## 3 AD and PD and Bioactive Rosemary Compounds with Health-Promoting Effects
### Rosmarinic Acid  
3.6.1. In Vitro Health-Promoting Effects against AD and PD  
The effects of RA were also investigated in a study on PD using the rat CGNs mentioned above. The findings suggested that RA could also decrease the CGN death caused by nitric oxide (NO) donors and sodium nitroprusside (nitroactive stress). Lastly, in contrast to CA's function, RA protected CGNs from glutamate-induced excitotoxicity [12]. RA has also been investigated in SH-SYSY cells induced with the ROS H\({}_{2}\)O\({}_{2}\) that causes cell apoptosis. RA reduced the cell death caused by ROS, decreased the upregulation of Bax and downregulation of Bcl2, and activated the heme oxygenase-1 (HO-1) enzyme, thus making RA a potential neuroprotective agent [13]. Another study in H\({}_{2}\)O\({}_{2}\)-treated cells (N2A mouse neuroblastoma cells) examined the neuroprotective effect of RA. The results of the experiments claimed that RA prevented the toxicity of the induced ROS. Moreover, RA lessened the interference from lactate dehydrogenase, the mitochondrial membrane potential, and ROS production in the cells. Adding to the above, RA prevented genotoxicity and increased the levels of TH and brain-derived neurotrophic factor genes to reduce the ROS-induced cell damage, making it a potential neurodegenerative agent to treat NDs, like PD [88].  
Concerning AD, a study that tested RA against cholinesterase enzymes proved that the compound was more active towards BChE than AChE after utilizing molecular docking studies [89]. In another trial, RA was also investigated for its AChE and BChE inhibition properties and the findings found that the induction of 85.8% inhibition against AChE required a concentration of just 1.0 mg/mL [90]. A similarly structured evaluation of the AChE inhibition ability and the antioxidant properties of RA confirmed noteworthy contraction responses in isolated guinea pig ilea. RA demonstrated higher radical scavenging abilities. Docking data for RA indicated strong similarities with AChE. In this study, in vitro and ex vivo studies and in silico docking of RA were synchronously utilized for the first time. In all the methods tested, RA showcased promising results [91]. On a comparative note, RA appears to be more effective than caffe acid (one of its monomer structural components) in terms of anti-AChE activity. However, caffe acid was found to be an essential structural feature that is responsible for RA's binding ability [92; 93]. Another study that investigated RA's ability to inhibit fibrillization further observed morphological changes in atomic force microscopy (AFM) images after saturation. More specifically, RA bound to tau protein in vitro, resulting in a downregulation in amide regions I and III and, as a result, proves that this structure halts \(\beta\)-sheet aggregation [94]. More specific studies based on the \"amyloid-\(\beta\) aggregation hypothesis\", which posits that A\(\beta\) aggregation inhibitors as therapeutic or preventive agents for AD, investigated the structure-reactivity relationships of RA-derived compounds and A\(\beta\) aggregation prevention abilities (molecular docking simulations and MSHTS assays). The study outcomes showed radical-scavenging abilities and simultaneously displayed significant hindrance to A\(\beta\)1-42 aggregation [93]. In cultures of PC12 cell lines that were exposed to A\(\beta\)1-42, cytotoxicity in connection with ROS formation, DNA fragmentation, lipid peroxidation, tau protein hyperphosphorylation, and caspase-3 activation were all found to be suppressed by RA [95]. Figure 4 summarizes all the above observations.