PPARδ Activation Mitigates 6-OHDA-Induced Neuronal Damage by Regulating Intracellular Iron Levels

Abstract

Intracellular iron accumulation in dopaminergic neurons contributes to neuronal cell death in progressive neurodegenerative disorders such as Parkinson’s disease. However, the mechanisms of iron homeostasis in this context remain incompletely understood. In the present study, we assessed the role of the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ) in cellular iron homeostasis. We identified that PPARδ inhibited 6-hydroxydopamine (6-OHDA)-triggered neurotoxicity in SH-SY5Y neuroblastoma cells. PPARδ activation with GW501516, a specific PPARδ agonist, mitigated 6-OHDA-induced neuronal damage. Further, PPARδ activation also suppressed iron accumulation, which contributes to 6-OHDA-induced neuronal damage. PPARδ activation attenuated 6-OHDA-induced neuronal damage in a similar manner to that of the iron chelator deferoxamine. We further elucidated that PPARδ modulated cellular iron homeostasis by regulating expression of divalent metal transporter 1, ferroportin 1, and ferritin, but not transferrin receptor 1, through iron regulatory protein 1 in 6-OHDA-treated cells. Interestingly, PPARδ activation suppressed 6-OHDA-triggered generation of reactive oxygen species and lipid peroxides. The effects of GW501516 were abrogated by shRNA knockdown of PPARδ, indicating that the effects of GW501516 were PPARδ-dependent. Taken together, these findings suggest that PPARδ attenuates 6-OHDA-induced neurotoxicity by preventing intracellular iron accumulation, thereby suppressing iron overload-associated generation of reactive oxygen species and lipid peroxides, key mediators of ferroptotic cell death.

Biochanin a Inhibits Excitotoxicity-Triggered Ferroptosis by Targeting Gpx4 in Hippocampal Neurons

“…The glucagon-like peptide-1 receptor agonist liraglutide attenuated accumulation of intracellular iron by decreasing TfR1 expression and increasing FPN1 expression in db/db mice (Song et al, 2022). The peroxisome proliferator-activated receptor delta agonist GW501516 suppressed 6-hydroxydopamine-induced iron accumulation by regulating expression of DMT1 protein in SH-SY5Y cells (Lee et al, 2022). Biochanin A was also shown to suppress intracellular iron levels by regulating the expression of TfR1 and FPN1 in iron overloaded mice (Ma et al, 2022).…”

The Protection of EGCG Against 6-OHDA-Induced Oxidative Damage by Regulating PPARγ and Nrf2/HO-1 Signaling

“… 27 , 28 6-OHDA can also cause iron release from cytosolic ferritin and increase intracellular free iron concentration. 29 Since iron is involved in PD progression due to its pro-oxidant nature, the interruption of iron homeostasis by 6-OHDA could cause neuronal damage, especially in the substantia nigra (SN). 30 , 31 Our previous study found that 6-OHDA regulated the expression of iron-related proteins, increased cellular iron uptake and retention in N27 cells.…”

Pharmacological Inhibition of Ferroptosis as a Therapeutic Target for Neurodegenerative Diseases and Strokes

“…[ 107 ] The elevated 4‐HNE in the cerebrospinal fluid (CSF) of PD patients is positively correlated with an increase of iron in the SN. [ 107 , 108 ] Recent studies have demonstrated that LPO is increased in PD in vitro and in vivo models induced by rotenone, [ 109 ] 6‐OHDA, [ 110 , 111 , 112 , 113 ] MPP + , [ 114 ] and MPTP. [ 115 ] Another study showed a direct association between endogenous α ‐synuclein ( α ‐syn) levels and the sensitivity of dopaminergic neurons to lipid peroxidation and ferroptosis via modulation of plasma membrane ether‐linked phospholipids.…”

“…Quercetin, [ 350 ] Dl‐3‐n‐butylphthalide, [ 109 , 351 ] β ‐hydroxybutyric acid, [ 352 ] thonningianin A, [ 112 ] GW501516 (a specific PPAR δ agonist), [ 111 ] hinokitiol, [ 113 ] paeoniflorin, [ 125 ] α ‐Lipoicacid, [ 114 ] iron chelator deferoxamine (DFO), [ 353 ] SK4/DFO, [ 354 ] clioquinol, [ 115 ] apoferritin, [ 126 ] ferrostatin‐1, [ 110 , 355 ] SK4/DFO, [ 354 ] and idebenone [ 356 ] alleviate PD through inhibiting ferroptosis (Table 1 ).…”