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Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of cancer treatment with chemotherapeutic agents. 20S proteasome inhibitors such as Bortezomib (BTZ) and Carfilzomib (CFZ) have been approved for treatment of multiple myeloma and other liquid tumors, also include CIPN among their side effects. To date, no effective treatment for this condition has been developed. Observations in patients treated with these drugs showed that BTZ induces a worse neuropathic phenotype when compared with ones treated with CFZ. While the strong BTZ induced neuropathic symptoms have been replicated in a preclinical setting, there is still no preclinical animal model of CFZ-induced neuropathy. Our aim is to investigate the behavioral and morphological differences between BTZ and CFZ in terms of nerve damage and fiber loss. Therefore, we first selected a CFZ dose able to guarantee a level of anti-neoplastic activity comparable to that of BTZ in terms of proteasome inhibition as well as good tolerability for the model animals. Then, we treated the animals via intravenous administration of 0.8 mg/kg 2qwx4 of BTZ and 2 mg/kg 2qwx4 of CFZ. Here, we evaluated general toxicity over time as well as the insurgence of neuropathy and neuropathic pain using conduction velocity analyses, dynamic Von Frey tests, and evaluation of intraepidermal fibers density (IENF): all these tests show clear neuropathy developing as early as 2 weeks after the beginning of treatment with BTZ, whereas mice treated with CFZ show only mild symptoms throughout. We next sought to dissect any difference in the morphological and morphometrical features in peripheral nerves between the two treatments. We observed a clear degeneration and loss of axonal fibers in both the caudal and sciatic nerves of BTZ-treated animals, that is already evident at half-treatment (2 weeks), whereas the impact on the CFZ-treated cohort is much less severe and becomes significant only at the end of treatment (4 weeks). Take

BACKGROUND: Parenting behavior is thought to affect child brain development, with implications for mental health. However, longitudinal studies that use whole-brain approaches are lacking. In this study, we investigated associations between parenting behavior, age-related changes in whole-brain functional connectivity, and psychopathology symptoms in children and adolescents. METHODS: Two hundred forty (126 female) children underwent resting-state functional magnetic resonance imaging at up to two time points, providing a total of 398 scans covering the age range 8 to 13 years. Parenting behavior was self-reported at baseline. Parenting factors (positive parenting, inattentive parenting, and harsh and inconsistent discipline) were identified based on a factor analysis of self-report parenting questionnaires. Longitudinal measures of child internalizing and externalizing symptoms were collected. Network-based R-statistics was used to identify associations between parenting and age-related changes in functional connectivity. RESULTS: Higher maternal inattentive behavior was associated with lower decreases in connectivity over time, particularly between regions of the ventral attention and default mode networks and frontoparietal and default mode networks. However, this association was not significant after strict correction for multiple comparisons. CONCLUSIONS: While results should be considered preliminary, they suggest that inattentive parenting may be associated with a reduction in the normative pattern of increased network specialization that occurs with age. This may reflect a delayed development of functional connectivity.

Chemotherapy-induced painful peripheral neurotoxicity (painful-CIPN), with paresthesia, numbness, dysaesthesia, and neuropathic pain ranks among the most common dose-limiting toxicity of widely used anticancer drugs. Beside peripheral neurons, for several years considered the only reasonable target for painful-CIPN study, the recent evaluation of the microvascular angiogenesis in the somatosensory pathway, reveals other important actors in the neuropathic pain development and chronicization. To elucidate the relation between chemotherapy-induced neuropathic pain and vascular alterations, we evaluated the microvasculature in central and peripheral nervous compartments of rats exposed to neurotoxic chemotherapy. Rats were treated with paclitaxel 10 mg/kg once a week for 4 weeks, or with cisplatin 2mg/kg twice a week for 4 weeks or with their vehicles. Animals were tested for neurophysiological abnormalities and pain before and after the treatments. Post-mortem samples were analyzed at synchrotron radiation sources by X-ray Phase-Contrast Tomography (XPCT) Imaging and processed for quantitative and morphological analyses of microvascular structures. Complementarily, histochemical and molecular evaluations were performed to validate the results. XPCT analysis revealed that rats exposed to paclitaxel (affected by a painful sensory axonopathy) showed an increased vascular density (putative sprouting angiogenesis) in the crucial districts of the central (somatosensory cortex and lumbar spinal cord) and peripheral nervous system (lumbar Dorsal Root Ganglia and peripheral nerves). However, the complexity of the vascular network and the size of neo-formed vessels were significantly decreased in some specific regions. On the other hand, no significant changes were observed in rats exposed to CDDP (affected by a painless mild neuronopathy) suggesting a specific involvement of neo-angiogenesis in the development of neuropathic pain. Molecular analysis performed on the DRG and S1

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

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.

Paclitaxel-induced peripheral neurotoxicity (PIPN) is a potentially dose-limiting side effect in anticancer chemotherapy. Several animal models of PIPN exist, but their results are sometimes difficult to be translated into the clinical setting. We compared 2 widely used PIPN models characterized by marked differences in their methodologies. Female C57BL/6JOlaHsd mice were used, and they received only paclitaxel vehicle (n = 38) or paclitaxel via intravenous injection (n = 19, 70 mg/kg) once a week for 4 weeks (Study 1) or intraperitoneally (n = 19, 10 mg/kg) every 2 days for 7 times (Study 2). At the end of treatment and in the follow-up, mice underwent behavioral and neurophysiological assessments of PIPN. At the same time points, some mice were killed and dorsal root ganglia, skin, and sciatic and caudal nerve samples underwent pathological examination. Serum neurofilament light levels were also measured. The differences in the neurotoxicity parameters were analyzed using a nonparametric Mann-Whitney test, with significance level set at P < 0.05. Study 1 showed significant and consistent behavioral, neurophysiological, pathological, and serological changes induced by paclitaxel administration at the end of treatment, and most of these changes were still evident in the follow-up period. By contrast, study 2 evidenced only a transient small fiber neuropathy, associated with neuropathic pain. Our comparative study clearly distinguished a PIPN model recapitulating all the clinical features of the human condition and a model showing only small fiber neuropathy with neuropathic pain induced by paclitaxel.

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect caused by many of the most commonly used chemotherapeutic agents, including anti-tubulins (paclitaxel, PTX) and platinum derivatives (cisplatin, CDDP). Due to incomplete understanding of the molecular mechanisms of CIPN, to date no effective therapy is available. Sensory neurons into dorsal root ganglia (DRG) have been investigated as principal targets of neurotoxicity so far. In this study, we focus on a possible novel target of CIPN, investigating the changes of satellite glial cells (SGCs) in the DRG and their crosstalk with neurons following repeated administration of PTX and CDDP in rats. Morpho-functional analyses were performed to verify the features of CIPN. Qualitative and quantitative immunohistochemistry, 3Dimmunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that after 4 weeks of PTX, but not CDDP treatment, SGCs were strongly activated. A similar activation remained after 4 weeks of follow up, when the painful component of neuropathy, but not the nerve damage, was resolved. In addition, nonphysiological connections between SGCs and/or SGC-neuron were evident in PTX rats: we observed activated SGCs surrounding different adjacent neurons and an increase in the intimate contact between SGCs and their associated neurons where a complex and peculiar pattern of glial cytoplasmic projections was present. Moreover, PTX increased the expression of Connexin43 with perineuronal localization and the expression of the adhesion molecule L1-CAM in the cytoplasm and plasma membrane of neurons. We conclude that SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for CIPN treatment and prevention.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other targets, which might be used as potential biomarkers of nerve impairment, need to be investigated.Twenty-four young (2 months of age) and 24 adult (9 months of age) Wistar male rats were randomized to either paclitaxel (PTX) treatment (10 mg/kg i.v. once/ week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed to investigate nerve damage at baseline, af er 4 eeks and the 2-week follow-up period. Skin biopsies from sacrifced animals were examined for intraepidermal nerve fiber (IENF) density assessment. Blood and liver samples were collected for targeted metabolomics analysis using UltraPerformance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS). At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < 0.05) in the caudal nerve of young PTX-treated animals, and in both the digital and caudal nerve of adult treated animals (p < 0.05). Behavioral tests revealed a significant decrease in the mechanical threshold in young PTX-treated animals (p < 0.001),while adult treated rats showed no signif cant dif erence in mechanical threshold compared to controls. Concerning IENF assessment, both young and adult PTX-rats had reduced IENF density (p < 0.0001), which persisted at the end of follow-up.T argeted metabolomics analysis showed signif cant dif erences in the plasma metabolite prof les between PTX-treated animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, phingolipids, and bile acids playing a major role in the respo

Background and Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Methods: Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. Results: At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p <.05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p <.05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p <.001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration. Interpretation Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of various cancer chemotherapy treatments. Typically, CIPN manifests in patients as numbness, tingling, altered sensation, usually associated with neuropathic pain and, therefore the adjustment of chemotherapy dosages or even discontinuation of the treatment. Although various chemotherapeutic agents induce neuropathy, they do so by targeting different cellular processes and having different mechanisms. The pathomechanism by which chemotherapeutics damage the nervous is multifactorial and involves microtubule disruption, oxidative stress and mitochondrial damage, altered ion channel activity, myelin sheath damage, DNA damage, immunological processes and neuroinflammation. Neuroinflammation is one of the host defensive mechanisms and occurs as one of the most common pathological outcomes in most neurological and neurodegenerative diseases make it the promising target. Several CIPN preclinical studies suggest critical neuro-immune interactions as a mechanism of neurotoxicity. In this study we analyzed the presence of neuroinflammatory marker proteins in rats treated with chemotherapy drugs, in order to identify the neuroinflammasome as a pathological mechanism. Expression of inflammasome protein NLRP3, interleukin IL6 and chemokine CCL2 was analyzed in nervous tissue (DRG, spinal cord, caudal nerve, sciatic nerve) after chemotherapy with Paclitaxel, Oxaliplatin and Bortezomib. All three proteins showed a significant increase in the caudal nerve in Paclitaxel treatment over 4 weeks. Treatment with Oxaliplatin did not give any increase in protein expression, while Bortezomib showed a significant increase only for CCL2. Immunohistochemical staining represents infiltration of macrophages in caudale nerves in rats treated with Paclitaxel and Borthezomib but not Oxaliplatin. Neurophysiology and dynamic tests showed that rats treated with Paclitaxel and Bortezomib develop allodynia, reduce nerve condu

Background and Aims: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. Methods: We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. Results: NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. Interpretation: NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Oxaliplatin (OHP) chemotherapy (CHT) is seriously limited by neurotoxic side effects for whom there is no treatment; this unmet clinical need is in part due to an uncompleted pathogenetic knowledge and, therefore, robust preclinical models are needed to advance patients’ care. OHP-induced peripheral neurotoxicity (OIPN) has a peculiar profile: it comprises an acute syndrome and a chronic sensory axonopathy. Acute OIPN is characterized by transient cold-induced paresthesia and cramps, lasting 2-3 days after each administration; acute OIPN has been attributed to a transient ion channel dysfunction. The worse acute OIPN is, the more severe the chronic neuropathy that ensues. Therefore, an OIPN model should be able to reproduce both conditions. We designed an in vivo study to this aim: we compared a control group with a treated group (OHP 3 mg/Kg twice a week over 4 weeks, iv). Nerve excitability testing (NET) was used to assess acute OIPN. Behavioural test, nerve conduction studies (NCS), and neuropathology were used to characterise chronic OIPN; the latter included: morphological/morphometrical assessments of the caudal nerve and dorsal root ganglia (DRG); intraepidermal nerve fiber density (IENFD); spinal cord immunohistochemistry for the transient receptor potential vanilloid type-1 (TRPV1) receptor. Data were collected at the end of treatment and 6 weeks after. NET allowed us to show that acute OIPN ensued as soon as the first administration and it did not persist after CHT (no NET alterations 1 week after CHT completion). Behavioural tests, NCS, nerve/DRG morphological/morphometrical analysis, and IENFD showed that a mild sensory neuronopathy/axonopathy had ensued at CHT completion and nearly completely resolved at follow-up. Densitometric analysis of TRPV1 immunolabeling in the dorsal horn of the spinal cord at the end of treatment showed an increased density of TRPV1 staining in OHP animals (in lamina I and inner lamina II). This difference was maintained at fol

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 (pHi) 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 pHi 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 Neuropathies (PN) are common conditions whose treatment is still lacking in most cases. Animal models are crucial, but experimental procedures should be refined in some cases. We performed a detailed characterization of the ventral caudal nerve to contribute to a more effective assessment of axonal damage in future PN studies. PN was induced via weekly systemic injection of a neurotoxic drug (paclitaxel); we compared the control and PN-affected rats, performing serial neurophysiological evaluations of the caudal nerve for its entire length. On the same nerve portions, we performed light microscopy and ultrastructural pathological observations to assess the severity of damage and verify the integrity of the surrounding structures. Neurophysiological and morphological analyses confirmed that a severe axonopathy had ensued in the PN group, with a length-dependent modality, matching morphological observations. The site of neurophysiological recording (e.g., distance from the base of the tail) was critical for achieving useful data. A flexible experimental paradigm should be considered in animal studies investigating axonal PN, particularly if the expected severity is relevant; the mid-portion of the tail might be the most appropriate site: there damage might be remarkable but neither as extreme as at the tip of the tail nor as mild as at the base of the tail.

Chemotherapy-induced peripheral neurotoxicity is one of the most common dose-limiting toxicities of several widely used anticancer drugs such as platinum derivatives (cisplatin) and taxanes (paclitaxel). Several molecular mechanisms related to the onset of neurotoxicity have already been proposed, most of them having the sensory neurons of the dorsal root ganglia (DRG) and the peripheral nerve fibers as principal targets. In this study we explore chemotherapy-induced peripheral neurotoxicity beyond the neuronocentric view, investigating the changes induced by paclitaxel (PTX) and cisplatin (CDDP) on satellite glial cells (SGC) in the DRG and their crosstalk. Rats were chronically treated with PTX (10 mg/Kg, 1qwx4) or CDDP (2 mg/Kg 2qwx4) or respective vehicles. Morpho-functional analyses were performed to verify the features of drug-induced peripheral neurotoxicity. Qualitative and quantitative immunohistochemistry, 3D immunofluorescence, immunoblotting, and transmission electron microscopy analyses were also performed to detect alterations in SGCs and their interconnections. We demonstrated that PTX, but not CDDP, produces a strong activation of SGCs in the DRG, by altering their interconnections and their physical contact with sensory neurons. SGCs may act as principal actors in PTX-induced peripheral neurotoxicity, paving the way for the identification of new druggable targets for the treatment and prevention of chemotherapy-induced peripheral neurotoxicity.