Oxidative Medicine and Cellular Longevity / 2019 / Article / Tab 2

Review Article

The Nrf2/HO-1 Axis as Targets for Flavanones: Neuroprotection by Pinocembrin, Naringenin, and Eriodictyol

Table 2

Neuroprotective effect of flavanones through the Nrf2/HO-1 mechanism: naringenin.

CompoundExperimental modelKey findingsReference

NaringeninPrimary rat midbrain neuron-glia coculturesShows concentration- and time-dependent neurotrophic effects to support dopaminergic neuron survival—effect dependent on astroglia; elicits astrogliosis and neurotrophic factor release; increases Nrf2 mRNA and protein expressions both in neuron-glia and astroglia-enriched cultures—Nrf2-siRNA inhibited the induced astrogliosis and neurotrophic factor release; or astroglial Nrf2-siRNA abolished the induced neurotrophic effects on neurons.Wang et al. [43]

NaringeninSH-SY5Y cells exposed to paraquat (pretreatment with 80 μM for 2 h)Decreases the levels of proinflammatory cytokines (IL-1β and TNF-α) and production of NO; downregulates the levels of COX-2 and iNOS and the activation of NF-κB—the induced antiapoptotic and anti-inflammatory effects were abolished by ZnPP IX (a specific inhibitor of HO-1) or by knockdown of Nrf2 by small interfering RNA (siRNA).de Oliveira et al. [47]

NaringeninLipopolysaccharide- (LPS-) induced cognitive decline in rat (25, 50, or 100 mg/kg/day p.o. for one week)Dose-dependent improvement in memory and learning; lowers hippocampal malondialdehyde (MDA); improves antioxidant defensive system (SOD, CAT, and GSH); decreases acetylcholinesterase (AChE) activity; lowers hippocampal NF-κB, TLR4, TNF-α, COX-2, iNOS, and glial fibrillary acidic protein (GFAP) level and its immunoreactivity; elevates Nrf2.Khajevand-Khazaei et al. [44]

NaringeninSH-SY5Y cells exposed to H2O2 (pretreatment with 80 μM for 2 h)Reduces LPO, protein carbonylation, and protein nitration in mitochondrial membranes; prevents the functional impairment of the enzymes aconitase, alpha-ketoglutarate dehydrogenase, and succinate dehydrogenase; restores the activities of the complexes I and V; suppresses the induced mitochondria-related apoptosis; promotes an increase in the levels of both total and mitochondrial GSH—silencing of Nrf2 abolished the protective effects.de Oliveira et al. [65]

NaringeninIn vitro, cortical neuron cells isolated from the brains of neonatal rats subjected to oxygen and glucose deprivation/reperfusion or middle cerebral artery occlusion (MCAO ischemic stroke model)Promotes cortical neuron cell proliferation and inhibits apoptosis and OS; regulates the localization of Nrf2 protein alleviated cerebral oedema; improves neurological defects and reduces apoptosis and OS—silencing Nrf2 mitigate the protective effect.Wang et al. [46]

NaringeninNeurons isolated from the brains of rats (model group received hypoxia and reoxygenation treatment, with 20, 40, and 80 μM treatment)Reduces (80 μM) the levels of ROS; improves mitochondrial dysfunction (increased levels of high-energy phosphates, enhanced mitochondrial transport activity, and increased MMP); increases cell viability and decreases the rate of cell apoptosis; increases the expression of Nrf2 and its downstream target genes.Wang et al. [49]

NaringeninAging mice exposed to D-galactose (open field test and Morris water maze test)Activates PI3K/Akt signaling and promotes the nuclear translocation of Nrf2 and induces the expression of HO-1 and NAD(P)H-quinone oxidoreductase 1; enhances antioxidant defenses (SOD, CAT, and thiobarbituric acid reactive substance (TBARS) assays).Zhang et al. [45]

Naringenin6-Hydroxydopamine- (6-OHDA-) induced neurotoxicity in models of PD both in vitro (SH-SY5Y cells) and in vivo (mice)Increases the Nrf2 protein levels and subsequent activation of ARE pathway genes in vitro and in vivo; protects neuronal cells from oxidative insults—effect dependent on Nrf2 (Nrf2 siRNA abolished the neurotoxic or induction of Nrf2-dependent cytoprotective genes); preserves nigrostriatal dopaminergic neurodegeneration and ameliorates oxidative damage in vivo.Lou et al. [50]