Fisetin tetrahydroxyflavone is a flavonol present in
Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a flavonol present in several fruits and vegetables such as grape, persimmon, strawberry, apple, and onion at concentrations rangeing from 2 to 160 μg/g. Fisetin is a well–known bioflavonoid with remarkable biological effects including chemopreventive/chemotherapeutic, antiproliferative, anti-apoptotic and antioxidant properties (Fazel Nabavi et al., 2016; Khan et al., 2013; Maher et al., 2011). Increasing evidence suggested that fisetin is able to modulate the Ras-ERK cascade in neural tissue, indicating the neuroprotective, neurotrophic and cognition-improving activities of fisetin. Maher et al., reported that this bioflavonoid has therapeutic benefits in HD, an inherited, late-onset and fatal neurodegenerative disorder; characterized by means of cognitive, psychiatric and motor symptoms. HD is initiated by a mutation in gene encoding the huntingtin protein, since the expansion of a trinucleotide repeat results in an abnormality of the long polyglutamine tract. Studies that induced mutations in vitro and in vivo models of HD, proposed that the ERK activation can offer a novel pharmacological target for treatment of such disorder (Apostol et al., 2006). Fisetin significantly alleviated the impact of mutant huntingtin in three different models of HD, including Drosophila expressing mutant Httex1, PC12 neural ret proto oncogene expressing mutant Httex1, and the R6/2 animal model of HD, which was mediated by activation of the Ras-ERK signaling pathway (Maher et al., 2011). Icariin, a main bioactive flavonoid of Epimedium sagittatum (Siebold & Zucc.) Maxim (Berberidaceae family), is a traditional Chinese herb frequently used to treat the kidney disorders, cardiovascular diseases, osteoporosis and rheumatoid arthritis, also the bioflavonoid is considered to be a potential medication for the management of different age-associated diseases (Wu et al., 2012). Icariin enhanced the level of striatal dopamine in animal models of PD by attenuating the MPTP-induced reduction of Bcl-2 protein expression as well as modulating the MPTP-induced enhancement of Bax and caspase 3 proteins. In the next step, inclusion of MEK/ERK (PD98059) and PI3K/Akt (LY294002) inhibitors, injected (by microinjection) to the lateral cerebral ventricle of PD animals, resulted in hindering of the icariin therapeutic effects. Besides, the direct effect of icariin on Akt and ERK signaling pathways was evaluated by means of the phosphorylation of Akt and ERK, also the blockade effects of PD98059 and LY294002 in dopaminergic MES23.5 cells. Their results demonstrated that 0.01 μm of icariin significantly enhanced the phosphorylation level of ERK cascade in a time dependent manner (Chen et al., 2017). 5, 7-dihydroxyflavanone, known as pinocembrin, is categorized as a natural flavonoid with well-established neurovascular protective function. Pinocembrin was approved by Food and Drug Administration of China for stroke management in 2008. The compound has been found to decrease the ischemic area of cerebral infarction and can protect neurovascular tissue the versus ischemic injury and Aβ-induced damages. Pinocembrin is capable of moderating the cognitive dysfunction that has been mediated by blocking the oxidative stress and inflammatory (Liu et al., 2008) pathways in the vascular dementia and the intra-cerebroventricular β amyloid-injected models. Later, the cellular signaling mechanisms involved in anti-AD effects of pinocembrin was assessed and it was shown that the RAGE, ERK, NF-kB p65 pathways are significantly inhibited where pinocembrin was used (p < 0.001), in both microvessels and in parenchyma in vitro neurovascular unit models. The authors concluded that among subfamilies of MAPKs, ERK has a crucial contribution in Aβ/RAGE-induced neurotoxicity via disturbance of the BBB infiltration and NF-kB-mediated overexpression of inflammatory cytokine, as well as glial activation. Accordingly, the inhibition of ERK phosphorylation and its downstream NF-kB p65 translocation has an important role in improving the pinocembrin neurotoxicity (Liu et al., 2014).