf2 and up-regulated downstream proteins associated with MeHg excretion, such as glutamate-cysteine ligase, glutathione S-transferase, and multidrug resistance–associated protein, in primary mouse hepatocytes. Under these conditions, intracellular glutathione levels increased in wild-type but not Nrf2-deficient primary mouse hepatocytes. Pretreatment with 6-HITC and SFN before MeHg exposure suppressed cellular accumulation of mercury and cytotoxicity in wild-type but not Nrf2-deficient primary mouse hepatocytes. In comparison, in vivo administration of MeHg to Nrf2-deficient mice resulted in increased sensitivity to mercury concomitant with an increase in mercury accumulation in the brain and liver. Injection of SFN before administration of MeHg resulted in a decrease in mercury accumulation in the brain and liver of wild-type, but not Nrf2-deficient, mice.Conclusions: Through activation of Nrf2, 6-HITC and SFN can suppress mercury accumulation and intoxication caused by MeHg intake.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Isothiocyanates Reduce Mercury Accumulation via an Nrf2-Dependent Mechanism during Exposure of Mice to Methylmercury

Toyama

Shinkai

Yasutake

et al. 2011

Environ Health Perspect

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“…DHA demonstrated neuroprotective roles against oxidative stress through its ability to scavenge intracellular free radical productions that were induced by hydrogen peroxide, superoxide anions, and hydroxyl radicals in cultured retinal ganglion cells [64–67]. …”

Section: Docosahexaenoic Acid (Dha) and Neuroprotectionmentioning

confidence: 99%

ER Stress and Effects of DHA as an ER Stress Inhibitor

Begum

Harvey

Dixon

et al. 2013

Transl. Stroke Res.

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The endoplasmic reticulum (ER) functions in the synthesis, folding, modification, and transport of newly synthesized transmembrane and secretory proteins. The ER also has important roles in the storage of intracellular Ca2+ and regulation of Ca2+ homeostasis. The integrity of the Ca2+ homeostasis in the ER lumen is vital for proper folding of proteins. A dysregulation of ER Ca2+ could result in an increase in unfolded or misfolded proteins and ER stress. ER stress triggers activation of the unfolded protein response (UPR), which is a fundamentally adaptive cell response and functions as a cytoprotective mechanism by over-expression of relevant chaperones and the global shutdown of protein synthesis. UPR activation occurs when three key ER membrane-sensor proteins detect an accumulation of aberrant proteins. The UPR acts to allievate ER stress, but if the stress is too severe or prolonged, apoptosis will be triggered. In this review, we focused on ER stress and the effects of docosahexaenoic acid (DHA) on ER stress. DHA and its bioactive compounds, such as protectins and resolvins, provide neuroprotection against oxidative stress, apoptosis, and have the ability to resolve inflammation in neurological diseases. New studies reveal that DHA blocks inositol trisphosphate receptor (IP3R)-mediated ER Ca2+ depletion and ER stress. The administration of DHA post-traumatic brain injury (TBI) reduces ER stress, aberrant protein accumulation, and neurological deficits. Therefore, DHA presents therapeutic potentials for TBI via its pleiotropic effects including inhibition of ER stress.

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“…Astrocytes are in close contact with neurons and readily release DHA into the extracellular fluid under basal and stimulated conditions, thus providing a source for neuronal DHA 21,22 . Considering astroglia support neurons by providing neurotrophic factors, the supply of DHA by astrocytes can also be trophic 23 . DHA is an especially promising therapeutic or preventive intervention because it may simultaneously exert beneficial effects on several of the injury cascades contributing to perinatal brain injury, including free radicals, inflammatory cytokines, bioactive lipid mediators, and apoptosis 21,[24][25][26] .…”

Section: Research Articlementioning

confidence: 99%

“…Authors have suggested that DHA may play an important role in antioxidative defence mechanism by enhancing the cerebral activities of CAT, GPx and glutathione. Afterward, many studies were reported that DHA increase the antioxidant enzyme activities including SOD, CAT and GPx in the different cell lines such as retinal ganglion cells, cerebellar astrocytes and neurons cells 23,25,26 . In an ischemia-reperfusion animal model study, Bas et al (2007) have reported that DHA increases SOD activity in rat hippocampus 24 .…”

mentioning

confidence: 99%