Toxicity of Necrostatin-1 in Parkinson’s Disease Models

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. This neuronal loss, inherent to age, is related to exposure to environmental toxins and/or a genetic predisposition. PD-induced cell death has been studied thoroughly, but its characterization remains elusive. To date, several types of cell death, including apoptosis, autophagy-induced cell death, and necrosis, have been implicated in PD progression. In this study, we evaluated necroptosis, which is a programmed type of necrosis, in primary fibroblasts from PD patients with and without the G2019S leucine-rich repeat kinase 2 (LRRK2) mutation and in rotenone-treated cells (SH-SY5Y and fibroblasts). The results showed that programmed necrosis was not activated in the cells of PD patients, but it was activated in cells exposed to rotenone. Necrostatin-1 (Nec-1), an inhibitor of the necroptosis pathway, prevented rotenone-induced necroptosis in PD models. However, Nec-1 affected mitochondrial morphology and failed to protect mitochondria against rotenone toxicity. Therefore, despite the inhibition of rotenone-mediated necroptosis, PD models were susceptible to the effects of both Nec-1 and rotenone.

β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

“…Here, we reported for INS-1 β-cells a high toxicity of rotenone after 24 h with an IC 50 = 30 nM, which is very similar to that found for dopaminergic-like cell lines. Intriguingly, in other cell types, such as microglial cells, breast cancer cells and fibroblasts, rotenone was toxic but at higher concentrations, showing a similarity between β-cells and dopaminergic cell lines in terms of high vulnerability to rotenone [42][43][44]. Regarding the mechanism of action, rotenone acts as mitochondrial complex I inhibitor and it has been used as a PD model for both in vitro and in vivo studies [25] (Figure 6).…”

Necrostatin-1 and necroptosis inhibition: Pathophysiology and therapeutic implications

“…Apart from retinal degeneration, the protective effect of Nec-1 has been observed in other neurological disease models as well (like PD [ 176 ] and axonal degeneration [ 177 ]). It is also reported that Nec-1 could ameliorate neural cell injury induced by aluminum, a common metal material which can be transported to the brain and contribute to AD etiology [ 178 ].…”

Preclinical Evidence for the Interplay between Oxidative Stress and RIP1-Dependent Cell Death in Neurodegeneration: State of the Art and Possible Therapeutic Implications

“…However, in mouse microglia cells (BV-2 or N9 cell lines, primary microglia) exposed to z-VAD-fmk and/or LPS and/or BV6 (SMAC mimetic), Nec-1 abolished cell damage induced by these factors, and this effect was associated with the inhibition of necroptotic factors (RIP1/RIP3/MLKL) and reduction in pJNK/JNK level [111]. Although Nec-1 was demonstrated to inhibit necroptosis induced by rotenone in SH-SY5Y cells measured by decreased level of pMLKL, it did not reduce but even exaggerated the Rot-evoked cell damage [112]. Additionally, in another neuronal cell type, namely RGC-5 cells, Nec-1 did not attenuate rotenone toxicity, whereas inhibitors of JNK and p38 pathways exerted beneficial effects in this model [113].…”