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  • Altered brain insulin signaling and CNS hypometabolism are a


    Altered (-)-Bicuculline methiodide insulin signaling and CNS hypometabolism are also associated with pathogenesis of neurodegeneration. Insulin receptors are mostly located in the cerebral cortex, hippocampus, cerebellum, hypothalamus and olfactory bulb, possess an effective role in the regulation of central glucose metabolism, neural functions, memory and feeding behaviors (De Felice et al., 2014). There is a growing body of evidence suggesting that patients with neurodegenerative disorders generally have altered insulin receptors sensitivity, damaged insulin receptor phosphorylation and disturbed downstream cascades (Ramalingam and Kim, 2014). Different cellular and animal studies demonstrated that the inhibition of the brain insulin phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway is accompanied with the production of Aβ plaques mediated by ganglioside clustering in the presynaptic membranes. As an example, the Aβi expression suppressed the insulin associated Akt phosphorylation in brain cells in vitro (Lee et al., 2009). In another study by Ali et al., melatonin improves Aβ-induced neurodegeneration through activation of the PI3/Akt, as well as the glycogen synthase kinase-3 (GSK)3β pathway in animal model (Ali and Kim, 2015). Activation of the insulin-induced AKT is able to alleviate Aβ-mediated neurodegeneration (O’ Neill, 2013). The family of neurotrophins (NTs) is composed of nerve growth factor (NGF), neurotrophin 3 (NT3), NT4/5 and brain-derived neurotrophic factor (BDNF); possess a protective role against apoptosis of nerve cells in different experimental models of neurodegeneration such as age related cognitive decline and dementia or Aβ overexpressing AD cases. It has been found that almost 50 NGFs are expressed in the brain and among them, two have key contribution in preventing neurodegeneration; BDNF and NGF. The NGF expression level is significantly reduced in patients with AD compared with healthy control (Xu et al., 2016). This has a regulatory effect on function of the basal forebrain cholinergic nervous system which is affected by prominent neurodegeneration. The BDNF has a protective effect against neural apoptosis and can regulate the function of cortical neurons. Aβ and ROS damage synaptic function and neural networks, also induce loss of NGF and BDNF, which could cause defect in learning and memory molecular transduction (Mattson, 2004; Tuszynski et al., 2015).
    Are flavonoids clinically effective in neurodegenerative diseases? Flavonoids are defined as the secondary polyphenolic metabolites having a 3-hydroxyflavone backbone (3-hydroxy-2-phenylchromen-4-one) (Fig. 1). The main sources of flavonoids are fungi and plants, more specifically appear in beverages like tea, coffee, red wine, fruit juices and in numerous fruits and vegetables (Aherne and O'Brien, 2002; Cirmi et al., 2016; Raffa et al., 2017). Although, flavonoids possess several pharmacological activities, they are not synthesized in human and animal body, nonetheless, they are known to be synthesized in almost all types of plants and display remarkable influence on human health (Aherne and O'Brien, 2002; Kozlowska and Szostak-Wegierek, 2014). Depending on the chemical structure, flavonoids are categorized into different subgroups including anthocyanins, flavones, flavanones, flavan-3-ols, flavonols, and isoflavones. Flavonoids are responsible in different mechanism involved in plant protection system. These compounds defend plants from different unfamiliar agents including UV radiation, viruses and parasites, likewise take a part in cell metabolism by regulation of different enzymes and scavenging of free radicals (Manach et al., 2004). Quercetin (3,3,4,5,7-pentahydroxyflavone), a chief constituent of the flavonol subclass of flavonoids comprises about 60–75% of entire flavonoid consumed as diet (Suganthy et al., 2016). Apart from its antioxidant properties, quercetin exerts different therapeutic effects such as anti-cancer, anti-viral, anti-inflammatory cardioprotective, antimicrobial, hepatoprotective and neuroprotective (Suganthy et al., 2016). Fig. 2 represents a number of the most important polyphenols and flavonoids; apigenin, quercetin, taxifolin, catechin, genistein, leucocyanidin, malvidin, naringenin, resveratrol, glabridin, icariin, kaempferol, baicalin, myricetin and rutin.