## 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  
Starting with Parkinson's, a study investigated the potential in vitro neuroprotection of CA in SH-SY5Y cells. Pretreatment with this phenolic dicterpene led to a rise in the protein expression of \(\gamma\)-glutamate-cysteine ligase catalytic subunit, \(\gamma\)-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase. The presence of a p38 (mitogen-activated protein kinase (MAPK)) inhibitor or a JNK (c-Jun N-terminal kinase 1) inhibitor in these cells counteracted the decrease in the Bcl-2 (B-cell lymphoma 2)/Bax ratio, the activation of caspase-3 cleavage, and the rise in poly (ADP-ribose) polymerase (PARP) cleavage by 6-hydroxydopamine (6-OHDA) shown in immunoblots. Nevertheless, a Bax enhancer, BAM7, weakened the impact of CA on cell death [10]. Another study on these cells was conducted, where CA effectively reverted the upregulation of ubiquitinated proteins and the phosphatase and tension homologue (PTEN)-induced putative kinase 1 (PINK1) depletion, as well as the depletion of Parkin protein, in the cells treated with 6-OHDA [16]. CA was also examined in these cells, and it serves as a neuroprotective agent by stimulating  
Figure 2: Predicted polarity and lipophilicity of rosemary bioactive, according to their logKow values (Kow = n-octanol/water partition coefficient). autophagy via Parkin and Beclin1. The results showed higher levels of Parkin protein, autophagy-related markers and gene 7, phosphatidylinositol 3-kinase p100, Beclin1, and microtubule-associated protein 1 light chain 3-II. 6-OHDA-treated cells had decreased levels, but pretreatment with CA reversed these effects. Last but not least, tests showed that the interface between Parkin and beclin1 was minimized by an oxidizing agent, but CA in the cells helped reverse those effects. Thus, the earlier hypothesis was confirmed [79]. Further studies were conducted on the neuroprotective function of CA against PD in a paraquat (PQ) model of the disease, as measured by redox indicators in the cells and mitochondria. The outcomes showed that the symptoms of the PQ model were blocked by CA, which protected the cells by reducing ROS and RNS production of the PQ and minimizing the toxicity that surfaced as mitochondrial dysfunction. Inhibiting the Pi3K pathway using LY294002 or suppressing the expression of nuclear factor erythroid-3-related factor 2 (Nrf2) resulted in some abrogation of the reversal of redox dysfunction triggered by CA. So, CA stimulation of Nrf2 through the regulation of the phosphatidylinositol 3-kinase (Pi3K)/Akt pathway led to an increased concentration of antioxidant enzymes, accounting for the neuroprotective activity of CA [17]. Moreover, taking a look into an older paper about 6-OHDA-treated cells and CA, immunoblots showed that the phosphorylation of JNK and p38, caused by 6-OHDA, were reduced by CA pretreatment. GSH levels were increased, and so were the levels of the \(\gamma\)-glutamate-cysteine ligase catalytic subunit and \(\gamma\)-glutamate-cysteine ligase modifier subunit in the presence of CA. It is worth mentioning that there was also an increase in Nrf2 activation, antioxidant response element (ARE)-luciferase reporter activity, and DNA connecting to the ARE, indicating that CA may be a potential neuroprotective agent against PD [15]. Lastly, in a study on rat cerebellar granule neurons (CGNs), there was an investigation on the factors that caused oxidative stress to neurons. CA decreased the CGN apoptosis initiated by an oxidizing factor, nitric oxide contributor (NO contributor), and sodium nitroprusside (nitroactive stress) and saved the rat's brain neurons from caspase-dependent death caused by a reduction in depolarizing extracellular potassium levels (5K apoptotic condition). The results also showed that CA could shield CGNs against 5 K-induced apoptosis by activating a PI3K mechanism that promotes cell survival [12].