Gastrodin and Isorhynchophylline Synergistically Inhibit MPP⁺-Induced Oxidative Stress in SH-SY5Y Cells by Targeting ERK1/2 and GSK-3β Pathways: Involvement of Nrf2 Nuclear Translocation

Abstract

The pathogenesis of Parkinson's disease (PD) is multifactorial event. Combination therapies might be more effective in controlling the disease. Thus, the studies reported were designed to test the hypothesis that gastrodin (GAS)-induced de novo synthesis of nuclear factor E2-related factor 2 (Nrf2) and isorhynchophylline (IRN) inhibition of Nrf2 nuclear export contribute to their additive or synergistic neuroprotective effect. Here, we have demonstrated that the combination of GAS and IRN (GAS/IRN) protects SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP) toxicity in a synergistic manner. Concomitantly, GAS/IRN led to a statistically significant reduction of oxidative stress, as assessed by reactive oxygen species (ROS) and lipid hydroperoxides (LPO), and enhancement of both glutathione (GSH) and thioredoxin (Trx) systems compared with treatment with either agent alone in MPP-challenged SH-SY5Y cells. Interestingly, GAS but not IRN activated extracellular signal-regulated kinases 1 and 2 (ERK1/2), leading to a increase in de novo synthesis of Nrf2 and nuclear import of Nrf2. Simultaneously, IRN but not GAS suppressed both constitutive glycogen synthase kinase (GSK)-3β and Fyn activation, which inhibited nuclear export of Nrf2. Importantly, simultaneous inhibition of GSK-3β pathway by IRN and activation of ERK1/2 pathway by GAS synergistically induced accumulation of Nrf2 in the nucleus in SH-SY5Y cells challenged with MPP. Furthermore, the activation of the ERK1/2 pathway and inhibition of GSK-3β pathway by GAS/IRN are mediated by independent mechanisms. Collectively, these novel findings suggest an in vitro model of synergism between IRN and GAS in the induction of neuroprotection warrant further investigations in vivo.

Gastrodin induced HO-1 and Nrf2 up-regulation to alleviate H2O2-induced oxidative stress in mouse liver sinusoidal endothelial cells through p38 MAPK phosphorylation

“…HO-1 induction potentially confers protection against oxidative stress in a variety of experimental models, such as liver IR secondary to transplantation or hemorrhage/resuscitation ( 30 , 31 ). The human liver generates comparable amounts of the HO-1-derived products in both Kupffer cells and hepatocytes in the presence of sufficient substrates ( 32 ). However, there are no reports regarding their function and expression in LSECs.…”

“…For example, AMPK activation by GSTD was reported to increase the levels of Nrf2 phosphorylation and ameliorate oxidative stress/proinflammatory response in a mouse model of NAFLD ( 6 ). ERK1/2 phosphorylation induced by GSTD was shown to regulate Nrf2 expression and nuclear translocation in response to both neurotoxicity in SH-SY5Y cells and rat hippocampal neurons, and motor deficits and oxidative stress in a mouse model of Parkinson's disease ( 32 , 39 , 40 ). To fully understand the mechanism of GSTD regulation of HO-1 and Nrf2 expression in H 2 O 2 -exposed LESCs, more comprehensive investigation is needed.…”

Natural Products and Their Bioactive Compounds: Neuroprotective Potentials against Neurodegenerative Diseases

“…Taken together, all these findings suggest that Uncaria rhynchophylla display neuroprotective action in protecting neuronal damage through multiple pathways which could be due to the beneficial effect of active compounds as well as the combination effect of those compounds present in Uncaria rhynchophylla. Several studies have reported on the neuroprotective effect of alkaloid in Uncaria rhynchophylla such as hirsutine [187], rhynchophylline [188][189][190][191], and isorhynchophylline [192][193][194][195].…”

Natural Drugs as a Treatment Strategy for Cardiovascular Disease through the Regulation of Oxidative Stress

“…It was found that gastrodin could inhibit the formation of and scavenge oxygen radicals as well as inhibiting LPO in the myocardium during the decompensated stage of heart failure [ 147 , 148 ]. Further, gastrodin was found to inhibit oxidative stress by activating ERK1/2 signaling and reducing GSK-3 β overexpression [ 149 ].…”