Protective effect of docosahexaenoic acid on lipotoxicity‐mediated cell death in Schwann cells: Implication of PI3K/AKT and mTORC2 pathways

Background and Aim Docosahexaenoic acid (DHA) exhibits neuroprotective properties and has been shown to preserve nerve cells following trauma and ischemic injury. Recently, we showed that DHA pretreatment improved locomotion and reduced neuropathic pain after acute spinal cord injury in adult rats. These improvements were associated with an increase in the levels of AKT in spinal cord injury neurons. In this study, we investigate the implication of PI3K/AKT and mTOR pathway in DHA‐mediated protection of primary cultured Schwann cells (pSC) undergoing palmitic acid‐induced lipotoxicity (PA‐LTx). Methods Primary cultured Schwann cells were treated with PA (PA:BSA, 2:1) in the presence or absence of DHA (1–200 µM) for 24–48 hr. Cell viability was determined by crystal violet staining and nuclear morphology was examined using Hoechst staining. Results We found that pSC cultures exposed to palmitic acid (PA) overload showed chromatin condensation, a decrease in cell viability and an inhibition of AKT phosphorylation in a time‐dependent manner. Next, pSC exposed to PA overload were treated with DHA. The data show that co‐treatment with DHA inhibited the loss of cell viability and apoptosis caused by PA. Moreover, treatment with DHA inhibited chromatin condensation, significantly stimulated p‐AKT phosphorylation under PA‐LTx condition, and DHA alone increased AKT phosphorylation. Additionally, when these pSC cultures were treated with PI3K inhibitors LY294002 and, BKM120 and mTOR inhibitors Torin 1 (mTORC1/mTORC2), but not rapamycin (mTORC1), the protective effects of DHA were not observed. Conclusion These findings suggest PI3K/AKT and mTORC2 kinase pathways are involved in the protective function (s) of DHA in PA‐induced Schwann cell death. Overload of saturated fatty acids results in lipotoxicity and induces cells and tissue damage; whereas docosahexaenoic acid (DHA), an n‐3 polyunsaturated fatty acids, has a beneficial effect. Primary Schwann cell cultures treated with high levels of palmitic acid (PA) showed a decrease in cell viability and chromatin condensation, which were reversed in the presence of DHA. However, PI3K inhibitors LY294002 and BMK120, and mTOR inhibitors Torin 1 but not Rapamycin diminished the protective effect of DHA under PA‐induced lipotoxicity. In conclusion, our results suggest that DHA is able to protect SC from PA‐LTx, through PI3K/AKT and mTORC2 kinase pathway.