Another clinical study indicated the daily consumption of gr

Another clinical study indicated the daily consumption of green tea with low concentrations of theanine and catechin would improve cognitive function (Ide et al., 2014). Further, in a double blind randomized clinical study involving 102 patients, the Hypericum extract was examined in terms of efficacy and tolerance in comparison to the maprotiline. There was not much clinical differences, also no increase in the sedative effect was found (Harrer et al., 1994). Although flavonoids are effectual in either the prevention or treatment of neurodegenerative impairments, still more researches are required clinically to prove the advantages of natural products donating persuasive neuroprotective effect in vivo and in vitro studies.
Toxicological data on flavonoids in neurodegeneration Taking into account, flavonoids are generally safe to humans, although some special compounds may interfere with a number of therapeutic drugs (Corcoran et al., 2012). To note, at high concentration, excessive intake of different flavonoids showed a series of adverse side effects including anti-nutritional (e.g. inhibition of proteolysis within the gut, reduced BS-181 uptake, impaired food utilization, and impaired mineral absorption), thyroid toxicity, drug interactions, genotoxicity/carcinogenicity and some developmental effects (Erdman et al., 2007; Galati and O\'Brien, 2004). Reports are also available on the adverse effects associated with breast cancer, male reproductive health, hemolytic anemia, contact dermatitis and liver failure and toxic drug interactions induced by flavonoids consumption (Galati and O\'brien, 2004). These compounds may act as pro-oxidants, mutagens, also as inhibitors of various important hormone metabolizing enzymes; caution is required while taking flavonoids during pregnancy as they can easily cross placenta (Skibola and Smith, 2000). Flavonoids type, dosage and intake duration, as well as inter-individual variability in polyphenols-metabolizing system within the human body have been correlated with the potential toxicity of these chemicals (Moon et al., 2006). Therefore, dose and formulation are important paradigms regarding flavonoid intake in general. Scientific findings disclosed that even in long term use, resveratrol does not possess significant side effects on mammals (Markus and Morris, 2008). In rats, at a dose of 300 mg/kg, resveratrol did not show any toxic effect. However, at higher dose i.e. 3000 mg/kg, some side effects such as decline in food intake and body weight, as well as increased concentrations of alkaline phosphatase, creatinine, red and white cell counts, kidney weight and higher nephropathy were recorded (Crowell et al., 2004). Moderate and reversible toxicity was recorded at doses of ≥0.5 g/day for prolonged administration of resveratrol (Cottart et al., 2014). Moreover, acute consumption of resveratrol was found safe and well tolerated up to the concentration of 5 g/day, yet mild to moderate side effects were recorded (Patel et al., 2011). In a toxicogenomic study in rats, resveratrol did not induce satisfactory changes in the gene expression but at higher concentration, resveratrol implicated significant toxicity in the rats liver genes (Hebbar et al., 2005). Most studies stated that resveratrol does not show much adverse effects and is properly well tolerated. However, new trials should be designed focusing on the long term evaluation of resveratrol safety and toxicological profile. Quercetin raised controversial scientific discussions, since in some animal studies there was no significant toxicity, whereas the risk of neurotoxicity is also considarable. High accessibility of quercetin to the brain (liposomal preparations or higher BBB permeability conditions) may elevate the risk of neurotoxicity due to its narrow therapeutic dose-range in vitro, although the risk may increases in vivo in CNS (Ossola et al., 2009). Ossola and colleagues have concluded that even quercetin showed toxicity in neuronal culture at very low concentration (1 μM), but many other animal studies reported no toxicity/carcinogenicity, which may be contributed to its inclusive metabolism by the digestive system (Ossola et al., 2009).