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Intravenous Immunoglobulin (IVIg) are human IgG derived from plasma pools of healthy donors. Although there are studies in literature evaluating their effectiveness in different pathological animal models, there are no data about their possible role on Bortezomib (BTZ)-induced peripheral neuropathies. Female Wistar rats were treated following a preventive schedule (BTZ and IVIg co-treatment for 3 and 8 weeks) and a therapeutic schedule (4 weeks of BTZ treatment followed by a 4-week IVIg-BTZ cotreatment). Caudal nerve conduction velocity (NCV), plantar and dynamic tests were performed at different time points. Animals were sacrificed after 3ws (acute phase) or 8ws (chronic phase) and tissue samples (Dorsal Root Ganglias -DRG-, sciatic nerve, caudal nerve, skin) were collected for morphological, morphometrical and immunohistological analysis.In the preventive schedule, IVIg was not able to rescue caudal NCV reduction caused by BTZ neither after 3 nor after 8 weeks of co-treatment. Same results were observed in the therapeutic schedule. On the other hand, the evaluation of mechanical allodynia and cold hyperalgesia showed that IVIg injection protected from BTZ effect in both treatment schedules. Morphometric analysis evidenced that, even if not statistically significant only the preventive schedule has a tendency to protect the caudal nerve from BTZ damage. This result is consistent with the morphological evaluation of the nerve. Also, intraepidermal nerve fibers density was preserved in the preventive schedule but not in the therapeutic one. Finally, sciatic nerve and DRG macrophage infiltration levels tended to be reduced in the therapeutic schedule and were brought back to ctrl (rats not treated or injected with IVIg alone) levels in the preventive one. In conclusion, we were able to demonstrate for the first time that IVIg treatment especially used as preventive treatment option may reduce BTZ-induced neuropathic painful pointing out the possible role of inflammati

BackgroundTo report our prospective experience on the incidence and pattern of oxaliplatin (OXA)-induced peripheral neuropathy (OXA-IPN) in patients with colorectal cancer (CRC) treated with either FOLFOX-4 or XELoda + OXaliplatin (XELOX).Patients and methodsOne hundred and fifty patients scheduled to be treated with either FOLFOX or XELOX for CRC were prospectively monitored at baseline and followed-up during chemotherapy. The incidence and severity of symptoms secondary to OXA-IPN were recorded using three different types of assessment, i.e. the motor and neurosensory National Cancer Institute common toxicity criteria, version 3.0 (NCI-CTCv3), the clinical version of the total neuropathy score (TNSc) and electrophysiological scores.ResultsPatients treated with either FOLFOX-4 or XELOX manifested similar incidence rates and severities of acute OXA-IPN. However, FOLFOX-4 was associated with increased incidence of chronic neurotoxicity, compared with XELOX-treated patients (n = 64/77 versus 44/73; P = 0.002), at a very similar OXA median cumulative dose during both regimens. Both the NCI-CTCv3 and TNSc demonstrated that the severity of cumulative OXA-IPN in FOLFOX-4-treated patients is higher than in those treated with XELOX.ConclusionThe incidence of acute neurotoxicity during FOLFOX-4 therapy is similar to XELOX. However, it seems that FOLFOX-4 is more neurotoxic than XELOX in terms of cumulative OXA-IPN, despite comparable OXA cumulative dose.

The mechanism(s) and site(s) of the neurotoxic effect of cisplatin (CDDP) are still not entirely elucidated. A more detailed knowledge of these aspects of CDDP treatment might be useful to obtain a better understanding of the pathogenesis of its peripheral neurotoxicity, which is the dose-limiting side effect of CDDP. In the present study, the occurrence of CDDP-induced DNA-platination in dorsal root ganglia (DRG) of rats was evaluated in relation to DRG neuron pathological changes and CDDP-induced neuronopathy. Eight adult Wistar rats were treated with 2 mg/kg i.p. CDDP twice weekly for 9 times to induce sensory peripheral neuropathy. DNA-platination in specimens of DRG and kidney was measured immunohistochemically, with a polyclonal antibody (GPt) detecting CDDP-induced Pt-DNA adducts. Results were compared with those of untreated rats. Chronic CDDP-induced neurotoxicity, in a well described experimental model of chronic CDDP neurotoxicity in the Wistar rat, was confirmed by sensory DRG neuronopathy with secondary neuropathy, and demonstrated by reduced pain detection, decreased nerve conduction velocity in the tail nerve as well as morphological and morphometric changes in DRG neurons. Nuclear immunostaining for Pt-DNA adducts was observed in tubular cells of the kidney in 75% of the evaluated CDDP-treated rats, while in DRG cells CDDP-induced Pt-DNA adducts formation was found in 43% of the evaluated CDDP-treated rats. CDDP-induced DNA-platination was demonstrated in rat DRG neurons using a schedule of chronic CDDP administration which induced the onset of a sensory neuronopathy with secondary peripheral neuropathy. This finding further supports the hypothesis that CDDP is neurotoxic because it directly damages the DRG neurons

Peripheral nervous system alterations were induced in adult rats by administration of cisplatin (CDDP) 2 mg/kg twice weekly for 4.5 weeks. Dorsal root ganglion neurons showed pathological changes. Morphometric determinations demonstrated a reduction in size of the somatic, nuclear and nucleolar area. The nucleoli were the most involved subcellular structures. Nerve conduction velocity and the tail-flick test for pain were both significantly altered in CDDP treated rats, whereas the rota-rod test for coordination revealed no changes in either treated or control rats. Analytical determinations demonstrated platinum accumulation in the DRG of CDDP treated rats. Spontaneous recovery, demonstrated by morphometric, electrophysiological, functional and analytical determinations, occurred after treatment discontinuation within about 7 weeks. A pilot study of the possible neuroprotective action of retinoic acid (RA) was also performed with this model of cisplatin neuronopathy. The rationale for using RA was based on its assumed antioxidant and neurotrophic effect. However, RA failed to prevent morphometric, electrophysiological, functional and analytical alterations induced by CDDP on DRG neurons. RA induced only a mild generalized protective effect

We evaluated clinically and neurophysiologically the immediate and long-term involvement of the peripheral nervous system in 22 selected patients with epithelial ovarian cancer successfully treated with DDP alone or in combination with non-neurotoxic drugs. While the motor nerves were unaffected, generally the involvement of sensory nerves was more severe at the examination performed several months after DDP discontinuation than at the evaluation performed after the "induction phase". We conclude that up to now the importance of long-term DDP-induced peripheral nerve damage has probably been underestimated. DDP-induced long-term damage is at least as severe as the immediate toxicity and, moreover, it is likely that complete recovery can occur, if ever, only years after DDP discontinuation

Cisplatin is known to induce a disabling sensory peripheral neuropathy. However, some authors have suggested that cisplatin may also cause motor impairment, raising doubts as to the pathogenetic hypothesis of primary damage to the dorsal root ganglia neurons induced by the drug. In order to clarify the real extent of motor nerve damage induced by cisplatin we performed a prospective neurophysiologic study on 33 patients affected by ovarian cancer in which cisplatin was administered as single anticancer agent. No motor nerve impairment ensued after cisplatin treatment and, therefore, we conclude that the occurrence of motor neuropathy during or immediately after, cisplatin treatment is probably coincidental and indicates the need for a careful search for concomitant causes of peripheral nerve damage

The authors prospectively evaluated the effects of three different schedules of cisplatin (DDP) administration in 60 patients with advanced epithelial ovarian cancer. The individual total dose of DDP was 450 mg/m2 in all three groups, and the anti-cancer response at the end of treatment was similar for the different regimens. The clinical and neurophysiologic results confirmed that axonal sensory neuropathy occurred after the standard administration of DDP (75 mg/m2 in 3-week cycles) and probably not only the peripheral, but also the central sensory pathway, was involved. Although the total dose of the drug was identical, the two less conventional schedules were less neurotoxic. These results suggest that not only the total-dose intensity, but also the single-dose intensity are relevant in the onset of DDP-induced sensory neuropathy; therefore, the use of less neurotoxic schedules may prevent or reduce sensory nerve damage.

Light-microscope findings and pathological ultrastructural changes in sural nerve biopsies from two patients affected by hypothyroidism, one with overt signs of peripheral neuropathy, the other asymptomatic, were studied. In both patients the endoneural vessels showed clear pathological changes similar to those of other metabolic neuropathies, but more marked in the symptomatic patient. It is proposed that the changes observed in the nerve fibers in hypothyroid neuropathy are secondary to changes in the endothelial cells and in the vessel wall