## 3 AD and PD and Bioactive Rosemary Compounds with Health-Promoting Effects
### Carnosic Acid
#### 3.5.1 In Vitro Health-Promoting Effects of Carnosic Acid against AD and PD
Regarding Alzheimer's, in vitro studies of CA found that it displays inhibition abilities for both AChE and BCHE (acetylcholinesteraseterase and butylcholinesteraseterase, respectively) enzymes [80]. In a human dopaminergic neuroblastoma cell line (SH-SYSY), the possible use of CA to counteract methylglyoxal (MG)-induced disease was investigated. MG is an effective activator of AGEs (which are present in AD). CA pretreatment alleviated cytotoxicity, and apoptosis was induced by MG by activating the PI3K/Akt/Nrf2 signaling pathway and antioxidant Nrf2-dependent enzymes. Therefore, its use can be beneficial in combating AD [81]. CA was investigated at 30 mM regarding A\(\beta\) production in SH-SYSY human neuroblastoma cells, where it was found to diminish A\(\beta\) secretion via \(\alpha\)-tumor necrosis factor (TNF\(\alpha\))-converting enzyme (TACE), without affecting the b-secretase BACE1 [82]. The researchers also suggested that A\(\beta\) has an immediate effect on SH-SYSY cell death due to PARP cleavage and the stimulation of caspases 3, 8, and 9, while pretreatment with 10 mM CA produced a fragmentary decrease in apoptosis and downregulation of the cellular A\(\beta\) content [83]. CA, in general, is considered a pro-electrophilic drug (PED) and is pathologically activated via stimulation of the Nrf2 pathway. CA, which is commonly extracted from _Rosmarinus officinalis_ or synthesized, acts as a catechol-type PED drug. To accomplish oxidative activation of the pro-electrophilic state to the electrophilic state, electron acceptors, including ROS, tend to play a pivotal role. As a result, the quinone compound reacts with cysteine thiols. During this process, a cysteine thiol stimulates a nucleophilic attack of the electrophilic compound to constitute the addition product, CA, and hence, changes from an inactive (pro-electrophilic) state to an active (electrophilic) state when oxidative stress is present. Consequently, CA transforms into its active state in conditions where oxidative and inflammatory stress are present in the tissue, protecting the tissue from stress in disordersincluding AD. This is accomplished by stimulating the KEAP1/Nrf2 mechanism via the quinone formation of CA. The Nrf2/KEAP1 pathway is one of the main constituents of the cellular defense mechanisms combating oxidative and inflammatory stress. Nrf2 works as a transcription factor responsible for the expression of phase II antioxidant and antiinflammatory enzymes. KEAP1 protein, under normal conditions, is connected to Nrf2 and operates as an adaptor protein for cullin 3 (Cul3 in humans) E3 ubiquitin ligase, which ensures that Nrf2 is polyubiquitinated. Subsequently, Nrf2 is degraded by the proteasome. Therefore, the transcriptional activity of Nrf2 is regulated and inhibited when pathogenesis is not present. KEAP1 consists of vital cysteine thiols that interact with CA after electrophilic conversion, as previously described. This reaction hinders KEAP1 from causing the ubiquitination and degradation of Nrf2. Nrf2, therefore, can be isolated from the cytoplasmic complex with KEAP1, and they can reach the nucleus and bind to AREs (antioxidant response elements) to induce target phase II genes in the well-coordinated formation of antioxidant as well as anti-inflammatory enzymes. These enzymes are responsible for the production of one major cellular antioxidant: glutathione (GSH). Thus, it can be concluded that Nrf2 activators have a protective role in numerous cell types, neurons included, via the regulation of chemical redox. In the brain, the upregulation of Nrf2 takes place predominantly in astrocytes as well as microglial cells; this biochemical pathway is shown in Figure 3[84].