Hepcidin Decreases Rotenone-Induced α-Synuclein Accumulation via Autophagy in SH-SY5Y Cells

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder, and the hallmarks of this disease include iron deposition and α-synuclein (α-syn) aggregation. Hepcidin could reduce iron in the central and peripheral nervous systems. Here, we hypothesized that hepcidin could further decrease α-syn accumulation via reducing iron. Therefore, rotenone or α-syn was introduced into human neuroblastoma SH-SY5Y cells to imitate the pathological progress of PD in vitro. This study investigated the clearance effects of hepcidin on α-syn induced by a relatively low concentration of rotenone exposure or α-syn overexpression to elucidate the potential clearance pathway involved in this process. We demonstrated that SH-SY5Y cell viability was impaired after rotenone treatment in a dose-dependent manner. α-syn expression and iron content increased under a low concentration rotenone (25 nM for 3 days) treatment in SH-SY5Y cells. Pre-treatment with hepcidin peptide suppressed the abovementioned effects of rotenone. However, hepcidin did not affect treatment with rotenone under high iron conditions. Hepcidin also played a role in reducing α-syn accumulation in rotenone and α-syn overexpression conditions. We identified that the probable clearance effect of hepcidin on α-syn was mediated by the autophagy pathway using pretreatment with autophagy inhibitors (3-MA and CQ) and detection of autophagy protein markers (LC3II/I and p62). In conclusion, hepcidin eliminated α-syn expression via the autophagy pathway in rotenone-treated and α-syn overexpression SH-SY5Y cells. This study highlights that hepcidin may offer a potential therapeutic perspective in α-syn accumulation diseases.

Empagliflozin attenuates neurodegeneration through antioxidant, anti-inflammatory, and modulation of α-synuclein and Parkin levels in rotenone-induced Parkinson’s disease in rats

“…Our result showed that ROT led to a significantly upregulated α-syn level by 239% compared to the control group, which agrees with ( Li et al, 2020 ) and significantly down-regulated parkin protein by 67%, which is compatible with ( Rahimmi et al,2015 ), while EMP + ROT resulted in significant preservation in these protein levels. α-syn is a fundamental contributor in PD, which can initiate and potentiates the neurodegeneration process by many pathways; inhibition of autophagy, induction of mitochondrial dysfunction, and increased oxidative stress in addition to microglial activation causing neuroinflammation and an increase in proinflammatory cytokines ( Segura-Aguilar, 2017 ).…”

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

“…Even though our studies examining rotenone-induced toxicity have employed short-term and relatively high levels of rotenone exposure, over a lifetime, the patients may have been exposed to the toxins for several years at relatively low concentrations. 104 Summing up, the results of these assays confirm the neuroprotective properties of the tested compounds 13−15, predominantly via inhibition of ROS production and the significantly lower effect on the metabolic activity of SH-SY5Y cells. The β-naphthyl dimethyl-branched derivative 15 turned out to be the relatively most potent neuroprotective agent in these studies.…”

“…It is worth noting that the concentration of rotenone in this study was adjusted based on a dose–response curve of rotenone, in which a significant increase in ROS level and decrease in metabolic activity of SH-SY5Y cells in vitro were observed. Even though our studies examining rotenone-induced toxicity have employed short-term and relatively high levels of rotenone exposure, over a lifetime, the patients may have been exposed to the toxins for several years at relatively low concentrations …”

Regulation of Autophagy by the Glycogen Synthase Kinase-3 (GSK-3) Signaling Pathway

“…Furthermore, cells treated with TCN, an AKT inhibitor, showed that the phosphorylation of GSK-3β in EGF treated PC3 cells was reduced [106]. Studies have shown that rotenone, a pesticide associated with α-synuclein aggregation, induces intercellular calcium levels and suppresses AKT and GSK-3β phosphorylation [104,108]. In this study, they showed that BAPTA, a chelator of intracellular calcium, can alleviate the downregulation of AKT and GSK-3β phosphorylation induced by rotenone treatment [104].…”