## 2 Sesquietpene Lactones with Significant In Vivo Activity
### Parthenolide
Furthermore, the effect of parthenolide on the development of colitis-associated colon cancer (CAC) was investigated using a murine model of azoxymethane (AOM)/dextran sulfate sodium (DSS) induced CAC. This study showed that parthenolide administration (**10**) at 2 and 4 mg/kg can significantly inhibit the inflammation-carcinoma sequence and be crucial in experimental CAC regulation. The mechanism of action involves decreased NF-kB p65 expression levels blocking phosphorylation and subsequent degradation of \(\upkappa\)B-\(\upalpha\) inhibitor (I\(\upkappa\)B\(\upalpha\)) [196]. The authors conclude that parthenolide (**10**) could be a novel chemopre agent for CAC treatment [196]. Oral cancer is one of the five most common cancers worldwide. Chemoprevention is a new approach to cancer research, focusing more on the prevention, suppression, and reversal of the carcinogenic process by the use of natural plant products and/or synthetic chemical compounds. Thus, [PERSON] et al. [197] tested the chemopre potential of parthenolide in DMBA-induced hamster buccal pouch carcinogenesis (DMBA, 7,12-dimethylbenz[a]anthracene). Oral administration of parthenolide (**10**) at 2 mg/kg b.w. completely prevented tumor formation and significantly reduced the nefarious histopathological changes. In addition, the parthenolide treated group showed significant improvement regarding antioxidants, detoxification enzymes and lipid peroxidation. Glioblastoma, or glioblastoma multiforme (GBM), is the most aggressive type of brain cancer and is very difficult to treat. [PERSON] and [PERSON] [198] examined the effect of compound **10** on tumor growth using a xenograft mouse model of glioblastoma, administering it intraperitoneally (10 mg/kg/day) for 22 days. It significantly inhibited the growth of transplanted glioblastoma cells with respect to the control group. [PERSON] et al. [199] demonstrated that a high parthenolide dose (8 mg/kg/day) impedes initiation of experimental autoimmune neuritis (EAN), an animal model for peripheral nervous system acute inflammatory disease. This is achieved by parthenolide suppressing TNF-\(\upalpha\), IFN-\(\upgamma\), IL-1\(\upbeta\) and IL-17 pathways and quickly decreasing Th1 and Th17 cells in the early stages. Although this anti-inflammatory effect is short-lived, compound **10** also suppresses late-stage recovery of EAN models, along with inhibiting the apoptosis of inflammatory cells. Such results suggest that parthenolide is not suitable for nervous system autoimmune disease treatment. Nitric oxide (NO) plays a key role in the etiopathology of central nervous system (CNS) diseases like multiple sclerosis (MS). It has been proposed that inhibition of NO synthesis could prove a relevant mechanism of action in treating multiple sclerosis and migraine. Accordingly, [PERSON] et al. [200] investigated the effect of parthenolide (**10**) on iNOS synthesis and NO release using primary rat microglia. The results indicated that compound **10** prevents iNOS/NO synthesis and inhibits the activation of p42/44 mitogen-activated protein kinase (MAPK), but not IkB\(\alpha\) degradation or NF-kB p65 activation. These results show parthenolide may be a potential therapeutic agent in the treatment of CNS diseases. Mechanisms of axon regeneration and optimal functional recovery after nerve injury are key to in higher animals. However, insufficient growth rates of injured axons often lead to incomplete peripheral nerve regeneration. [PERSON] et al. [201], demonstrated that a single parthenolide injection at 5 nM into the injured sciatic nerve or its systemic intraperitoneal application was already enough to significantly increase the number and length of regenerating axons in the distal nerve at three days post-lesion. This application of parthenolide (**10**) appears to act on the great instability of microtubules in promoting axonal growth, at least in the CNS [174].