Purinergic receptor P2Y6 contributes to 1‐methyl‐4‐phenylpyridinium‐induced oxidative stress and cell death in neuronal SH‐SY5Y cells

Abstract

Oxidative stress and neural degeneration have been shown to be involved in the pathogenesis of Parkinson's disease (PD). The P2Y6 purinergic receptor (P2Y6R) has been shown to participate in the activation of microglia and the production of pro-inflammatory factors induced by lipopolysaccharide to cause neuronal loss. However, the function of P2Y6R during oxidative stress in neurons is unclear. In the present study, 1-methyl-4-phenylpyridinium (MPP ) treatment increased the level of UDP/P2Y6R on neuronal SH-SY5Y cells. Importantly, pharmacological inhibition of P2Y6R or knockdown of P2Y6R using a siRNA exerted an increased protective effect by preventing MPP -induced increases in the levels of reactive oxygen species (ROS), superoxide anion, inducible nitric oxide synthase (iNOS), and malondialdehyde (MDA) and down-regulation of superoxide dismutase 1 (SOD1) expression. UDP, an agonist of P2Y6R, enhanced the effects of MPP , which was also inhibited by apyrase or MRS2578. Additionally, P2Y6R knockdown also significantly reversed both the loss of cell viability and the increase in the levels of phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) and p38 (p-p38) caused by MPP stimulation. However, the inhibition of the ERK1/2 and p38 kinase signaling pathways had no effect on P2Y6R expression. Taken together, these results support the hypothesis that P2Y6R expressed on neuronal SH-SY5Y cell is associated with the progression of oxidative stress and cell death induced by MPP , suggesting that P2Y6R may play an important role in the pathogenesis of PD.

The role of P2Y6 receptors in the maintenance of neuropathic pain and its improvement of oxidative stress in rats

“…10 Furthermore, more and more research validated that P2Y6 receptors expressed in microglia of the SDH contribute importantly to the maintenance of neuropathic pain and production of chronic constriction injury (CCI)-induced oxidative stress. 11 In present study, the CCI of the sciatic nerve was the neuropathic pain model to explore the participation of P2Y6 receptors in the maintenance of neuropathic pain and the involvement of oxidative stress. 12,13 Herein, we observed the tactile allodynia of rats following CCI over time, besides, the messenger RNA (mRNA) expression of oxidative-stress markers, including SOD, GSH, and HO-1, were determined in rats following CCI by real-time polymerase chain reaction (RT-PCR).…”

Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal

“…Recent studies are drawing attention to the role of P2Y6 receptors in PD development and progression. An in vitro study showed that P2Y6 receptor gene expression is increased in SH-SY5Y cells-a human neuroblastoma lineage that when differentiated presents markers for dopaminergic neuronswhen challenged with neurotoxin 1-methyl-4-phenylpyridinium (MPP + ) (Qian et al, 2017). Thus, its antagonism or deletion decreased MPP + effects in cell death through reduced ROS production (Yang et al, 2017).…”

Papel dos receptores purinérgicos em modelo animal de doença de Parkinson

“…Um estudo recente mostrou que a expressão gênica do receptor P2Y6 está aumentada em células de neuroblastoma humano SH-SY5Y quando submetidas a um insulto com a neurotoxina 1-metil-4-fenilpiridinium (MPP + ) (Qian et al, 2017).…”

“…Além, disso, o antagonismo ou deleção da expressão desse receptor diminuiu a morte celular provocada pelo MPP + pela diminuição da produção de espécies reativas de oxigênio (Qian et al, 2017). No processo de morte celular in vivo, a liberação de UDP pelas células apoptóticas e consequente ativação de P2Y6 induz a produção das citocinas CCL2 e CCL3 em células da microglia e sua ativação fagocítica, indicando que esse subtipo de receptor pode estar envolvido na resposta inflamatória de doenças neurodegenerativas (Kim et al, 2011 Os resultados obtidos na caracterização indicam que após uma semana da injeção de 6-OHDA na dose de 7μg/µl no feixe prosencefálico medial encontramos um perfil comportamental e bioquímico característico deste modelo animal.…”

“…Há na literatura dados envolvendo o efeito protetor do MRS2578 em células SH-SY5Y submetidas a morte celular, porém não há relatos da ação frente a exposição das células à morte induzida pela droga 6-OHDA (Qian et al, 2017).…”