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La tossicità dei farmaci antitumorali rappresenta una delle principali limitazioni nella pratica clinica. Tra gli effetti collaterali dei farmaci chemioterapici, la neurotossicità periferica è uno dei più invalidanti per i pazienti malati di cancro. Oxaliplatino (OHP), un composto ampiamente usato per il trattamento del carcinoma del colon-retto metastatico, è uno dei farmaci antineoplastici più neurotossici. I pazienti possono sviluppare due forme clinicamente distinte di neuropatia periferica: una forma acuta aggravata dal freddo ed una neuropatia sensoriale distale cronica. A causa della mancanza di efficaci terapie farmacologiche in grado di prevenire e/o alleviare i sintomi neuropatici, la riduzione o l'interruzione della dose di OHP è spesso necessaria. Nonostante approfondite ricerche, la patogenesi della neurotossicità periferica indotta da OHP (OIPN) è ancora in gran parte sconosciuta. In letteratura sono descritti numerosi studi preclinici in vivo, diversi tra loro per la schedula di trattamento con OHP utilizzata, tuttavia la caratterizzazione della neurotossicità periferica è limitata. Infatti, per verificare l'insorgenza della OINP, oltre alla valutazione del dolore neuropatico, dovrebbero essere effettuate analisi neurofisiologiche ed istopatologiche. La disfunzione mitocondriale è stata recentemente suggerita come possibile meccanismo coinvolto nell'insorgenza della neurotossicità periferica indotta dai farmaci chemioterapici. Il primo obiettivo di questo lavoro è stato confrontare tre modelli murini di OIPN pubblicati con il modello murino di OIPN attualmente in uso nel nostro laboratorio, mediante una valutazione multimodale. Inoltre, dato il potenziale ruolo dello stress ossidativo nella patogenesi della neuropatia periferica, è stata analizzata la possibilità che il trattamento con OHP potesse indurre stress ossidativo e disfunzione mitocondriale. I risultati di questo studio indicano che una singola dose di OHP 5 mg/kg somministra, The toxicity of anticancer drugs represents one of the major limitation in their clinical use. Among the side effects of chemotherapy, peripheral neurotoxicity is one of the most disabling for cancer patients. Oxaliplatin (OHP) is one of the most neurotoxic antineoplastic drug widely used for the treatment of metastatic colorectal cancer. Patients undergoing OHP-regimen experience two clinically distinct forms of peripheral neuropathy: an acute cold-enhanced form and a chronic distal sensory neuropathy. Due to the lack of effective pharmacological therapies in preventing and/or alleviating neuropathic symptoms, OHP dose reduction or interruption is often mandatory. Despite extensive investigation, the pathogenesis of OHP-induced peripheral neurotoxicity (OIPN) is still largely unknown. In literature several preclinical in vivo studies, different from each other in schedules of OHP treatment, are described but the characterization of peripheral neurotoxicity is limited. In fact, to verify the OINP onset, in addition to the evaluation of neuropathic pain, neurophysiological and histopathological analyses should be assessed. Mitochondrial dysfunction has recently been suggested as putative mechanisms possibly involved in the onset and development of chemotherapy-induced peripheral neurotoxicity. Mitochondrial dysfunction and associated oxidative stress may result in chronic neuronal energy impairment leading to neuropathic symptoms. The first aim of this study was to compare OIPN mouse models reported in three published studies with OIPN mouse model currently used in our laboratory, using a multimodal assessment. Moreover, given the potential role of oxidative stress in the pathogenesis of peripheral neuropathy, the possibility that OHP treatment could induce oxidative stress and eventually mitochondrial dysfunctions has also been analysed. Taken together, the results of this study indicate that a single dose of OHP 5 mg/kg administrated in tail vein is able to reprodu

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a potentially dose-limiting side effect of the treatment of several cancers. CIPN is predominantly or exclusively sensory, and it is frequently associated with unpleasant symptoms, overall referred to as “pain.” However, given the markedly different clinical presentation and course of CIPN depending on the antineoplastic drug used, the broad term “pain” in the specific context of CIPN needs to be reconsidered and refined. In fact, a precise identification of the features of CIPN has relevant implication in the design of rational-based clinical trials and in the selection of possible active drugs.

Ethoxyquin was recently identified as a neuroprotective compound against toxic neuropathies and efficacy was demonstrated against paclitaxel-induced neurotoxicity in vivo. In this study we examined the efficacy of ethoxyquin in preventing neurotoxicity of cisplatin in rodent models of chemotherapy-induced peripheral neuropathy and explored its mechanism of action. Ethoxyquin prevented neurotoxicity of cisplatin in vitro in a sensory neuronal cell line and primary rat dorsal root ganglion neurons. In vivo, chronic co-administration of ethoxyquin partially abrogated cisplatin-induced behavioral, electrophysiological and morphological abnormalities. Furthermore, ethoxyquin did not interfere with cisplatin's ability to induce tumor cell death in ovarian cancer cell line in vitro and in vivo. Finally, ethoxyquin reduced the levels of two client proteins (SF3B2 and ataxin-2) of a chaperone protein, heat shock protein 90 (Hsp90) when co-administered with cisplatin in vitro. These results implied that the neuroprotective effect of ethoxyquin is mediated through these two client proteins of Hsp90. In fact, reducing levels of SF3B2 in tissue-cultured neurons was effective against neurotoxicity of cisplatin. These findings suggest that ethoxyquin or other compounds that inhibit chaperone activity of Hsp90 and reduce levels of its client protein, SF3B2 may be developed as an adjuvant therapy to prevent neurotoxicity in cisplatin-based chemotherapy protocols.

This study is aimed at describing the changes occurring in the entire peripheral nervous system sensory pathway along a 2-year observation period in a cohort of C57BL/6 mice. The neurophysiological studies evidenced significant differences in the selected time points corresponding to childhood, young adulthood, adulthood, and aging (i.e., 1, 7, 15, and 25 months of age), with a parabolic course as function of time. The pathological assessment allowed to demonstrate signs of age-related changes since the age of 7 months, with a remarkable increase in both peripheral nerves and dorsal root ganglia at the subsequent time points. These changes were mainly in the myelin sheaths, as also confirmed by the Rotating-Polarization Coherent-Anti-stokes-Raman-scattering microscopy analysis. Evident changes were also present at the morphometric analysis performed on the peripheral nerves, dorsal root ganglia neurons, and skin biopsies. This extensive, multimodal characterization of the peripheral nervous system changes in aging provides the background for future mechanistic studies allowing the selection of the most appropriate time points and readouts according to the investigation aims.

Peripheral neuropathies are frequent in association with systemic diseases as well as isolated disorders. Recent advances in the therapy of specific neuropathies led to the approval of new drugs/treatments. This review selected those peripheral neuropathies where the most recent approvals were provided and revised the potential future developments in diabetic and toxic-induced neuropathies, although they do not have a currently available causal therapy in view of their epidemiological and social relevance. Data have been extracted from the most important published trials and from clinical experience. In addition, data from the Food and Drug Administration and European Medicine Agency indications on the treatment of the selected peripheral neuropathies and from recently updated international guidelines have also been included. The website of the U.S. National Institutes of Health www.clinicaltrials.gov registry has been used as the reference database for phase III clinical trials not yet published or ongoing. This review gives a general overview of the most recent advances in the treatment of amyloid, inflammatory, and paraproteinemic peripheral neuropathies. Moreover, it briefly describes the unmet medical need in disabling and frequent conditions, such as diabetic and chemotherapy-induced neuropathy, highlighting the most promising therapeutic approaches to their treatment.

Introduction Depending on their content, negative or positive, emotions can promote or slow down the cognitive functions. The inhibiting influence of negative affects on the cognitive control has been attributed to the reciprocal inhibition of the neuronal systems implicated in emotion and cognitive functions, but the mechanisms and the temporal process are not well established. The anterior cingulate cortex has been classically subdivided in two major regions with distinct functions: a dorsal-cognitive division and a rostral–ventral affective division. Recent evidence, however, do not support this traditional differentiation but indicate that both subdivisions of the anterior cingulate make important contributions to emotional processing. Aim of the study The project consisted on performing an analysis of the cerebral activity (mainly in the gamma band: > 30Hz) during a protocol of alternating tasks which necessitated the taking of simples decisions, either within an emotionally neutral and within an emotionally negative context, with the aim (i) to compare the performance in an emotionally-negative condition with the performance in an emotionally-neutral condition, (ii) to search the electrophysiological responses of the cerebral areas implanted, implicated in the cognitive and in the emotional control in the different conditions, (iii) to compare the frequency modulations of the different subregions of the cingulate cortex implanted in the different conditions. Patients and methods The study was realized with 6 adult patients (female/male: 3/3) undergoing invasive presurgical evaluation for epilepsy surgery by stereo-electroencephalography (SEEG) in the Claudio Munari Epilepsy Surgery Center, Niguarda Hospital. Monopolar SEEG data were converted to the format of the software Elpho-SEEG developed in LabView, in the Besta Institute. A total of 1365 contacts were analysed. Contacts exploring lesional areas and those showing ictal paroxystic abnormalities were exclud

Systemic chemotherapy is a cornerstone of the modern medical management of cancer, although its use is limited by toxicity on normal tissues and organs, including the nervous system. Long-surviving or cured people strongly require a high level of wellness in addition to prolongation of life (the concept of the quality of survival), but neurologic dysfunction can severely affect daily life activities. Chemotherapy-related peripheral neurotoxicity is becoming one of the most worrisome long-term side effects in patients affected by a neoplasm. The central nervous system has a limited capacity to recover from injuries, and it is not surprising that severe damage can determine long-term or permanent neurologic dysfunction. However, the peripheral nervous system also can be permanently damaged by anticancer treatments despite its better regeneration capacities, and the effect on patients' daily life activities might be extremely severe. However, only recently, the paradigms of peripheral neurotoxicity reversibility have been scientifically challenged, and studies have been performed to capture the patients' perspectives on this issue and to measure the effect of peripheral neurotoxicity on their daily life activities. Despite these efforts, knowledge about this problem is still largely incomplete, and further studies are necessary to clarify the several still-unsettled aspects of long-term peripheral neurotoxicity of conventional and targeted anticancer chemotherapy.

Laser-scanning imaging techniques are frequently used to probe the molecule spatial orientation in a sample of interest by exploiting selection rules depending on the polarisation of the excitation light. For the successful implementation of these techniques the precise control of the polarisation at the sample level is of fundamental importance. Polarisation distortions induced by the optical elements are often the main limitation factor for the maximum size of the field-of-view in polarisation-resolved (PR) laser-scanning microscopy, since for large scanning angles the polarisation distortions may mask the real sample structure. Here we shall demonstrate the implementation of large-field-of-view PR microscopy and show PR CARS imaging of mouse spinal cord thanks to a careful design of the laser-beam optical path. We shall show that this design leads to strongly suppressed distortions and quantify their effects on the final images. Although the focus of this work is on CARS imaging, we stress that the approaches described here can be successfully applied to a wide range of PR laser-scanning techniques.

Oxaliplatin is one of the most widely used anticancer drugs representing the cornerstone of the treatment of colorectal cancer. Yet a number of side effects, including oxaliplatin-induced peripheral neurotoxicity (OIPN) which represents a dose-limiting side effect in the clinical use of oxaliplatin, limit its use and a better understanding of its pathogenesis would offer a great opportunity to improve the "quality of survival" of cancer patients. So far, no treatment able to prevent or limit OIPN has been approved, and one of the reasons for this unmet clinical need is the incomplete knowledge of its pathogenesis preventing the development of rationalebased pharmacological interventions. Preclinical and clinical evidence raised the hypothesis that intracellular calcium-related events might play an important role in the onset of OIPN. Yet, the results of mechanistic pre-clinical studies appear inconsistent and, therefore, their relevance in neuroprotective drugs design is still uncertain. Indeed, it is at present unclear whether aberrant calcium signalling is the key pathogenetic moment or whether it just constitutes the mediator of the clinical phenotype. This review will summarize the preclinical results involving calcium-related events and OIPN with the aim to provide an updated overview of the available evidence and highlight the most promising strategies to design effective neuroprotective drugs. In particular, we will focus on the pre-clinical evidence suggesting that TRPV1, TRPM8 or TRPA1 might be involved, as these appear particularly amenable to pharmacological modulation.

Purpose of review Chemotherapy-induced peripheral neurotoxicity (CIPN) is clinically relevant because it is frequent, it might be dose-limiting, it affects the cancer survivors' quality of life, and no treatment is available. Better understanding of CIPN might lead to an improvement in its management. Recent findings Conventional chemotherapy is a well known cause of peripheral neurotoxicity, which mostly manifest with sensory impairment. CIPN has also been described for new, highly effective compounds, which are, therefore, limited in their more widespread use. Even several 'targeted drugs', which should be free from the risk of CIPN by definition, are neurotoxic, occasionally inducing severe motor impairment. Summary Precise definition of CIPN clinical features can be obtained by only using validated outcome measures. Therefore, a major aim of clinical research is to standardize CIPN assessment, also considering that healthcare providers and patients frequently have a different perception of CIPN severity. A second major aim in clinical research is to maintain a high level of attention to the possible neurotoxicity of drugs more recently introduced into clinical practice. Preclinical studies are of pivotal importance to identify druggable targets for pharmacological intervention in order to prevent or limit CIPN.

Cortical reorganization occurring in multiple sclerosis(MS)patients isthoughtto playakeyrole in limiting the effect of structural tissuedamage. Conversely, its exhaustionmaycontribute to the irreversible disability that accumulates with disease progression. Several aspects of MS-related cortical reorganization, including the overall functional effect and likely modulation by therapies, still remain to be elucidated. The aim of this work was to assess the extent of functional cortical reorganization and its brain structural/pathological correlates in Dark Agouti rats with experimental autoimmune encephalomyelitis (EAE), a widely accepted preclinical model of chronic MS. Morphological and functional MRI (fMRI) were performed before disease induction and during the relapsing and chronic phases of EAE. During somatosensory stimulation of the right forepaw, fMRI demonstrated that cortical reorganization occurs in both relapsing and chronic phases of EAE with increased activated volume and decreased laterality index versus baseline values. Voxel-based morphometry demonstrated gray matter (GM) atrophy in the cerebral cortex, and both GM and white matter atrophy were assessed by ex vivo pathology of the sensorimotor cortex and corpus callosum. Neuroinflammation persisted in the relapsing and chronic phases, with dendritic spine density in the layer IV sensory neurons inversely correlating with the number of cluster of differentiation 45-positive inflammatory lesions. Our work provides an innovative experimental platform that may be pivotal for the comprehension of key mechanisms responsible for the accumulation of irreversible brain damage and for the development of innovative therapies to reduce disability in EAE/MS.

The proteasome inhibitor bortezomib is an antineoplastic drug mainly used for the treatment of multiple myeloma (MM). Despite its effectiveness, bortezomib clinical use is often limited by the onset of peripheral neuropathy (BiPN). To better understand the mechanisms of BiPN several rat and mice models have been proposed, but no studies in MM-bearing animals allowing to test the antitumor activity of the selected schedules and the role of MM by itself in peripheral nervous system damage have been reported to date. Here, we carried out a study using immunodeficient C.B-17/Prkdcscid (SCID) mice injected with RPMI8266 human MM cells and treated with bortezomib 1 mg/kg once a week for five weeks. Animals were assessed with neurophysiological, behavioral and pathological methods and tumor volume measurement was performed along the study. At the end of the study BiPN was evident in bortezomib-treated animals, and this neurotoxic effect was evident using a schedule able to effectively prevent tumor growth. However, neurophysiological and pathological evidence of MM induced peripheral nervous system damage was also reported. This model based on MM-bearing animals is more reliable in the reproduction of the clinical setting and it is, therefore, more suitable than the previously reported models of BiPN to study its pathogenesis. Moreover, it represents an optimal model to test the efficacy of neuroprotective agents and at the same time their non-interference with bortezomib antineoplastic activity.

Cisplatin, paclitaxel and bortezomib are effective chemotherapy drugs in cancer treatment. However, they share severe peripheral neurotoxicity (PN) as one of their major dose-limiting side effects, often impairing cancer patients' quality of life and sometimes being permanent. Even if preclinical oncology is largely based on the use of immune-deficient mice, rodent models used to study the chemotherapy-induced PN are available only in immune-competent animals. In this study we characterized for the first time the PN induced by these chemotherapies through neurophysiological, behavioral, morphological and morphometric studies in athymic nude mice, a commonly employed strain in the preclinical oncology. The animals, divided into four groups, were chronically treated with cisplatin, paclitaxel or bortezomib once or twice a week for 4 or 6. weeks or were left untreated. These schedules were tolerated, neurotoxic and in the range of antineoplastic effectiveness. Despite similarities, differences in the features of PN were evident if compared with immune-competent models under comparable regimens of treatment. The results of this study may provide a basis for future combined analysis of antineoplastic and neurotoxic effects of chemotherapy in the same animals.