# Iridoids and Other Monoterpenes in the Alzheimer's Brain: Recent Development and Future Prospects
## 4 Therapeutic Potential for Alzheimer's Disease  
### In Vitro Protective Effects  
The vast arrays of neuroprotective effects of iridoids and some monoterpenes are shown in Table 1[26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56]. The A\(\beta\) formation, aggregation and function have been the major target areas of AD for in vitro experiments. In a study by [PERSON] et al. [26], the \(\beta\)-secretase (recombinant human BACE1) inhibitory activities of some monoterpenes have been evaluated. Even though the inhibitory activity of these compounds were confirmed, their activity was moderate (above  
Figure 3: Structures of compounds with potential effects on the [PERSON]’s brain. Note that compounds containing a sugar moiety (oleuropein, loganin, geniposide, catalpol and paeoniflorin) are highly polar and hence are not components of essential oils. 50 \(\upmu\)M) with geranyl acetone being the most active (IC\({}_{50}\) value of 51.9 \(\pm\) 3.9 \(\upmu\)M) followed by (+)-camphor (95.9 \(\pm\) 11.0 \(\upmu\)M), (\(-\))-fenchone (106.3 \(\pm\) 14.9 \(\upmu\)M), (+)-fenchone (117.0 \(\pm\) 18.6 \(\upmu\)M), and (\(-\))-camphor (134.1 \(\pm\) 16.4 \(\upmu\)M). A number of in vitro experiments have also been devoted to studying the inhibitory effects of monoterpenes against A\(\beta\)-induced cytotoxicity in neuronal cells in vitro. Treatment of cells with borneaol suppressed the A\(\beta\)-induced cytotoxicity and oxidative stress in the SH-SY5Y (human neuroblastoma) cells [31] while 1,8-cineole (eucalypt) showed similar effect in PC12 (rat pheochromocytoma) cells [32]; and genipin in cultured hippocampal neurons [34]. The antioxidant activity of these monoterpenes is also evident from their ameliorating effect on the H\({}_{2}\)O\({}_{2}\)-induced oxidative stress as shown by catalpol in astrocytes [29], and \(\upalpha\)-pinene and 1,8-cineole in PC12 cells [33]. Cultured primary cortical neurons exposed to A\(\beta\) could also be rescued by geniposide from toxicity and oxidative stress [37]. In a further experiment to show the mechanism of action of geniposide in primary cultured cortical neurons' protection, the geniposide-induced \(\uptau\) protein phosphorylation and phosphorylation of Akt at Ser-473 site and GSK-3\(\upbeta\) at Ser-9 site were shown to be inhibited by leptin antagonists [38]. The role of leptin as potential mechanism of iridoids action on the [PERSON]'s brain is discussed in detail in the following section. With respect to the A\(\beta\)-induced toxicity in the central neuronal cells, the role of insulin-degrading enzyme (IDE) has been highlighted in recent years. In addition to degradation and clearance of A\(\beta\), the IDE play pivotal role in the regulation of A\(\beta\) activity. By using primary cortical neurons in a culture media, [PERSON] et al. [39] have demonstrated that geniposide enhance the phosphorylation of peroxisome proliferatorator-activated receptor \(\upgamma\) (PPAR\(\upgamma\)). The effect of geniposide in the activation of the IDE promoter was also shown to be mediated via the glucagon-like peptide-1 (GLP-1) receptor while other pathways confirmed to be involved by inhibitor studies (see Table 1) where phosphatidyl inositol 3-kinase, PI3K, proto-oncogene tyrosine-protein kinase Src (c-Src), PPAR\(\upgamma\), protein kinase A (PKA) and epidermal growth factor receptor (EGFR) [39; 40]. Furthermore, in the SH-SY5Y cells, geniposide has been shown to ameliorate the cytotoxicity of A\(\beta\) along with its oligomer assembly and cytotoxicity [41]. The protective effect of geniposide in the SH-SY5Y cells treated with other toxicants such as formaldehyde has also been reported [42]. The effect of paeoniflora in PC12 cells protection from A\(\beta\) was similar with geniposide in that its activity was correlated with upregulation of the protein kinase B (Akt) phosphorylation level, B-cell lymphoma 2 (Bcl-2) protein expression, reducing Bax protein expression and is inhibited by LY294002 [52].