So far several important flovonoids
So far, several important flovonoids and polyphenoilc compounds were subjected to various human studies regarding their potential therapeutic and adverse effects (Ide et al., 2014; Turner et al., 2015; Witte et al., 2014) (Table 1). Resveratrol (trans-3,4, 5-trihydroxystilbene) is widespread stilbene type of a sirtuin1 activator and caloric restriction mimetic nutrient, mainly occurs in several plants including peanuts, berries, grape skin, blueberries, Japanese knotweed, and red wine (Bhat and Pezzuto, 2002; Chin et al., 2017, 2014; Ingram et al., 2007; Pervaiz, 2003; Witte et al., 2014). The annual sale of resveratrol supplements exceeded $30 million in the United States alone (McDermott et al., 2017). Resveratrol was subjected to a phase 2 clinical trial on 119 subjects to monitor its beneficial and adverse effects on patients with AD (Turner et al., 2015). The study was a double blind, randomized, multicentric 52 weeks investigation, on the purpose to reveal resveratrol impacts on different biomarkers along with the primary and secondary outcomes; MRI and clinical outcomes, respectively. The trial exposed that resveratrol was a safe and well tolerable drug with general side effects like nausea, weight loss and diarrhea; however these results were similar to the placebo. Resveratrol also increased the stat 3 inhibitor volume loss and most of its key metabolites penetrated BBB, which was shown by changed CSF Aβ 40 trajectory (Turner et al., 2015). In another pilot clinical study conducted on 66 old patients with peripheral artery disease, resveratrol was effective on patients walking scale and performance with no unswerving effect on walking performance progress (McDermott et al., 2017). Witte and colleagues were reported that resveratrol demonstrated positive effect in hippocampal functional connectivity in 23 overweight old healthy individuals, indeed resveratrol caused a noteworthy enhancement in hippocampal functional connectivity in addition to decreased body fat and glycated hemoglobin (HbA1c) level (Witte et al., 2014). Thus, this study provided a potential indication towards the improvement of memory performance and augmented hippocampal functional connectivity in old adults supplemented with resveratrol (Witte et al., 2014). Diet, more specifically Mediterranean, Asian and healthy diet regimen are believed to be protective against various neurodegenerative diseases (Casamenti and Stefani, 2017). This effect is most probably due to the presence of ample plant polyphenols, which are considered functional against various age- and diseases associated with neurodegenerative processes (Feart et al., 2013). Olive oil is an important lipid component of the Mediterranean diet. Olive polyphenols generally consists oleocanthal, oleuropein, hydroxytyrosol and also resveratrol. Extra virgin olive oil contains many phenolic compounds with potential benefits towards different degenerative diseases; tau and Aβ pathologies (Casamenti and Stefani, 2017; Daccache et al., 2011; Grossi et al., 2013; Monti et al., 2012). A clinical study by Berr et al. (2009) showed that olive oil was useful on different cognitive dysfunctions such as cognitive deficit and decline (Berr et al., 2009). Pterostilbene, an important phenolics was found beneficial for the brain health and subjected to a human study on 80 patients to evaluate its safety and pterostilbene at a dose up to 250 mg/day was safe (Riche et al., 2013). Yet, pterostilbene efficacy against neurodegeration disorders was not assessed in this trial. Recently, registration of 20 clinical trials were evidenced pertaining to the clinical effectiveness of polyphenols in the treatment of primary and secondary dementia, of which 8 studies were completed and 12 are in progress (Molino et al., 2016). These studies showed curcumin was the most effective compound followed by resveratrol and Epigallocatechin gallate (EGCG) either alone or in combination with other drugs, interestingly in one trial along with yoga (Baum et al., 2008; Molino et al., 2016; Ringman et al., 2012). The adverse and biological effects of curcumin were clinically studied in two different double blind placebo controlled investigations for AD treatment and it was found that the compound was well tolerated (Baum et al., 2008; Ringman et al., 2012).