%0 Journal Article
%T Differential Effects of Methyl-4-Phenylpyridinium Ion, Rotenone, and Paraquat on Differentiated SH-SY5Y Cells
%A Jo£¿o Barbosa Martins
%A Maria de Lourdes Bastos
%A F¨¦lix Carvalho
%A Jo£¿o Paulo Capela
%J Journal of Toxicology
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/347312
%X 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¦Ø-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
%U http://www.hindawi.com/journals/jt/2013/347312/