## 4 Discussion  
In this study, we assessed the antioxidant and protective effects of nine different botanical extracts on human neural stem cells (NSCs), using the ROS/RNS antioxidant assay. Additionally, we evaluated the protective capacity of different products measuring gene expression regulation after H\({}_{2}\)O\({}_{2}\)-induced toxicity in NSCs. The botanical extracts chosen for the analysis were based on a bibliographical review of potential candidates, where both preclinical and clinical studies were performed on patients with dementia and healthy older adults. Both _Vaccinium myrtillus_ (bilberry) and _Vaccinium angusifolium_ (blueberry) were selected because they are rich in anthocyanins, which have been demonstrated to display anti-inflammatory and neuroprotective properties [19; 20]. Specifically, bilberry anthocyanins have been shown to help reduce inflammation in aging rats [21]. Blueberries have been tested in a clinical setting on several occasions, with significant improvements observed in cognitive performance, execution and greater brain activity [22; 23; 24; 25]. _Bacopa monnieri_ (bacopa) contains bacosides, which have been shown to possess anti-inflammatory and antioxidant properties in the brain [26]. Clinical trials in patients with Alzheimer's disease revealed significant results in various aspects ofthe MMSE [27], while studies in healthy adults revealed more limited results [28; 29; 30; 31; 32]. _Salvia officinalis_ (sage) may not be as well known as other popular nootropics such as the bacopa or ginkgo biloba, but there is previous evidence that its components can act upon the brain through several mechanisms, including antioxidant/anti-inflammatory effects, cholinergic activity, trophic factor release and, amyloid-beta [33]. A few clinical studies have shown positive results in cognitive health and mood both in patients with Alzheimer's disease and healthy older adults [34; 35; 36]. _Crocus sativa_ stigmas (saftron) contain safranal and crocins [37] and are suggested to exert their effect on the brain through their antioxidant properties. Several clinical studies have also been conducted in both patients with Alzheimer's disease and healthy adults, with results in both cognitive health and mood [38; 39; 40; 41]. _Rhodiodia rosea_ (arctic root) is considered an adaptogen and is suggested to possess neuroprotective properties [42; 43]. Clinical results with this botanical have shown positive effects related to mood and mental performance [44; 45; 46]. _Ginkgo biloba_ is one of the most studied botanical extracts for cognitive health, where numerous studies suggest potential benefits in memory, concentration, fatigue, stress and mood [47; 48]. The same can be said of _Panax ginseng_[48; 49]. Lastly, _Centella asatica_ (gotu kola) contains asiaticosides, which have been shown to possess neuroprotective properties mainly by reducing amyloid-beta deposition [50]. Clinical trials are less abundant with gotu kola, although some positive results have been observed in healthy older adults [51]. The in vitro results indicated that only blueberry, sage and arctic root revealed a significant antioxidant effect, while the other extracts either did not have an effect or were pro-oxidant (such as saffron and ginkgo). As for trophic factor release, sage was the only extract to increase the expression of all the factors analyzed: Nrf2, NGF and VEGF. For this reason, _Salvia officinalis_, or sage, was chosen as the main ingredient for a nootropic formula. After selecting _Salvia officinalis_ as the candidate botanical extract, tests were conducted analyzing sage in combination with rutin, a polyphenol with known nootropic properties [14; 16]. The results revealed an enhanced effect in increasing BDNF production when combining sage with rutin. BDNF is considered one of the most important molecules implicated in memory [52]. Studies revealed that low BDNF levels could be a biomarker for early dementia diagnosis, especially Alzheimer's disease [53].