DHA protects PC12 cells against oxidative stress and apoptotic signals through the activation of the NFE2L2/HO-1 axis

Abstract

docosahexaenoic acid (dHA) is an omega-3 polyunsaturated fatty acid, derived mainly from fish oil. It is well known that DHA is present in high concentrations in nervous tissue and plays an important role in brain development and neuroprotection. However, the molecular mechanisms underlying its role remain to be fully elucidated. In this study, to enhance our understanding of the pathophysiological role of DHA, we investigated the possible neuroprotective mechanisms of action of dHA against hydrogen peroxide (H 2 O 2 )-induced oxidative damage in a rat pheochromocytoma cell line (PC12). Specifically, we evaluated the viability, oxidation potential, and the expression and production of antioxidant/cytoprotective enzymes, and eventual apoptosis. We found that pre-treatment with DHA (24 h) protected the cells from H 2 O 2 -induced oxidative damage. In particular, pre-treatment with DHA: i) Antagonized the consistent decrease in viability observed following exposure to H 2 O 2 for 24 h; ii) reduced the high levels of intracellular reactive oxygen species (ROS) associated with H 2 O 2 -induced oxidative stress; iii) increased the intracellular levels of enzymatic antioxidants [superoxide dismutase (SOd) and glutathione peroxidase (GSH-Px)] both under basal conditions and following H 2 O 2 exposure; iv) augmented the intracellular levels of reduced glutathione (GSH) and ascorbic acid, while it reduced the malondialdehyde (MdA) levels under conditions of oxidative stress; v) upregulated the expression of nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) and its downstream target protein, heme-oxygenase-1 (HO-1); and vi) induced an anti-apoptotic effect by decreasing Bax and increasing Bcl2 expression. These findings provide evidence suggesting that dHA is able to prevent H 2 O 2 -induced oxidative damage to PC12 cells, which is attributed to its antioxidant and anti-apoptotic effects via the regulation NFE2L2/HO-1 signaling. Therefore, dHA may play protective role in neurodegenerative diseases associated with oxidative stress.

DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy

“…As a crucial organ, the liver is easily harmed by oxidative stress. Many studies have indicated that DHA up-regulates the expression of HO-1 or SOD to relieve oxidative stress in neuronal cells, and is involved in the treatment of a variety of neurodegenerative diseases [ 24 ]. However, its antioxidant function in hepatocytes has been less reported.…”

Dietary docosahexaenoic acid inhibits neurodegeneration and prevents stroke

“…Taken together, these results suggest a dual antioxidant and anti‐apoptotic role for DHA. Furthermore, the protective effect of DHA on oxidative damage by hydrogen peroxide (H 2 O 2 ) was demonstrated using the rat pheochromocytoma cell line PC12 (Clementi, Lazzarino, Sampaolese, Brancato, & Tringali, 2019). DHA supplementation prevented the loss of viability; ROS loss was induced after 24 hr exposure to H 2 O 2 .…”

“…Taken together, these results suggest a dual antioxidant and anti-apoptotic role for DHA. Furthermore, the protective effect of DHA on oxidative damage by hydrogen peroxide (H 2 O 2 ) was demonstrated using the rat pheochromocytoma cell line PC12 (Clementi, Lazzarino, Sampaolese, Brancato, & Tringali, 2019 Similarly, the inhibitory effect of DHA on oxidative stress induced by H 2 O 2 and tert-butyl hydroperoxide was shown in PC12 cells (Che et al, 2018). On the other hand, it was shown that the addition of DHA-PS significantly induced the survival rate of PC12 and inhibited leakage of lactate dehydrogenase, and markedly suppressed the induction of apoptosis.…”

Anti-inflammatory and Neuroprotective Agents in Clinical Trials for CNS Disease and Injury: Where Do We Go From Here?

“…Docosahexaenoic acid (DHA) is an omega-3 fatty acid mainly found in fish oil which possesses anti-oxidative ( 100 ), anti-inflammatory ( 101 , 102 ), and neuroprotective effects ( 103 ). DHA has been shown to reduce the level of endoplasmic reticulum stress and to inhibit abnormal protein accumulation [such as amyloid precursor protein (APP) and phospho-Tau proteins] within the brain following TBI ( 104 ).…”