δ‐Opioid Receptor Activation Inhibits Ferroptosis by Activating the Nrf2 Pathway in MPTP‐Induced Parkinson Disease Models

Abstract

Introduction. Recent studies suggest the involvement of ferroptosis in the pathogenesis of Parkinson disease (PD). δ-Opioid receptors (DORs) have neuroprotective effects in PD. It is not known whether the neuroprotective effects of DORs in PD are attributable to the inhibition of ferroptosis. Therefore, we aimed to investigate the role of DORs in ferroptosis in MPTP-induced PD models. Methods. To identify the influence of DORs on ferroptosis in MPTP-induced PD models, we measured the malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels, analyzed the levels of ferroptosis-related proteins (GXP4 and SLC7a11) and Nrf2 expression by using western blotting, and assessed mitochondrial dysfunction by using JC-1 staining and transmission electron microscopy. Results. DOR activation reduced the 4-HNE and MDA levels, increased the GXP4 and SLC7a11 levels, and ameliorated mitochondrial dysfunction in MPTP-induced PD models. These neuroprotective effects of DORs could be blocked by Nrf2-siRNA. Thus, the effects of DORs on ferroptosis in PD models were partially controlled by Nrf2, which regulated GXP4 and SLC7a11 synthesis. Conclusion. DORs exert neuroprotective effects in PD models by inhibiting ferroptosis partially via activating the Nrf2 pathway.

Advances in Ferroptosis-Inducing Agents by Targeted Delivery System in Cancer Therapy

“… 25 The NRF2 target genes not only regulate the key process of iron metabolism but also control the catabolism of foreign organisms and reactive aldehydes, as well as the synthesis of GSH and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH), making it a versatile regulator of cellular resistance to iron degradation. 108 , 109 …”

Opioids Alleviate Oxidative Stress via the Nrf2/HO-1 Pathway in LPS-Stimulated Microglia

“…We have previously reported that ORs (μ-, δ-, and κ-ORs) are present in microglia, and we observed that their activation could convert the LPS-induced proinflammatory subset of microglia into an anti-inflammatory subset by inhibiting the excessive production of nitric oxide, decreasing the expression of proinflammatory cytokines, and increasing the expression of anti-inflammatory molecules [ 22 ]. There is growing evidence that opioids may be neuroprotective under certain conditions [ 23 , 24 , 25 , 26 ]. In the present study, we investigated the mechanism underlying the antioxidant and anti-inflammatory effects of selected OR agonists (DAMGO, DADLE, and U-50488) in microglial cells.…”