Addition of docosahexaenoic acid, but not arachidonic acid, activates glutathione and thioredoxin antioxidant systems in murine hippocampal HT22 cells: potential implications in neuroprotection

Abstract

Docosahexaenoic acid (DHA, 22:6n-3) is a major constituent of nerve cell membrane phospholipids. Besides a role in membrane architecture, DHA is a pleiotropic molecule involved in multiple facets of neuronal biology and also in neuroprotection. We show here that supplementation with DHA (but not arachidonic acid) to mouse hippocampal HT22 cells modulates the expression of genes encoding for antioxidant proteins associated with thioredoxin/peroxiredoxin and glutathione/glutaredoxin systems. Thus, within the thioredoxin system, DHA increased Txn1-2, Trxrd1-2, Prdx3, and Srxn1 gene expression. Paralleling these changes, DHA increased thioredoxin reductase activity, the main enzyme involved in thioredoxin regeneration. For the glutathione system, the most important change triggered by DHA was the upregulation of Gpx4 gene, encoding for the nuclear, cytosolic and mitochondrial isoforms of phospholipid-hydroperoxide glutathione peroxidase (PH-GPx/GPx4, the main enzyme protecting cell membranes against lipid peroxidation), which was followed by a significant increase in total glutathione peroxidase and GPx4 activities. Noticeably, DHA also upregulated a new Gpx4 splicing variant that retained part of the first intronic region. Finally, we demonstrate that DHA treatment, under the same time course, protects HT22 cells from the oxitoxic exposure to amyloid beta (Aβ25-35 ) peptide. Altogether, our data pinpoint to a role of DHA as Indirect Antioxidant that modulates neuronal defences in neuroprotection. DHA improves the antioxidant capacity of cultured hippocampal HT22 cells. We propose that DHA supplementation induces the remodelling of membrane phospholipids, and also triggers a transcriptional program to increase the expression of members of the glutathione and thioredoxin systems. We postulate that this transcriptional effect is mediated by a signal arising from non-enzymatic oxidation of DHA.

Keywords: docosahexaenoic acid; gene expression; hippocampal cells; intron retention; neuroprotection; thioredoxin and glutathione antioxidant systems.