Abstract
Oxidative stress and apoptosis are the major mechanisms that induce dopaminergic cell death. Our study investigates the protective effects of atractylenolide-I (ATR-I) on 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity in human dopaminergic SH-SY5Y cells, as well as its underlying mechanism. Our experimental data indicates that ATR-I significantly inhibits the loss of cell viability induced by MPP+ in SH-SY5Y cells. To further unravel the mechanism, we examined the effect of ATR-I on MPP+-induced apoptotic cell death characterized by an increase in the Bax/Bcl-2 mRNA ratio, the release of cytochrome-c, and the activation of caspase-3 leading to elevated levels of cleaved poly(ADP-ribose) polymerase (PARP) resulting in SH-SY5Y cell death. Our results demonstrated that ATR-I decreases the level of pro-apoptotic proteins induced by MPP+ and also restored Bax/Bcl-2 mRNA levels, which are critical for inducing apoptosis. In addition, ATR-I demonstrated a significant increase in the protein expression of heme-oxygenase in MPP+-treated SH-SY5Y cells. These results suggest that the pharmacological effect of ATR-I may be, at least in part, caused by the reduction in pro-apoptotic signals and also by induction of anti-oxidant protein.
Highlights
A new flow of information indicates that oxidative stress induced by reactive oxygen species (ROS) is involved in selective nigral cell degeneration [1]
MPP+ is the active metabolite of MPTP, which accumulates within dopaminergic neurons up to millimolar concentration in the mitochondria, and selectively inhibits nicotinamide adenine dinucleotide coenzyme (NADH Co) Q1 reductase of the mitochondrial electron transport chain [8]
Our results indicated that ATR-I (1, 5, 25 μM) did not show any significant cytotoxicity in SH-SY5Y cells for 24 h
Summary
A new flow of information indicates that oxidative stress induced by reactive oxygen species (ROS) is involved in selective nigral cell degeneration [1]. The intrinsic mitochondrial signaling pathway is involved in executing cell death initiated by 1-methyl-4-phenyl-2,3,6-tetrahydropyridine (MPTP) [6]. MPP+ is the active metabolite of MPTP, which accumulates within dopaminergic neurons up to millimolar concentration in the mitochondria, and selectively inhibits nicotinamide adenine dinucleotide coenzyme (NADH Co) Q1 reductase (complex I) of the mitochondrial electron transport chain [8]. The death of dopaminergic neurons by apoptosis might be initiated by oxidative stress and neuroinflammation [13,14]. Inhibition of pro-apoptotic signaling molecules, along with ROS, may have therapeutic benefits for protecting dopaminergic neurons in PD
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