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 Nω-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. 1. Introduction Parkinson’s disease (PD) is considered the second most common neurodegenerative disorder worldwide, affecting 0.5 to 1% of the population aged between 65 and 69 years and 1 to 3% of the population over 80 years [1]. PD develops from a loss of nigrostriatal neuromelanin-containing dopaminergic neurons, whose cell bodies lay in the substantia nigra pars compacta (SNpc) [2]. This nigrostriatal pathway is essential for a normal motor function and movement control. PD is thought to have a multifactorial etiology, frequently including genetic and environmental factors [2, 3]. Several neurotoxic chemicals to dopaminergic neurons leading to PD-like symptoms have been used to study this disease. The synthetic compounds 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP) were the first to be associated with PD symptoms, as described by Langston and Ballard [4]. MPTP enters the blood-brain barrier and is
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