Diquat causes caspase-independent cell death in SH-SY5Y cells by production of ROS independently of mitochondria

Abstract

Evidence indicates that Parkinson’s disease (PD), in addition to having a genetic aetiology, has an environmental component that contributes to disease onset and progression. The exact nature of any environmental agent contributing to PD is unknown in most cases. Given its similarity to paraquat, an agrochemical removed from registration in the EU for its suspected potential to cause PD, we have investigated the in vitro capacity of the related herbicide Diquat to cause PD-like cell death. Diquat showed greater toxicity towards SH-SY5Y neuroblastoma cells and human midbrain neural cells than paraquat and also MPTP, which was independent of dopamine transporter-mediated uptake. Diquat caused cell death independently of caspase activation, potentially via RIP1 kinase, with only a minor contribution from apoptosis, which was accompanied by enhanced reactive oxygen species production in the absence of major inhibition of complex I of the mitochondrial respiratory chain. No changes in α-synuclein expression were observed following 24-h or 4-week exposure. Diquat may, therefore, kill neural tissue by programmed necrosis rather than apoptosis, reflecting the pathological changes seen following high-level exposure, although its ability to promote PD is unclear.

SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson’s disease

“…3). Western blot analysis failed to detect the levels of cleaved caspase 3, a finding that has been observed previously [13].

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The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

“…Previous studies reported that exposure to nM concentrations of rotenone for 24 hours was found to decrease SH-SY5Y cell viability to 50% when compared to untreated cells [29,30]. However, rotenone at higher concentrations were needed to effect cellular viability in our study model, similar to recent studies [31,32]. At lower concentrations, we could not observe any damage.…”

Necrosis in human neuronal cells exposed to paraquat

“…We also could not observe necroptosis in PQ-exposed SH-SY5Y cells (Fig. 2), in contrast to the case of diquat that is an herbicide structurally resembling PQ and has been shown to cause necroptosis of SH-SY5Y cells (Nisar et al, 2015). Therefore, the unique feature of necroptosis-and ferroptosis-independent necrosis caused by PQ on SH-SY5Y cells might represent a model in which to search for a novel mechanism of necrosis.…”

“…Although there is much literature showing that apoptosis is the main mode of SH-SY5Y cell death during exposure to these substances, recent studies have shown possible involvement of necroptosis and/or ferroptosis in cell death by diquat and MPP+ (Nisar et al, 2015;Ito et al, 2017). Oxidative cellular stress is the main cause of PQ toxicity (Suntres, 2002) and the generation of lipid peroxides has been implicated mostly in PQ cytotoxicity (McCormack et al, 2005).…”