# \(\beta\)-Caryophyllene: A Sesquiterpene with Countless Biological Properties
## 2 Biological properties of \(\beta\)-caryophyllene
### \(\beta\)-Caryophyllene and Nervous System
The main mechanism of action regarding this aspect is the stimulation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) following the activation of cannabinoid receptors CB2. Nrf2 is a transcription factor, whose activity is stimulated by oxidative stress (in particular, reactive oxygen species or ROS) and oncogenes, such as KRAS, BRAF and MYC. Nrf2 increases the expression of the genes involved in cell survival and in the reduction of the inflammatory process and the oxidative stress in SNC. Moreover, nerve growth factor (NGF) is stimulated through Tropomyosin receptor kinase A (Trk A) pathway, which stimulates in turn PI3K-Akt pathway [68]. BCP, through Nrf2 activation, increases the expression of antiapoptotic genes (B-cell leukemia/lymphoma-2 (BCL-2), Mouse double minute 2 (mdm-2), COX-2, c-Myb) and, at the same time, reduces the one of proapoptotic genes (Bax, Bak-1, caspase-8, caspase-9) [31]. All these cellular events determine cell survival and proliferation and angiogenesis [9]. BCP also diminishes the expression of matrix metallopeptidase (MMP-9) and increases the one of occludin, claudin-5, Tight Junction Protein ZO-1 and Growth Associated Protein 43 (GAP-43) [32]. Furthermore, BCP, at the concentrations of 0.5 and 1 \(\upmu\)M, exerts cytoprotective effect on C6 glioma cells, increasing the antioxidant activity, through CB2-R-dependent Nrf2 pathway [33]. In addition, administered orally in Wistar rats, at the dosages of 34, 102 and 306 mg/kg, it reduces oxidative stress and neuronal apoptosis, due to the increased expression of Nrf2 and OH-1. BCP also inhibits the production of nitric oxide, hydrogen peroxide, TNF-\(\alpha\), interferon gamma (IFN-\(\gamma\)), interleukin-17 (IL-17) reducing the extent of macrophage infiltration [9]. BCP can induce neurogenesis with a mechanism independent from the activation of CB2-R, Nrf2 and NGF, stimulating Tropomyosin receptor kinase A (TrkA) in SH-SYSY (Cell lines Homo sapiens, human, bone marrow) and PC12 (Cell line derived from a pheochromocytoma of the rat adrenal medulla) neuroblastoma cells [34]. There are numerous studies regarding the analgesic effects of the sesquiterpene, isolated or in mixture in essential oils. In fact, the essential oil of _Erymanthos erythromycinopus_, containing BCP as one of the main components, administered orally at the doses of 200 and 400 mg/kg, induces analgesia in Wistar rats [23]. Further, the essential oil of _Senecio rufinervis_, containing about the 6% of BCP, is responsible for the analgesic effect in mice, when administered orally at the doses of 50 and 75 mg/kg [35]. Other studies have reported the same results in mice at the doses of 1 and 5 mg/kg intraperitoneally and at the dosages of 2.6 mg/kg/die per _os_ for 2 weeks, alone or in combination with the docosahexaenoicenoic acid (DHA) [9]. The essential oil of _Vitex agnus-castus_ (BCP accounts for about 7% of the oil), has exhibited analgesic effect in Wistar rats which were subjected to an immersion test. BCP, at the dose of 25 mg/kg, decreases the extent of peripheral neuropathy mice, by the activation of cannabinoid receptors CB2-R and the inhibition of the MAPK p38, resulting in a reduced transcriptional activity of NF-kB, involved in phlogosis [36]. It has been demonstrated in mice that BCP actually exerts its antinociceptive action by activating CB2-Rs, in particular towards primary sensory neurons. In fact, the analgesic effect manifests itself in wild-type mice, but not in the CB2-R knockout mice. The activation of cannabinoid system indirectly leads to the modulation of opioid system. In more detail, it stimulates \(\beta\)-endorphin release, activating opioid receptors \(\mu\) on primary afferent neurons. BCP has been shown to boost the painkilling effect of morphine, used in the treatment of severe pain, making possible the reduction of the dose of the drug and, consequently, decreasing its side effects [37]. Instead, there was no indication of synergy between BCP and the other components of the essential oils [13].