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Observations so far obtained in experimental autoimmune encephalomyelitis (EAE) have revealed the promising neuroprotective effects exerted by progesterone (PROG). The findings suggest that this neuroactive steroid may potentially represent a therapeutic tool for multiple sclerosis (MS). However, up to now, the efficacy of PROG has been only tested in the acute phase of the disease, whereas it is well known that MS expresses different features depending on the phase of the disease. Accordingly, we have evaluated the effect of PROG treatment in EAE induced in Dark Agouti rats (i.e. an experimental model showing a protracted relapsing EAE). Data obtained 45 days after EAE induction show that PROG treatment exerts a beneficial effect on clinical score, confirming surrogate parameters of spinal cord damage in chronic EAE (i.e. reactive microglia, cytokine levels, activity of the Na(+) ,K(+) -ATPase pump and myelin basic protein expression). An increase of the levels of dihydroprogesterone and isopregnanolone (i.e. two PROG metabolites) was also observed in the spinal cord after PROG treatment. Taken together, these results indicate that PROG is effective in reducing the severity of chronic EAE and, consequently, may have potential with respect to MS treatment.

Several effective antineoplastic drugs are severely neurotoxic and induce the onset of disabling peripheral neuropathies. The clinical presentation of this side effect depends on the type of antineoplastic agent administered. The signs and symptoms shown are predominantly motor (e.g. in the case of vinca alkaloids), sensorimotor (e.g. with the taxanes) or sensory (e.g. using platinum-derived drugs). The pathogenesis of these antineoplastic drug-induced peripheral neuropathies is still poorly understood, although a relationship has been suggested between some neuronal growth factors (neurotrophins) and the toxic action of cisplatin (CDDP) and paclitaxel. In this study we correlated the changes in the circulating levels of Nerve Growth factor (NGF) in a series of 24 women affected by locally advanced squamous cervical carcinoma treated with cisplatin and paclitaxel-based chemotherapy with the severity of chemotherapy-induced peripheral neuropathy (CIPN) as assessed by the Total Neuropathy Score (TNS). After informed consent, blood samples were drawn before chemotherapy and after treatment and NGF circulating levels were determined by ELISA (EmaxTM ImmunoAssay System, Promega, USA; plasma working dilutions NGF 1:80) following the manufacturer protocols. The results obtained in this series of patients evidenced a significant correlation between the severity of CIPN and the reduction in the circulating levels of NGF (r = − 0.480, p = 0.017 by two-tailed Spearman correlation test, 95% CL −0.745 to −0.082), thus confirming similar results previously obtained in a rat model of CDDP peripheral neurotoxicity. In conclusion, our data suggest that a relationship exists between CIPN and NGF circulating levels in patients treated with cisplatin and paclitaxel. Therefore, this preliminary observation support the need for further studies in order to explore the possibility of reducing the severity of platinum-drug sensory neurotoxicity with treatments aimed at increasing the circulating levels of NGF.

We have demonstrated in the SH-SY5Y human neuroblastoma cell line that the antineoplastic drug paclitaxel induces apoptosis associated with the phosphorylation of c-raf and Bcl-2, thus causing Bcl-2 inactivation. In addition, we have observed the cleavage of caspase 7 and PARP, and the involvement of JNK/SAPK cascade. In this study, we investigated the possible anti-apoptotic effect of resveratrol on paclitaxel-induced apoptosis. Resveratrol is a natural antioxidant occurring in grapes and wine that as been shown to have anticancer and anti-inflammatory effects. Studies on the effect(s) of resveratrol on nervous cells are very few and limited to testing its ability in preventing oxidative stress in rat pheocromocytoma PC12 cells. However, the biological and pharmacological properties of resveratrol suggest that this natural compound might act on neuronal cells with a mode of action that is different from the antioxidant ones. To confirm this hypothesis, we studied the possible antagonist effect(s) of resveratrol on paclitaxel-induced apoptosis pathways. Our results indicate that the simultaneous treatment of 50M resveratrol and 1M paclitaxel induces a significant reduction of the percentage of apoptotic cells in comparison with 1M paclitaxel alone. Furthermore, we have demonstrated that resveratrol treatment determines a significant reduction of the phosphorylation of c-raf and Bcl-2 and a partial reduction of cleavage of caspase 7 and PARP. Finally, we observed an evident reduction of activation of JNK/SAPK in the presence of resveratrol. On the contrary, resveratrol does not affect the tubulin polymerization induced by paclitaxel. In conclusion, our results suggest that resveratrol is able to partially antagonize a nonoxidative stress apoptotic stimulus by influencing the typical signal pathways involved in apoptosis.