br Role of ERK signaling in preventive
Role of ERK signaling in preventive and therapeutic potential of flavonoids in neurodegenerative diseases ERK is one of the main pharmacological targets of natural phenolic compounds and contributes to several therapeutic approaches including anti-atherogenic, anti-cancer, anti-colitis, anti-arthritis and anti-inflammatory effects (Farzaei et al., 2016a; Pang et al., 2009; Suh et al., 2006). Escalating evidence revealed that numerous bioflavonoids, obtained from a variety of dietary fruits or medicinal herbal sources, possess their protective or therapeutic benefits versus development of neurodegenerative diseases through the modulation of different compartments of ERK signaling pathway (Shahpiri et al., 2016). Amentoflavone is a flavonoid elicited from Selaginella tamariscina (P.Beauv.) Spring (Selaginellaceae family) with various pharmacological properties including antibacterial, anti-inflammatory, antioxidant, anti-radiation, anticancer, anti-apoptosis, as well as neuroprotective activities (Cao et al., 2017; Shin et al., 2006). Shin et al. (2006), reported that neuroprotective potential of amentoflavone on neonatal hypoxic-ischemic GW 6471 damage is mediated through different cellular mechanisms that suppress the nitrergic pathway and inducible nitric oxide synthase, further inhibits the activation of inflammatory response and COX-2. This natural flavonoid also protects neural cells against Aβ-induced neurotoxicity and fibrillogenesis, also harbors the hippocampal neurons versus neuroinflammation (Zhang et al., 2015). A number of in vitro studies demonstrated that amentoflavone has a modulatory effect on ERK/MAPK pathway in various cell types. In a cellular experiment reported by Cao et al., the potential therapeutic effect of this bioflavonoid on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD was evaluated. MPTP is a neurotoxin that blocks mitochondrial complex I and selectively damages dopaminergic neurons, thus is responsible for the induction of different symptoms of PD. Subsequent to MPTP transition through BBB, the toxin is transferred to the main metabolite 1-methyl-4-phenylpyridinium (MPP+) through monoamine oxidase-B (MAO-B) enzyme and causes interruption of mitochondrial energy metabolism and respiratory function, thus initiates oxidative stress pathological condition in neural system. Amentoflavone demonstrated protective effect versus damages of dopaminergic neurons and facilitated PD therapy by regulating the ratio of Bcl-2/Bax and caspase-3 activity through ERK and PI3K/Akt signaling cascades (Cao et al., 2017). Ampelopsin (dihydromycrietin) is the main flavonoid and bioactive phytochemical of Ampelopsis grossedentata (Hand.-Mazz.) W.T.Wang (Vitaceae family). Phytochemical analysis showed that ampelopsin constitutes 20–30% (w/w) of the stems and leaves of the herb (Sun et al., 2013). Several biological effects have been proven for ampelopsin including anti-inflammatory, hepatoprotective, antiapoptotic and antioxidant activities (Zhang et al., 2007). Ampelopsin is a well-known antioxidant and has a remarkable protective effect against H₂O₂-induced apoptosis in neural cells which is mediated by upregulation of heme oxygenase-1 expression. The enzyme has an important contribution in maintaining cells survival against toxicity that caused by several oxidants. Moreover, ampelopsin significantly reduced levels of proteins cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3, which have vital role in cell apoptosis. Activation of ERK and Akt has been associated with the overexpression of heme oxygenase-1protein, as well as the inhibition of PARP and caspases function by ampelopsin (Kou et al., 2012). Apigenin (4′,5,7-trihydroxyflavone), is a flavone that has been detected in a wide range of fruits, and vegetables such as bell pepper celery and cabbage. This natural flavonoid covers a broad spectrum of pharmacological activities in regard to antioxidant, anti-mutagenic, sedative, anxiolytic, and antidepressant effects. Apigenin demonstrated a significant preventive effect on the Aβ-induced dementia that was arbitrated by ameliorating redox imbalance and reinforcing barrier function of neural cells in animal models. Apigenin was proven to launch neurovascular protection by reducing oxidative stress parameters and blocking neuronal cholinergic pathway. Three-month oral administration of apigenin has a worthwhile therapeutic effect on learning and memory deficits on amyloid precursor protein/presenilin 1 (APP/PS1) double-transgenic mouse models of AD (Zhao et al., 2011). This bioflavonoid diminished the Aβ burden and decreased β-site APP-cleaving enzyme 1 (BACE1) level and β-amyloidogenesis. Apigenin also suppressed oxidized hydroethidine, which is a marker of superoxide anion level in the cerebral cortex. The therapeutic values of apigenin have been explosively correlated with its ability to activate ERK/CREB/BDNF cascade in cerebral cortex (Zhao et al., 2013).