Abstract
The neurotoxin 6-hydroxydopamine (6-OHDA), which causes transcriptional changes associated with oxidative and proteotoxic stress, has been widely used to generate an experimental model of Parkinson’s disease. The food-derived compound luteolin has multi-target actions including antioxidant, anti-inflammatory and neurotrophic activities. The aim of this study is to investigate how luteolin affects 6-OHDA-mediated stress response pathways. The results showed that when PC12 cells were pre-treated with luteolin (20 µM) 30 min prior to 6-OHDA (100 µM) exposure, 6-OHDA-induced ROS overproduction, cytotoxicity, caspase-3 activation, and mRNA expression of BIM, TRB3 and GADD34 were significantly attenuated. Moreover, 6-OHDA-mediated cell cycle arrest and transcription of p53 target genes, p21, GADD45α and PUMA, were reduced by luteolin. Luteolin also significantly down-regulated 6-OHDA-mediated unfolded protein response (UPR), leading to decreases in phospho-eIF2α, ATF4, GRP78 and CHOP. In addition, luteolin attenuated 6-OHDA-induced Nrf2-mediated HO-1 and GCLC. Taken together, these results suggest that diminishing intracellular ROS formation and down-regulation of p53, UPR and Nrf2-ARE pathways may be involved in the neuroprotective effect of luteolin.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and/or the presence of Lewy bodies, which are mainly composed by fibrillary aggregated asynuclein, within neurons [1]
It has been reported that 6-OHDA-generated reactive oxygen species (ROS) induce DNA damage and subsequent activation of p53, and the expression of PUMA (p53-upregulated mediator of apoptosis), which is required for cell death in murine midbrain neurons [8]
Increasing evidence suggests that PD mimetic 6-OHDA exposure causes PC12 cell death through oxidative stress [17]
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and/or the presence of Lewy bodies, which are mainly composed by fibrillary aggregated asynuclein, within neurons [1]. A growing body of evidence indicates that elevated oxidative stress and the pro-inflammatory response occur early in the development of the disease and these processes contribute to and exacerbate nigrostriatal degeneration [2]. 6-OHDA destroys catecholaminergic structures by the combined effect of reactive oxygen species (ROS) and quinones. It is thought that the ROS initiate cellular oxidative stress and p-quinone mediates 6-OHDAinduced cell death [5]. It has been reported that 6-OHDA-generated ROS induce DNA damage and subsequent activation of p53, and the expression of PUMA (p53-upregulated mediator of apoptosis), which is required for cell death in murine midbrain neurons [8]
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