Differential Effects of Methyl-4-Phenylpyridinium Ion, Rotenone, and Paraquat on Differentiated SH-SY5Y Cells

Abstract

Paraquat (PQ), a cationic nonselective bipyridyl herbicide, has been used as neurotoxicant to modulate Parkinson's disease in laboratory settings. Other compounds like rotenone (ROT), a pesticide, and 1-methyl-4-phenylpyridinium ion (MPP+) have been widely used as neurotoxicants. We compared the toxicity of these three neurotoxicants using differentiated dopaminergic SH-SY5Y human cells, aiming to elucidate their differential effects. PQ-induced neurotoxicity was shown to be concentration and time dependent, being mitochondrial dysfunction followed by neuronal death. On the other hand, cells exposure to MPP+ induced mitochondrial dysfunction, but not cellular lyses. Meanwhile, ROT promoted both mitochondrial dysfunction and neuronal death, revealing a biphasic pattern. To further elucidate PQ neurotoxic mechanism, several protective agents were used. SH-SY5Y cells pretreatment with tiron (TIR) and 2-hydroxybenzoic acid sodium salt (NaSAL), both antioxidants, and N ω-nitro-L-arginine methyl ester hydrochloride (L-NAME), a nitric oxide synthase inhibitor, partially protected against PQ-induced cell injury. Additionally, 1-(2-[bis(4-fluorophenyl)methoxy]ethyl)-4-(3-phenyl-propyl)piperazine (GBR 12909), a dopamine transporter inhibitor, and cycloheximide (CHX), a protein synthesis inhibitor, also partially protected against PQ-induced cell injury. In conclusion, we demonstrated that PQ, MPP+, and ROT exerted differential toxic effects on dopaminergic cells. PQ neurotoxicity occurred through exacerbated oxidative stress, with involvement of uptake through the dopamine transporter and protein synthesis.

Lithium protects against paraquat neurotoxicity by NRF2 activation and miR-34a inhibition in SH-SY5Y cells

“…Many recent studies have shown that exogenous environmental toxins, such as PQ are linked to PD (Tufekci et al, 2011 ; Baltazar et al, 2014 ). Here, we show that PQ is significantly toxic to SH-SY5Y cells in a time and dose dependent manner which is consistent with a recent study (Martins et al, 2013 ). PQ exposure leads to neuronal cell death in vitro and in vivo; though exact mechanisms of selective neurodegeneration induced by PQ in dopaminergic neurons are still unknown (Berry et al, 2010 ).…”

Manganese‐ and 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity display differences in morphological, electrophysiological and genome‐wide alterations: implications for idiopathic Parkinson's disease

“…MPP + did not induce extracellular LDH suggesting the absence of plasma membrane damage (Martins et al . ), while Mn elevated extracellular LDH (Fig. d).…”

Differential Expression of Tyrosine Hydroxylase Protein and Apoptosis-Related Genes in Differentiated and Undifferentiated SH-SY5Y Neuroblastoma Cells Treated with MPP+

“…A previous study showed that significant cell death of RA-differentiated cells was observed after 24 hours of exposure to 500 and 1000 μ M MPP + , and there was no apparent increase in the cell death by extending the exposure period to 48 hours [ 22 ]. For undifferentiated cells, studies showed that cell viability decreased to approximately 50% when cells were treated with 500 μ M MPP + for 24 hours [ 7 , 23 , 24 ].…”