Abstract
In our ongoing research to discover natural products with neuroprotective effects, hyperoside (quercetin 3-O-galactoside) was isolated from Acer tegmentosum, which has been used in Korean traditional medicine to treat liver-related disorders. Here, we demonstrated that hyperoside protects cultured dopaminergic neurons from death via reactive oxygen species (ROS)-dependent mechanisms, although other relevant mechanisms of hyperoside activity remain largely uncharacterized. For the first time, we investigated the neuroprotective effects of hyperoside on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in neurons, and the possible underlying mechanisms. Hyperoside significantly ameliorated the loss of neuronal cell viability, lactate dehydrogenase release, excessive ROS accumulation and mitochondrial membrane potential dysfunction associated with 6-OHDA-induced neurotoxicity. Furthermore, hyperoside treatment activated the nuclear erythroid 2-related factor 2 (Nrf2), an upstream molecule of heme oxygenase-1 (HO-1). Hyperoside also induced the expression of HO-1, an antioxidant response gene. Remarkably, we found that the neuroprotective effects of hyperoside were weakened by an Nrf2 small interfering RNA, which blocked the ability of hyperoside to inhibit neuronal death, indicating the vital role of HO-1. Overall, we show that hyperoside, via the induction of Nrf2-dependent HO-1 activation, suppresses neuronal death caused by 6-OHDA-induced oxidative stress. Moreover, Nrf2-dependent HO-1 signaling activation represents a potential preventive and therapeutic target in Parkinson′s disease management.
Highlights
The neuropathology of Parkinson s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), as a result of many contributing factors, including oxidative stress-mediated, mitochondrial dysfunction, environmental toxins and inflammation, leading to the death of neuronal cells [1]
To obtain direct evidence of the role of nuclear erythroid 2-related factor 2 (Nrf2)-mediated heme oxygenase-1 (HO-1) signaling in hyperoside-induced neuroprotective activities, we examined the effects of Nrf2-small interfering RNA (siRNA) transfection on hyperoside neuroprotection using multiple analyses of human dopaminergic SH-SY5Y cells
Our study demonstrated that hyperoside induces HO-1 expression levels and that Nrf2 knockdown by small interfering RNA blocked hyperoside-induced neuroprotective effects, indicating that Nrf2/HO-1 plays an essential role in mediating the neuroprotective effects of hyperoside
Summary
The neuropathology of Parkinson s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), as a result of many contributing factors, including oxidative stress-mediated, mitochondrial dysfunction, environmental toxins and inflammation, leading to the death of neuronal cells [1]. We selected 6-hydroxydopamine (6-OHDA)-induced neurotoxicity and oxidative stress to mimic the neuropathological symptoms of PD in an in vitro cellular model [2]. Oxidative stress can be defined as an imbalance between cellular antioxidant defense systems and the endogenous or exogenous pro-oxidant burden [6]. Excessive production and the accumulation of reactive oxygen species (ROS) induced by 6-OHDA can lead to DNA cleavage, protein oxidation and lipid peroxidation, resulting in cellular dysfunction and apoptosis [7]. Controlling ROS production and scavenging may be therapeutically beneficial in the management of PD [8]
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