Trans‐4‐hydroxy‐2‐hexenal is a neurotoxic product of docosahexaenoic (22:6; n‐3) acid oxidation

Abstract

Lipid peroxidation of docosahexaenoic (22:6; n‐3) acid (DHA) is elevated in the CNS in patients with Alzheimer’s disease and in animal models of seizure and ethanol withdrawal. One product of DHA oxidation is trans‐4‐hydroxy‐2‐hexenal (HHE), a six carbon analog of the n‐6 fatty acid derived trans‐4‐hydroxy‐2‐nonenal (HNE). In this work, we studied the neurotoxic potential of HHE. HHE and HNE were toxic to primary cultures of cerebral cortical neurons with LD50’s of 23 and 18 μmol/L, respectively. Toxicity was prevented by the addition of thiol scavengers. HHE and HNE depleted neuronal GSH content identically with depletion observed with 10 μmol/L of either compound. Using an antibody raised against HHE–protein adducts, we show that HHE modified specific proteins of 75, 50, and 45 kDa in concentration‐ and time‐dependent manners. The time‐dependent formation of HHE differed from that of F4‐neuroprostanes following in vitro DHA oxidation likely as a result of the different oxidation pathways involved. Using purified mitochondrial aldehyde dehydrogenase ALDH5A, we found that HHE was oxidized 6.5‐fold less efficiently than HNE. Our data demonstrate that HHE and HNE have similarities but also differences in their neurotoxic mechanisms and metabolism.

Immunohistochemical Detection of Polyunsaturated Fatty Acid Oxidation Markers in Acetaminophen-Induced Liver Injury in Rats

“…Kristal et al [25] demonstrated that 4-HHE-induced mitochondrial permeability transition (MPT), led to the breakdown of the mitochondrial membrane potential, the inability to synthesize ATP, and finally cell death [22,25]. Long et al [30] reported that 4-HHE also depletes neuronal glutathione (GSH) content and neuronal reactive oxygen species (ROS) in rat cerebral cortical neurons. CRA can penetrate through the cell membrane and bind to GSH without metabolic activation [29].…”

Retinoid X receptor activation is essential for docosahexaenoic acid protection of retina photoreceptors

“…DHA acts in a narrow window of concentrations in cultured retina neurons, and over 10 M is deleterious for photoreceptors ( 2 ). DHA is peroxidized during neurodegenerative diseases of the retina and its products are toxic to neurons ( 64 ), depleting cellular detoxifi cation systems. It is noteworthy that despite its sensitivity to peroxidation, DHA protects photoreceptors in culture from oxidative stressinduced apoptosis ( 5 ), supporting the relevance of a precisely regulated release.…”

Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio

“…Similarly, when fish oil (3 g EPA＋3 g DHA/day) was administered in patients scheduled for dant in nervous tissue, and the oxidized DHA metabolite trans-4-hydroxy-2-hexenal (HHE) has been reported to exhibit neural toxicity. The concentration of HHE required for 50% cell death in primary cultures of cerebral cortical neurons is 23 μmol/L 46) . The extractable HHE level in the hippocampus/parahippocampal gyrus of normal control subjects is 11.3 pmol/mg protein 47) .…”