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An exciting and relevant topic is addressed in this paper collection encompassing both peripheral and central nervous system mechanisms of damage [...].An exciting and relevant topic is addressed in this paper collection encompassing both peripheral and central nervous system mechanisms of damage [...].

Chemotherapy-Induced Peripheral Neurotoxicity (CIPN) is a severe and long-lasting side effect of anticancer therapy, which can severely impair patients’ quality of life. It is a sensory and length-dependent neuropathy, which predominantly affects large myelinated fibers. Easy and reliable monitoring of CIPN in patients is still an unmet clinical need. Since increasing clinical evidence supports the potential use of neurofilament light chain (NfL) as a biomarker of axonal injury, in this study we measured serum NfL levels in animals chronically treated with cisplatin (CDDP) and paclitaxel (PTX), two antineoplastic drugs with different neuronal targets. Wistar rats were treated with CDDP (2 mg/kg i.p. twice/week for 4 weeks) or PTX (10 mg/kg i.v. once/week for 4 weeks). Repeated serum NfL quantification was obtained using the Single Molecule Array (Simoa) technology. The onset and progression of peripheral neurotoxicity were evaluated through neurophysiology, morphological assessments and intraepidermal nerve fibers density quantification. Our results showed that serum NfL measurements correlated with the severity of axonal damage. In fact, both treatments induced serum NfL increase, but higher levels were evidenced in PTX-treated animals, compared with CDDP-treated rats, affected by a milder neurotoxicity. Notably, also the timing of the NfL level increase was associated with the severity of morphological and functional alterations of axonal structure. Therefore, NfL could be a useful biomarker for axonal damage in order to follow the onset and severity of axonal degeneration and possibly limit the occurrence of serious PNS disease.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one common side effect associated with antineoplastic agents. Despite its relevance, the underlying mechanisms remain poorly understood. In this study, we explored cytokines and macrophages that contribute to two chronic models of CIPN comparing paclitaxel (PTX)- and oxaliplatin (OHP)-induced CIPN in rats. To detect chemotherapy-induced sensory or neuronal abnormalities behavioral tests, pathological and morphometric analysis were used. To investigate systemic inflammation, a panel including IL-6, IL-1β, IL-2, IL-10, GRO/KC(CXCL1), TNFα, IFNγ were tested in serum. Besides, we analyzed dorsal root ganglia (DRG), caudal nerves and spinal cord mRNA expression of a panel of pro-inflammatory markers IL-6, CCL2 and NLRP3, as well as caudal macrophage infiltration. We evidenced a remarkable difference in caudal macrophage infiltration in PTX- vs. OHP-treated rats, which was associated with serum CXCL1 and to a different IL-6 expression pattern in serum, DRG, spinal cord and caudal nerve. Moreover, CCL2, NLRP3 upregulation was also increased in the caudal nerves in PTX-treated animals. On the contrary, OHP induced IL-6 and CCL2 expression in DRG. Since our results suggest that CXCL1 or IL-6 could be considered as critical lynchpins between inflammation pain and CIPN, targeting early inflammatory events could be a promising therapeutic approach.

Peripheral neurotoxicity is one of the most distressing side effects of oxaliplatin therapy for cancer. Indeed, most patients that received oxaliplatin experience acute and/or chronic severe sensory peripheral neuropathy. However, despite similar co-morbidities, cancer stage, demographics and treatment schedule, patients develop oxaliplatin-induced peripheral neurotoxicity with remarkably different severity. This suggests individual genetic variability, which might be used to glean the mechanistic insights into oxaliplatin neurotoxicity. We characterized the susceptibility of different mice strains to oxaliplatin neurotoxicity investigating the phenotypic features of neuropathy and gene expression profiles in dorsal root ganglia of six genetically different mice strains (Balb-c, C57BL6, DBA/2J, AJ, FVB and CD1) exposed to the same oxaliplatin schedule. Differential gene expression in dorsal root ganglia from each mice strain were assayed using a genome-wide expression analysis and selected genes were validated by RT-PCR analysis. The demonstration of consistent differences in the phenotypic response to oxaliplatin across different strains is interesting to allow the selection of the appropriate strain based on the pre-defined read-out parameters. Further investigation of the correlation between gene expression changes and oxaliplatin-induced neurotoxicity phenotype in each strain will be useful to deeper investigate the molecular mechanisms of oxaliplatin neurotoxicity.

The medical and surgical management of uncomplicated diverticulitis has changed over the last several years. Although immunocompetent patients or those without comorbidities can be treated with antibiotics as an outpatient, the efficacy of high-fiber intake or drugs such as mesalamine or rifaximin is not yet clearly established in the treatment of acute episodes and in the prevention of recurrences. On the other hand, the choice between antibiotic treatment and percutaneous drainage is not always obvious in diverticulitis complicated by abscess formation, especially for larger abscesses; although the results of studies comparing the two approaches remain controversial, surgery must be pursued for abscesses > 8 cm. For emergency surgery, the debate is still ongoing regarding laparoscopic lavage and surgical resection followed by primary anastomosis, since for both approaches the published reports are not in agreement regarding possible benefits. Therefore, these approaches are recommended only for selected patients under the care of experienced surgeons. Also, the contribution of elective surgery toward the overall approach has been revised; currently, it is reserved primarily for patients with a high risk of recurrence and whenever more conservative treatments were not effective.

Oxaliplatin (OHP)-induced peripheral neurotoxicity (OIPN), one of the major dose-limiting side effects of colorectal cancer treatment, is characterized by both acute and chronic syndromes. Acute exposure to low dose OHP on dorsal root ganglion (DRG) neurons is able to induce an increase in intracellular calcium and proton concentration, thus influencing ion channels activity and neuronal excitability. The Na + /H + exchanger isoform-1 (NHE1) is a plasma membrane protein that plays a pivotal role in intracellular pH (pH i ) homeostasis in many cell types, including nociceptors. Here we show that OHP has early effects on NHE1 activity in cultured mouse DRG neurons: the mean rate of pH i recovery was strongly reduced compared to vehicle-treated controls, reaching levels similar to those obtained in the presence of cariporide (Car), a specific NHE1 antagonist. The effect of OHP on NHE1 activity was sensitive to FK506, a specific calcineurin (CaN) inhibitor. Lastly, molecular analyses revealed transcriptional downregulation of NHE1 both in vitro, in mouse primary DRG neurons, and in vivo, in an OIPN rat model. Altogether, these data suggest that OHP-induced intracellular acidification of DRG neurons largely depends on CaN-mediated NHE1 inhibition, revealing new mechanisms that OHP could exert to alter neuronal excitability, and providing novel druggable targets.

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1—an active metabolite of molsidomine—prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1’s neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.

The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors’ quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.

Background Chemotherapy-induced peripheral neurotoxicity (CIPN) is a severe adverse effect in patients receiving antitumor agents, and no effective treatment is available. Although the mechanisms responsible for the development of CIPN are poorly understood, recent findings make neuroinflammation an attractive target to be investigated, particularly when neuropathic pain is a prominent feature such as after bortezomib administration. The aim of our study was to evaluate the effect of intravenous immunoglobulins (IVIg) delivery in chronic CIPN. The related neuro-immune aspects were investigated in a well-characterized rat model of bortezomib-induced peripheral neurotoxicity (BIPN). Methods After determination of a suitable schedule based on a preliminary pharmacokinetic pilot study, female Wistar rats were treated with IVIg 1 g/kg every 2 weeks. IVIg treatment was started at the beginning of bortezomib administration (“preventive” schedule), or once BIPN was already ensued after 4 weeks of treatment (“therapeutic” schedule). Neurophysiological and behavioral studies were performed to assess the extent of painful peripheral neurotoxicity induced by bortezomib, and these functional assessments were completed by pathologic examination of peripheral nerves and intraepidermal nerve fiber quantification (IENF). The role of the innate immune response in BIPN was investigated by immunochemistry characterization of macrophage infiltration in peripheral nerves. Results Both schedules of IVIg administration were able to significantly reduce bortezomib-induced heat and mechanical allodynia. Although these changes were not evidenced at the neurophysiological examination of peripheral nerves, they behavioral effects were paralleled in the animals treated with the preventive schedule by reduced axonopathy in peripheral nerves and significant protection from loss of IENF. Moreover, IVIg administration was very effective in reducing infiltration in peripheral nerves of macrophages with the M1, pro-inflammatory phenotype. Conclusion Our results suggest a prominent role of neuroinflammation in BIPN and that IVIg might be considered as a possible safe and effective therapeutic option preventing M1 macrophage infiltration. However, since neuropathic pain is frequent also in other CIPN types, it also indicates the need for further investigation in other forms of CIPN.

Chemotherapy-induced peripheral neuropathy remains a significant side effect of cancer treatment, often requiring dose reductions or even discontinuation of therapy. Paclitaxel (PTX), a widely used chemotherapeutic agent for solid tumors, is particularly neurotoxic, and no effective treatment exists for paclitaxel-induced peripheral neuropathy (PIPN). Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone and non-histone proteins, including transcription factors and cytoskeletal components. This study evaluates the HDAC6 inhibitor ITF6475 for its potential to prevent PIPN and compares its effects with ricolinostat, a well-established HDAC6 inhibitor previously studied in cisplatin-induced neuropathy models. Female C57BL/6 mice received PTX vehicle (VEH) or PTX (70 mg/kg intravenously, once per week for four weeks), and the remaining four groups received PTX with co-treatment of either ricolinostat (50 mg/kg orally, daily) or ITF6475 (1, 6, or 12.5 mg/kg orally, daily). Neurophysiological assessments at the end of treatment showed a significant reduction in caudal sensory nerve action potential amplitude across all PTX-treated groups compared to the VEH group. At the same time, PTX treatment led to the development of mechanical allodynia. However, co-treatment with the HDAC6 inhibitor prevented significant differences compared to the VEH group. PTX-induced reduction in intraepidermal nerve fiber density was significantly prevented in the PTX + ITF6475 (1 mg/kg) group, and PTX-induced increase in neurofilament light levels was reduced in all ITF6475 co-treated groups. These findings support the potential of ITF6475 in preventing small fiber damage in a severe, chronic PIPN model.