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Abstract Background Several groups have shown that the performance of motor neuroprostheses can be significantly improved by detecting specific sensory events related to the ongoing motor task (e.g., the slippage of an object during grasping). Algorithms have been developed to achieve this goal by processing electroneurographic (ENG) afferent signals recorded by using single-channel cuff electrodes. However, no efforts have been made so far to understand the number and type of detectable sensory events that can be differentiated from whole nerve recordings using this approach. Methods To this aim, ENG afferent signals, evoked by different sensory stimuli were recorded using single-channel cuff electrodes placed around the sciatic nerve of anesthetized rats. The ENG signals were digitally processed and several features were extracted and used as inputs for the classification. The work was performed on integral datasets, without eliminating any noisy parts, in order to be as close as possible to real application. Results The results obtained showed that single-channel cuff electrodes are able to provide information on two to three different afferent (proprioceptive, mechanical and nociceptive) stimuli, with reasonably good discrimination ability. The classification performances are affected by the SNR of the signal, which in turn is related to the diameter of the fibers encoding a particular type of neurophysiological stimulus. Conclusions Our findings indicate that signals of acceptable SNR and corresponding to different physiological modalities (e.g. mediated by different types of nerve fibers) may be distinguished.

Background and Aims: Cell culture is a fundamental experimental tool for understanding cell physiology. However, translating these findings to in vivo settings has proven challenging. Replicating donor tissue conditions, including oxygen levels, is crucial for achieving meaningful results. Nevertheless, oxygen culture conditions are often overlooked, particularly in the context of chemotherapy-induced neurotoxicity., Methods: In this study, we investigated the role of oxygen levels in primary neuronal cultures by comparing neuronal performance under cisplatin exposure (1 μg/mL) in supraphysiological normoxia (representing atmospheric conditions in a standard incubator; 18.5% O 2 ) and physioxia (representing physiologic oxygen conditions in nervous tissue; 5% O 2 ). Experiments were also conducted to assess survival, neurite development, senescence marker expression, and proinflammatory cytokine secretion., Results: Under control conditions, both oxygen concentration conditions exhibited similar behaviors. However, after cisplatin administration, sensory neurons cultured under supraphysiological normoxic conditions show higher mortality, exhibit an evolutionarily proinflammatory cytokine profile over time, and activate apoptotic-regulated neuron death markers. In contrast, under physiological conditions, neurons treated with cisplatin exhibited senescence marker expression and an attenuated inflammatory secretome., Interpretation: These results underscore the critical role of oxygen in neuronal culture, particularly in studying compounds where neuronal damage is mechanistically linked to oxidative stress. Even at identical doses of evaluated neurotoxic drugs, distinct cellular phenotypic fates can emerge, impacting translatability to the in vivo setting., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Peripheral neurons are heterogeneous and functionally diverse, but all share the capability to switch to a pro-regenerative state after nerve injury. Despite the assumption that the injury response is similar among neuronal subtypes, functional recovery may differ. Understanding the distinct intrinsic regenerative properties between neurons may help to improve the quality of regeneration, prioritizing the growth of axon subpopulations to their targets. Here, we present a comparative analysis of regeneration across four key peripheral neuron populations: motoneurons, proprioceptors, cutaneous mechanoreceptors, and nociceptors. Using Cre/Ai9 mice that allow fluorescent labeling of neuronal subtypes, we found that nociceptors showed the greater regeneration after a sciatic crush, followed by motoneurons, mechanoreceptors, and, finally, proprioceptors. By breeding these Cre mice with Ribotag mice, we isolated specific translatomes and defined the regenerative response of these neuronal subtypes after axotomy. Only 20% of the regulated genes were common, revealing a diverse response to injury among neurons, which was also supported by the differential influence of neurotrophins among neuron subtypes. Among differentially regulated genes, we proposed MED12 as a specific regulator of the regeneration of proprioceptors. Altogether, we demonstrate that the intrinsic regenerative capacity differs between peripheral neuron subtypes, opening the door to selectively modulate these responses., Competing Interests: SB, ES, DO, DZ, EU No competing interests declared, (© 2023, Bolívar et al.)

One of the challenges of the mature nervous system is to maintain the stability of neural networks while providing a degree of plasticity to generate experience-dependent modifications. This plasticity-stability dynamism is regulated by perineuronal nets (PNNs) and is crucial for the proper functioning of the system. Previously, we found a relation between spinal PNNs reduction and maladaptive plasticity after spinal cord injury (SCI), which was attenuated by maintaining PNNs with activity-dependent therapies. Moreover, transgenic mice lacking the cartilage link protein 1 ( Crtl1 KO mice) showed aberrant spinal PNNs and increased spinal plasticity. Therefore, the aim of this study is to evaluate the role of link protein 1 in the activity-dependent modulation of spinal PNNs surrounding motoneurons and its impact on the maladaptive plasticity observed following SCI. We first studied the activity-dependent modulation of spinal PNNs using a voluntary wheel-running protocol. This training protocol increased spinal PNNs in WT mice but did not modify PNN components in Crtl1 KO mice, suggesting that link protein 1 mediates the activity-dependent modulation of PNNs. Secondly, a thoracic SCI was performed, and functional outcomes were evaluated for 35 days. Interestingly, hyperreflexia and hyperalgesia found at the end of the experiment in WT-injured mice were already present at basal levels in Crtl1 KO mice and remained unchanged after the injury. These findings demonstrated that link protein 1 plays a dual role in the correct formation and in activity-dependent modulation of PNNs, turning it into an essential element for the proper function of PNN in spinal circuits.

Introduction: Peripheral neuroprostheses are aimed to restore loss of sensory and motor functions by interfacing axons in the peripheral nerves. Most common interfaces in neuroprostheses are electrodes that establish electrical connection with peripheral axons. However, some challenges arise related to long-term functionality, durability, and body response. Recently, focused ultrasound stimulation (FUS) has emerged as a non-invasive approach to modulate the nervous system. However, it is controversial whether FUS can induce axon depolarization., Methods: We have assessed FUS applied in vivo to the rat peripheral nerve, with two objectives: first, to test whether FUS activates peripheral nerves under different stimulation conditions, and second, to evaluate if FUS inflicts damage to the nerve. FUS was delivered with three ultrasound transducers (Sonic Concept H115, H107, and H102) covering the largest set of parameters examined for FUS of peripheral nerves so far., Results: We did not obtain reliable evoked action potentials in either nerves or muscles, under any FUS condition applied, neither over the skin nor directly to the nerve exposed. Additional experiments ex vivo and in vivo on mice, confirmed this conclusion. When FUS stimulation was applied directly to the exposed sciatic nerve, neuromuscular function decreased significantly, and recovered one week later, except for FUS at 0.25 MHz. Histologically, degenerating nerve fibers were observed, with a tendency to be higher with the lower FUS frequency., Discussion: Past reports on the ability of ultrasound to stimulate the peripheral nerve are controversial. After testing a wide range of FUS conditions, we conclude that it is not a reliable and safe method for stimulating the peripheral nerve. Special consideration should be taken, especially when low-frequency FUS is applied, as it may lead to nerve damage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rodríguez-Meana, Santos-Nogueira, Trujillo-Vázquez, Jakob, Udina, Fournelle and Navarro.)

Background and Objectives: Peripheral nerve injuries resulting in a nerve defect require surgical repair. The gold standard of autograft (AG) has several limitations, and therefore, new alternatives must be developed. The main objective of this study was to assess nerve regeneration through a long gap nerve injury (50 mm) in the peroneal nerve of sheep with a decellularized nerve allograft (DCA)., Methods: A 5-cm long nerve gap was made in the peroneal nerve of sheep and repaired using an AG or using a DCA. Functional tests were performed once a month and electrophysiology and echography evaluations at 6.5 and 9 months postsurgery. Nerve grafts were harvested at 9 months for immunohistochemical and morphological analyses., Results: The decellularization protocol completely eliminated the cells while preserving the extracellular matrix of the nerve. No significant differences were observed in functional tests of locomotion and pain response. Reinnervation of the tibialis anterior muscles occurred in all animals, with some delay in the DCA group compared with the AG group. Histology showed a preserved fascicular structure in both AG and DCA; however, the number of axons distal to the nerve graft was higher in AG than in DCA., Conclusion: The decellularized graft assayed supported effective axonal regeneration when used to repair a 5-cm long gap in the sheep. As expected, a delay in functional recovery was observed compared with the AG because of the lack of Schwann cells., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Peripheral nerve injuries (PNIs) induce the retraction from the ventral horn of the synaptic collaterals of Ia afferents injured in the nerve, effectively removing Ia synapses from α-motoneurons. The loss of Ia input impairs functional recovery and could explain, in part, better recovery after PNIs with better Ia synaptic preservation. Synaptic losses correlate with injury severity, speed, and efficiency of muscle reinnervation and requires ventral microglia activation. It is unknown whether this plasticity is age dependent. In neonates, axotomized motoneurons and sensory neurons undergo apoptosis, but after postnatal day 10 most survive. The goal of this study was to analyze vesicular glutamate transporter 1 (VGluT1)-labeled Ia synapses (which also include II afferents) after nerve crush in 10 day old rats, a PNI causing little Ia/II synapse loss in adult rats. We confirmed fast and efficient reinnervation of leg muscles; however, a massive number of VGluT1/Ia/II synapses were permanently lost. This synapse loss was similar to that after more severe nerve injuries involving full transection in adults. In adults, disappearance of ventrally directed Ia/II collaterals targeting α-motoneurons was associated with a prolonged microglia reaction and a CCR2 mechanism that included infiltration of CCR2 blood immune cells. By contrast, microgliosis after P10 injuries was fast, resolved in about a week, and there was no evidence of peripheral immune cell infiltration. We conclude that VGluT1/Ia/II synapse loss in young animals differs in mechanism, perhaps associated with higher microglia synaptic pruning activity at this age and results in larger losses after milder nerve injuries., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Arbat-Plana et al.)

Despite advances in microsurgery, full functional recovery of severe peripheral nerve injuries is not commonly attained. The sheep appears as a good preclinical model since it presents nerves with similar characteristics to humans. In this study, we induced 5 or 7 cm resection in the peroneal nerve and repaired with an autograft. Functional evaluation was performed monthly. Electromyographic and ultrasound tests were performed at 6.5 and 9 months postoperation (mpo). No significant differences were found between groups with respect to functional tests, although slow improvements were seen from 5 mpo. Electrophysiological tests showed compound muscle action potentials (CMAP) of small amplitude at 6.5 mpo that increased at 9 mpo, although they were significantly lower than the contralateral side. Ultrasound tests showed significantly reduced size of tibialis anterior (TA) muscle at 6.5 mpo and partially recovered size at 9 mpo. Histological evaluation of the grafts showed good axonal regeneration in all except one sheep from autograft 7 cm (AG7) group, while distal to the graft there was a higher number of axons than in control nerves. The results indicate that sheep nerve repair is a useful model for investigating long-gap peripheral nerve injuries.

Decellularized nerve allografts (DC) are an alternative to autografts (AG) for repairing severe peripheral nerve injuries. We have assessed a new DC provided by VERIGRAFT. The decellularization procedure completely removed cellularity while preserving the extracellular matrix. We first assessed the DC in a 15 mm gap in the sciatic nerve of rats, showing slightly delayed but effective regeneration. Then, we assayed the DC in a 70 mm gap in the peroneal nerve of sheep compared with AG. Evaluation of nerve regeneration and functional recovery was performed by clinical, electrophysiology and ultrasound tests. No significant differences were found in functional recovery between groups of sheep. Histology showed a preserved fascicular structure in the AG while in the DC grafts regenerated axons were grouped in small units. In conclusion, the DC was permissive for axonal regeneration and allowed to repair a 70 mm long gap in the sheep nerve.

Objectives: Peripheral neuropathy is a relevant dose-limiting adverse event that can affect up to 90% of oncologic patients with colorectal cancer receiving oxaliplatin treatment. The severity of neurotoxicity often leads to dose reduction or even premature cessation of chemotherapy. Unfortunately, the limited knowledge about the molecular mechanisms related to oxaliplatin neurotoxicity leads to a lack of effective treatments to prevent the development of this clinical condition. In this context, the present work aimed to determine the exact molecular mechanisms involved in the development of oxaliplatin neurotoxicity in a murine model to try to find new therapeutical targets., Methods: By single-cell RNA sequencing (scRNA-seq), we studied the transcriptomic profile of sensory neurons and satellite glial cells (SGC) of the Dorsal Root Ganglia (DRG) from a well-characterized mouse model of oxaliplatin neurotoxicity., Results: Analysis of scRNA-seq data pointed to modulation of inflammatory processes in response to oxaliplatin treatment. In this line, we observed increased levels of NF-kB p65 protein, pro-inflammatory cytokines, and immune cell infiltration in DRGs and peripheral nerves of oxaliplatin-treated mice, which was accompanied by mechanical allodynia and decrease in sensory nerve amplitudes., Interpretation: Our data show that, in addition to the well-described DNA damage, oxaliplatin neurotoxicity is related to an exacerbated pro-inflammatory response in DRG and peripheral nerves, and open new insights in the development of anti-inflammatory strategies as a treatment for preventing peripheral neuropathy induced by oxaliplatin., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Specificity in regeneration after peripheral nerve injuries is a major determinant of functional recovery. Unfortunately, regenerating motor and sensory axons rarely find their original pathways to reinnervate appropriate target organs. Although a preference of motor axons to regenerate towards the muscle has been described, little is known about the specificity of the heterogeneous sensory populations. Here, we propose the comparative study of regeneration in different neuron subtypes. Using female and male reporter mice, we assessed the regenerative preference of motoneurons (ChAT-Cre/Ai9), proprioceptors (PV-Cre/Ai9), and cutaneous mechanoreceptors (Npy2r-Cre/Ai9). The femoral nerve of these animals was transected above the bifurcation and repaired with fibrin glue. Regeneration was assessed by applying retrograde tracers in the distal branches of the nerve 1 or 8 weeks after the lesion and counting the retrotraced somas and the axons in the branches. We found that cutaneous mechanoreceptors regenerated faster than other populations, followed by motoneurons and, lastly, proprioceptors. All neuron types had an early preference to regenerate into the cutaneous branch whereas, at long term, all neurons regenerated more through their original branch. Finally, we found that myelinated neurons extend more regenerative sprouts in the cutaneous than in the muscle branch of the femoral nerve and, particularly, that motoneurons have more collaterals than proprioceptors. Our findings reveal novel differences in regeneration dynamics and specificity, which indicate distinct regenerative mechanisms between neuron subtypes that can be potentially modulated to improve functional recovery after nerve injury., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Decellularized nerve allografts are an alternative to autograft for repairing severe nerve injuries, since they have higher availability and do not induce rejection. In this study, we have assessed the regenerative potential of a novel decellularization protocol for human and rat nerves for repairing nerve resections, compared to the gold standard autograft. A 15-mm gap in the sciatic nerve was repaired with decellularized rat allograft (DC-RA), decellularized human xenograft (DC-HX), or fresh autograft (AG). Electrophysiology tests were performed monthly to evaluate muscle reinnervation, whereas histological and immunohistochemical analyses of the grafts were evaluated at 4 months. A short-term study was also performed to compare the differences between the two decellularized grafts (DC-RA and DC-HX) in early phases of regeneration. The decellularization process eliminated cellularity while preserving the ECM and endoneurial tubules of both rat and human nerves. Higher amount of reinnervation was observed in the AG group compared to the DC-RA group, while only half of the animals of the DC-HX showed distal muscle reinnervation. The number of regenerating myelinated axons in the mid-graft was similar between AG and DC-RA and lower in DC-HX graft, but significantly lower in both DC grafts distally. At short term, fibroblasts repopulated the DC-RA graft, supporting regenerated axons, whereas an important fibrotic reaction was observed around DC-HX grafts. In conclusion, the decellularized allograft sustained regeneration through a long gap in the rat although at a slower rate compared to the ideal autograft, whereas regeneration was limited or even failed when using a decellularized xenograft., (© 2022. The Author(s).)

Neurons of the peripheral nervous system retain the intrinsic capability of regenerate their axons after injury, by triggering a complex activation response. This genetic switch is dependent of signals from the injured axon. Schwann cells (SCs) in the distal stump of an injured nerve also play an active role in the local regulation of axonal programs, by using cell-to-cell contacts but also secreted signals, the so-called secretome. Secretome contains all the proteins (cytokines, growth factors and others) secreted by the cell and includes extracellular vesicles. The released vesicles can transport signaling proteins and both coding and regulatory RNAs, thus facilitating multilevel communication. It is nowadays clear that secretome of SCs is fundamental to both orchestrate Wallerian degeneration and to sustain axonal regeneration. Therefore, the use of secretome has emerged as an alternative to cell therapy in the field of tissue regeneration. In fact, separate components of SC secretome have been extensively used in experimental models to enhance peripheral nerve regeneration after injury. However, the most used secretome in neural therapies has been the one derived from mesenchymal (MSC) or other derived stem cells. In fact, the effects of cell therapy with MSCs have been mainly associated with the secretion of bioactive molecules and extracellular vesicles, which constitute their secretome. In this review, we first describe the role of SC and macrophage secretomes on Wallerian degeneration and axonal regeneration after peripheral nerve injury. Then, we review the different works reported in the literature that have used secretomes of SCs or MSCs in the treatment of peripheral nerve injuries in experimental models, to highlight the use of secretomes as a promising cell-free therapeutic approach, that reduces some of the risks associated with the use of cells, such as tumor formation or rejection., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Rather than being a stable scaffold, perineuronal nets (PNNs) are a dynamic and specialized extracellular matrix involved in plasticity modulation. They have been extensively studied in the brain and associated with neuroprotection, ionic buffering, and neural maturation. However, their biological function in the spinal cord and the effects of disrupting spinal PNNs remain elusive. The goal of this review is to summarize the current knowledge of spinal PNNs and their potential in pathological conditions such as traumatic spinal cord injury (SCI). We also highlighted interventions that have been used to modulate the extracellular matrix after SCI, targeting the glial scar and spinal PNNs, in an effort to promote regeneration and stabilization of the spinal circuits, respectively. These concepts are discussed in the framework of developmental and neuroplastic changes in PNNs, drawing similarities between immature and denervated neurons after an SCI, which may provide a useful context for future SCI research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sánchez-Ventura, Lane and Udina.)

Background: Decellularized human nerves overcome the limitations of the current treatments for large peripheral nerve injuries. However, the use of decellularized nerves requires an "off-the-shelf" availability for useful and actual clinical application. In this study, we addressed the preservation of the native and decellularized human nerve matrix in an integrative approach for tissue scaffold production. Materials and Methods: For native nerve matrix preservation analysis, we used histological examination and immunofluorescence to examine the structure, biomechanical assays to evaluate the tensile strength and Young's modulus, and analyzed the extracellular matrix (ECM) composition using enzyme-linked immunosorbent assay (ELISA) and biochemical assays for laminin, collagen and sulfated glycosaminoglycans (sGAG). After decellularization, nuclear remnants and DNA content were evaluated using 4',6-diamidino-2-phenylindole (DAPI) staining and the picogreen quantification assay, as well as immunofluorescence or ELISA for cell rests (S100 protein and myelin staining) evaluation. Decellularized cryopreserved scaffolds were assayed for biomechanics, ECM composition, and structural maintenance. Cytotoxicity assays were performed to evaluate the biocompatibility of the nerve matrix extracts after cryopreservation. Results: We compared different strategies for native nerve storage and found that preservation up to 7 days at 4°C in Roswell Park Memorial Institute medium maintained biomechanical properties, such as Young's modulus and tensile strength, along with the structure and ECM composition, regarding laminin, collagen, and sGAG. After a successful decellularization process, that eliminated cell remnants, nerve scaffolds were frozen in an "in house" formulated cryoprotectant, using an automatic controlled rate freezer. Nerve structure, ECM composition, and biomechanical properties were maintained before and after the freezing process in comparison with native nerves. The extracts of the nerve scaffolds after thawing were not cytotoxic and the freezing process sustained good viability in 3T3 cells (graphical abstract). Conclusion: Since our approach facilitates transport, storage, and provide a ready-to-use alternative, it could be used in a clinical application for the treatment of long-gap peripheral nerve injuries in regenerative medicine.

Background: Cisplatin-induced peripheral neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development., Methods: By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well-characterized neurophysiological mouse model of CIPN., Results: Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the upregulation of biological pathways related to DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-H2AX, and nuclear factor kappa B (Nfkb)-p65 proteins., Conclusions: In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a nonfunctional senescence-like state., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Peripheral nerve injuries result in the loss of the motor, sensory and autonomic functions of the denervated segments of the body. Neurons can regenerate after peripheral axotomy, but inaccuracy in reinnervation causes a permanent loss of function that impairs complete recovery. Thus, understanding how regenerating axons respond to their environment and direct their growth is essential to improve the functional outcome of patients with nerve lesions. Schwann cells (SCs) play a crucial role in the regeneration process, but little is known about their contribution to specific reinnervation. Here, we review the mechanisms by which SCs can differentially influence the regeneration of motor and sensory axons. Mature SCs express modality-specific phenotypes that have been associated with the promotion of selective regeneration. These include molecular markers, such as L2/HNK-1 carbohydrate, which is differentially expressed in motor and sensory SCs, or the neurotrophic profile after denervation, which differs remarkably between SC modalities. Other important factors include several molecules implicated in axon-SC interaction. This cell-cell communication through adhesion (e.g., polysialic acid) and inhibitory molecules (e.g., MAG) contributes to guiding growing axons to their targets. As many of these factors can be modulated, further research will allow the design of new strategies to improve functional recovery after peripheral nerve injuries.

Introduction: Recent studies explored promising new quantitative methods to analyze electroencephalography (EEG) signals. This paper analyzes the correlation of two EEG parameters, Brain Symmetry Index (BSI) and Laterality Coefficient (LC), with established functional scales for the stroke assessment., Methods: Thirty-two healthy subjects and thirty-six stroke patients with upper extremity hemiparesis were recruited for this study. The stroke patients where subdivided in three groups according to the stroke location: Cortical, Subcortical, and Cortical + Subcortical. The participants performed assessment visits to record the EEG in the resting state and perform functional tests using rehabilitation scales. Then, stroke patients performed 25 sessions using a motor-imagery based Brain Computer Interface system (BCI). BSI was calculated with the EEG data in resting state and LC was calculated with the Event-Related Synchronization maps., Results: The results of this study demonstrated significant differences in the BSI between the healthy group and Subcortical group ( P = 0.001), and also between the healthy and Cortical+Subcortical group ( P = 0.019). No significant differences were found between the healthy group and the Cortical group ( P = 0.505). Furthermore, the BSI analysis in the healthy group based on gender showed statistical differences ( P = 0.027). In the stroke group, the correlation between the BSI and the functional state of the upper extremity assessed by Fugl-Meyer Assessment (FMA) was also significant, ρ = -0.430 and P = 0.046. The correlation between the BSI and the FMA-Lower extremity was not significant (ρ = -0.063, P = 0.852). Similarly, the LC calculated in the alpha band has significative correlation with FMA of upper extremity (ρ = -0.623 and P < 0.001) and FMA of lower extremity (ρ = -0.509 and P = 0.026). Other important significant correlations between LC and functional scales were observed. In addition, the patients showed an improvement in the FMA-upper extremity after the BCI therapy (ΔFMA = 1 median [IQR: 0-8], P = 0.002)., Conclusion: The quantitative EEG tools used here may help support our understanding of stroke and how the brain changes during rehabilitation therapy. These tools can help identify changes in EEG biomarkers and parameters during therapy that might lead to improved therapy methods and functional prognoses., (Copyright © 2020 Sebastián-Romagosa, Udina, Ortner, Dinarès-Ferran, Cho, Murovec, Matencio-Peralba, Sieghartsleitner, Allison and Guger.)

Background: Public hospitals in Catalonia (Spain) recommend using the Spanish version of the Pain Assessment in Advanced Dementia (PAINAD-Sp) scale for assessing pain in adult patients unable to self-report. However, since its inclusion in Catalonian nursing care plans in 2010, there have been no training programs for nurses, contributing to its current underuse., Aims: The aim of this study was to assess the impact of a nurse training intervention on the PAINAD-Sp scale in noncommunicative inpatients unable to self-report., Design: Before-after study., Settings: Two public hospitals in Catalonia (Spain)., Participants/subjects: Four hundred and one nurses participated in the training course and 219 patients received PAINAD-Sp assessments., Methods: We used a before-after study design, evaluating the use of the PAINAD-Sp scale over two 6-month periods before and after an online training intervention for nurses in February 2017, in two public hospitals. Data were collected from patient records in each center. The primary outcome was the number of patients receiving PAINAD-Sp assessments during admission. Secondary outcomes were the number of assessments undertaken per patient during admission, the total (0-10) and item-specific (0-2) PAINAD-Sp score, and pharmacologic treatment administered., Results: There were 401 nurses who took part in the training program. Over the study period, 219 patients received PAINAD-Sp assessments: 29 in the preintervention period and 190 in the postintervention period (p < .001). Administration of analgesics and antipyretics decreased (p < .001) after the intervention, whereas use of hypnotic drugs and sedatives increased., Conclusions: Theoretical and practical training may be an effective way to improve nurses' approach to identifying, assessing, and managing pain in patients unable to self-report., (Copyright © 2019 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.)

Physical rehabilitation is one of the cornerstones for the treatment of lesions of the nervous system. After peripheral nerve injuries, activity dependent therapies promote trophic support for the paralyzed muscles, enhance axonal growth and also modulate the maladaptive plastic changes induced by the injury at the spinal level. We have previously demonstrated that an intensive protocol of treadmill running (TR) in rats reduces synaptic stripping on axotomized motoneurons, preserves their perineuronal nets (PNN) and attenuates microglia reactivity. However, it is not clear through which mechanisms exercise is exerting these effects. Here we aimed to evaluate if activation of the locus coeruleus (LC), the noradrenergic center in the brain stem, plays a role in these effects. Since LC is strongly activated during stressful situations, as during intensive exercise, we selectively destroyed the LC by administering the neurotoxin DPS-4 before injuring the sciatic nerve of adult rats. Animals without LC had increased microglia reactivity around injured motoneurons. In these animals, an increasing intensity protocol of TR was not able to prevent synaptic stripping on axotomized motoneurons and the reduction in the thickness of their PNN. In contrast, TR was still able to attenuate microglia reactivity in DSP-4 treated animals, thus indicating that the noradrenergic projections are important for some but not all the effects that exercise induces on the spinal cord after peripheral nerve injury. Moreover, animals subjected to treadmill training showed delayed muscle reinnervation, more evident if treated with DSP-4. However, we did not find differences in treated animals regarding the H/M amplitude ratio, which increased during the first stages of regeneration in all injured groups.

Minocycline has been reported to be both beneficial and detrimental for nerve regeneration after peripheral nerve injury. By reducing the inflammatory response, minocycline administration reduces pain and has neuroprotective effects, but it also inhibits Wallerian degeneration in the distal stump, and reduces microglia and macrophages activity on motor and sensory neurons, which could reduce their intrinsic regenerative capacity. The aim of this study was to determine if the administration of minocycline after nerve injury inhibits the regenerative capacity of motoneurons and sensory neurons after a conditioning lesion. We used two groups of mice: a control group and a group treated with minocycline (30 mg kg -1 ip twice daily). We labeled motor and sensory neurons that had regenerated to a distance of 3 mm in a predegenerated graft, after a conditioning lesion. Our results indicate that minocycline administration is not detrimental for nerve regeneration. Indeed, it even promoted a slight, no significant increase 7 days after the nerve graft. These results indicate that minocycline, given at a dose able to reduce pain after peripheral nerve injury, does not interfere with the intrinsic growth capacity of injured peripheral neurons. Anat Rec, 301:1638-1645, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Downregulation of the potassium chloride cotransporter type 2 (KCC2) after a spinal cord injury (SCI) disinhibits motoneurons and dorsal horn interneurons causing spasticity and neuropathic pain, respectively. We showed recently (Bos et al., 2013) that specific activation of 5-HT 2A receptors by TCB-2 [(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide] upregulates KCC2 function, restores motoneuronal inhibition and reduces SCI-induced spasticity. Here, we tested the potential analgesic effect of TCB-2 on central (thoracic hemisection) and peripheral [spared nerve injury (SNI)] neuropathic pain. We found mechanical and thermal hyperalgesia reduced by an acute administration of TCB-2 in rats with SCI. This analgesic effect was associated with an increase in dorsal horn membrane KCC2 expression and was prevented by pharmacological blockade of KCC2 with an intrathecal injection of DIOA [(dihydroindenyl)oxy]alkanoic acid]. In contrast, the SNI-induced neuropathic pain was not attenuated by TCB-2 although there was a slight increase of membrane KCC2 expression in the dorsal horn ipsilateral to the lesion. Up-regulation of KCC2 function by targeting 5-HT 2A receptors, therefore, has therapeutic potential in the treatment of neuropathic pain induced by SCI but not by SNI., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Introduction: The structural correspondence of neurodevelopmental impairments related to intrauterine growth restriction (IUGR) that persists later in life remains elusive. Moreover, early postnatal stimulation strategies have been proposed to mitigate these effects. Long-term brain connectivity abnormalities in an IUGR rabbit model and the effects of early postnatal environmental enrichment (EE) were explored., Materials and Methods: IUGR was surgically induced in one horn, whereas the contralateral one produced the controls. Postnatally, a subgroup of IUGR animals was housed in an enriched environment. Functional assessment was performed at the neonatal and long-term periods. At the long-term period, structural brain connectivity was evaluated by means of diffusion-weighted brain magnetic resonance imaging and by histological assessment focused on the hippocampus., Results: IUGR animals displayed poorer functional results and presented altered whole-brain networks and decreased median fractional anisotropy in the hippocampus. Reduced density of dendritic spines and perineuronal nets from hippocampal neurons were also observed. Of note, IUGR animals exposed to enriched environment presented an improvement in terms of both function and structure., Conclusions: IUGR is associated with altered brain connectivity at the global and cellular level. A strategy based on early EE has the potential to restore the neurodevelopmental consequences of IUGR., (© 2017 S. Karger AG, Basel.)

OBJECTIVE Artificial nerve guides are being developed to substitute for autograft repair after peripheral nerve injuries. However, the use of conduits is limited by the length of the gap that needs to be bridged, with the success of regeneration highly compromised in long gaps. Addition of aligned proregenerative cells and extracellular matrix (ECM) components inside the conduit can be a good strategy to achieve artificial grafts that recreate the natural environment offered by a nerve graft. The purpose of this study was to functionalize chitosan devices with different cell types to support regeneration in limiting gaps in the rat peripheral nerve. METHODS The authors used chitosan devices combined with proteins of the ECM and cells in a rat model of sciatic nerve injury. Combinations of fibronectin and laminin with mesenchymal stem cells (MSCs) or Schwann cells (SCs) were aligned within tethered collagen-based gels, which were placed inside chitosan tubes that were then used to repair a critical-size gap of 15 mm in the rat sciatic nerve. Electrophysiology and algesimetry tests were performed to analyze functional recovery during the 4 months after injury and repair. Histological analysis was performed at the midlevel and distal level of the tubes to assess the number of regenerated myelinated fibers. RESULTS Functional analysis demonstrated that SC-aligned scaffolds resulted in 100% regeneration success in a 15-mm nerve defect in this rat model. In contrast, animals that underwent repair with MSC-aligned constructs had only 90% regeneration success, and those implanted with acellular bridges had only 75% regeneration success. CONCLUSIONS These results indicate that the combination of chitosan conduits with ECM-enriched cellular gels represents a good alternative to the use of autografts for repairing long nerve gaps.

After peripheral nerve injury, there are important changes at the spinal level that can lead to disorganization of the central circuitry and thus compromise functional recovery even if axons are able to successfully regenerate and reinnervate their target organs. Physical rehabilitation is a promising strategy to modulate these plastic changes and thus to improve functional recovery after the damage of the nervous system. Forced exercise in a treadmill is able to partially reverse the synaptic stripping and the loss of perineuronal nets that motoneurons suffer after peripheral nerve injury in animal models. The aim of this study was to investigate whether passive exercise, by means of cycling in a motorized bicycle, or voluntary free running in a wheel is able to mimic the effects induced by forced exercise on the changes that axotomized motoneurons suffer after peripheral nerve injury. Partial preservation of synapses and perineuronal nets was observed only in axotomized motoneurons from animals subjected to high-intensity cycling and the ones that freely ran long distances, but not when low-intensity exercise protocols were applied. Therefore, the intensity but not the type of exercise used is the key element to prevent synaptic stripping and loss of perineuronal nets in motoneurons after axotomy., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Key Points: Smn +/- transgenic mouse is a model of the mildest form of spinal muscular atrophy. Although there is a loss of spinal motoneurons in 11-month-old animals, muscular force is maintained. This maintained muscular force is mediated by reinnervation of the denervated fibres by surviving motoneurons. The spinal motoneurons in these animals do not show an increased susceptibility to death after nerve injury and they retain their regenerative capacity. We conclude that the hypothesized immaturity of the neuromuscular system in this model cannot explain the loss of motoneurons by systematic die-back., Abstract: Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn +/- transgenic mouse model of the mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections. Thereby, we investigated whether incomplete maturation of the neuromuscular system induced by survival motoneuron protein (SMN) defects is responsible for die-back of axons relative to survival of motoneurons. First, a reduction of ∼30% of backlabelled motoneurons began relatively late, at 11 months of age, with a significant loss of 19% at 7 months. Motor axon die-back was affirmed by motor unit number estimation. Loss of functional motor units was fully compensated by axonal sprouting to retain normal contractile force in four hindlimb muscles (three fast-twitch and one slow-twitch) innervated by branches of the sciatic nerve. Second, our evaluation of whether axotomy of motoneurons in the adult Smn +/- transgenic mouse increases their susceptibility to cell death demonstrated that all the motoneurons survived and they sustained their capacity to regenerate their nerve fibres. It is concluded the systematic die-back of motoneurons that innervate both fast- and slow-twitch muscle fibres is not related to immaturity of the neuromuscular system in SMA., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Background: Autograft is still the gold standard technique for the repair of long peripheral nerve injuries. The addition of biologically active scaffolds into the lumen of conduits to mimic the endoneurium of peripheral nerves may increase the final outcome of artificial nerve devices. Furthermore, the control of the orientation of the collagen fibers may provide some longitudinal guidance architecture providing a higher level of mesoscale tissue structure., Objective: To evaluate the regenerative capabilities of chitosan conduits enriched with extracellular matrix-based scaffolds to bridge a critical gap of 15 mm in the rat sciatic nerve., Methods: The right sciatic nerve of female Wistar Hannover rats was repaired with chitosan tubes functionalized with extracellular matrix-based scaffolds fully hydrated or stabilized and rolled to bridge a 15 mm nerve gap. Recovery was evaluated by means of electrophysiology and algesimetry tests and histological analysis 4 months after injury., Results: Stabilized constructs enhanced the success of regeneration compared with fully hydrated scaffolds. Moreover, fibronectin-enriched scaffolds increased muscle reinnervation and number of myelinated fibers compared with laminin-enriched constructs., Conclusion: A mixed combination of collagen and fibronectin may be a promising internal filler for neural conduits for the repair of peripheral nerve injuries, and their stabilization may increase the quality of regeneration over long gaps., (Copyright © 2017 by the Congress of Neurological Surgeons)

After peripheral nerve injury, transected fibers distal to the lesion are disconnected from the neuronal body. This results in target denervation but also massive stripping of the central synapses of axotomized motoneurons, disrupting spinal circuits. Even when axonal regeneration is successful, the non-specific target reinnervation and the limited rebuilding of spinal circuits impair functional recovery. Therefore, strategies aimed to preserve spinal circuits after nerve lesions may improve the functional outcome. Activity-dependent therapy in the form of early treadmill running reduces synaptic stripping, mainly of excitatory synapses, and the disorganization of perineuronal nets (PNNs) on axotomized motoneurons. The mechanism underlying these effects remains unknown, although the benefits of exercise are often attributed to an increase in the neurotrophin brain-derived neurotrophic factor (BDNF). In this study, tropomyosin-related kinase (TrkB) agonist and antagonist were administered to rats subjected to sciatic nerve injury in order to shed light on the role of BDNF. The maintenance of synapses on axotomized motoneurons induced by treadmill running was partially dependent on TrkB activation. Treatment with the TrkB agonist at a low dose, but not at a high dose, prevented the decrease of excitatory glutamatergic synapses, and both doses increased the density of inhibitory synapses. TrkB inactivation counteracted only some of the positive effects exerted by exercise after nerve injury, such as maintenance of excitatory synapses surrounding motoneurons. Therefore, specific regimes of physical exercise are a better strategy to attenuate the alterations that motoneurons suffer after axotomy than pharmacological modulation of the TrkB pathway., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM) components and neurotrophic factors (NTFs) exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF)/neurotrophin-3 (NT3) or collagen, fibronectin and brain-derived neurotrophic factor (BDNF) selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid) (PLGA) microspheres (MP) (LM + MP.NGF/NT3), or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF). Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation., Competing Interests: The authors declare no conflict of interest.

Bortezomib is a proteasome inhibitor with a remarkable antitumor activity, used in the clinic as first line treatment for multiple myeloma. One hallmark of bortezomib mechanism of action in neoplastic cells is the inhibition of nuclear factor kappa B (NFκB), a transcription factor involved in cell survival and proliferation. Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity that often requires adjustment of treatment and affects patient's prognosis and quality of life. Since disruption of NFκB pathway can also affect neuronal survival, we assessed the role of NFκB in bortezomib-induced neuropathy by using a transgenic mouse that selectively provides blockage of the NFκB pathway in neurons. Interestingly, we observed that animals with impaired NFκB activation developed significantly less severe neuropathy than wild type animals, with particular preservation of large myelinated fibers, thus suggesting that neuronal NFκB activation plays a positive role in bortezomib induced neuropathy and that bortezomib treatment might induce neuropathy by inhibiting NFκΒ in non-neuronal cell types or by targeting other signaling pathways. Therefore, inhibition of NFκB might be a promising strategy for the cotreatment of cancer and neuropathy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

After peripheral nerve injuries, damaged axons can regenerate but functional recovery is limited by the specific reinnervation of targets. In this study we evaluated if motor and sensory neurites have a substrate preference for laminin and fibronectin in postnatal and adult stages. In postnatal dorsal root ganglia (DRG) explants, sensory neurons extended longer neurites on collagen matrices enriched with laminin (~50%) or fibronectin (~35%), whereas motoneurons extended longer neurites (~100%) in organotypic spinal cord slices embedded in fibronectin-enriched matrix. An increased percentage of parvalbumin-positive neurites (presumptive proprioceptive) vs. neurofilament-positive neurites was also found in DRG in fibronectin-enriched matrix. To test if the different preference of neurons for extracellular matrix components was maintained in vivo, these matrices were used to fill a chitosan guide to repair a 6-mm gap in the sciatic nerve of adult rats. However, the number of regenerating motor and sensory neurons after 1 month was similar between groups. Moreover, none of the retrotraced sensory neurons in DRG was positive for parvalbumin, suggesting that presumptive proprioceptive neurons had poor regenerative capabilities compared with other peripheral neurons. Using real-time PCR we evaluated the expression of α5β1 (receptor for fibronectin) and α7β1 integrin (receptor for laminin) in spinal cord and DRG 2 days after injury. Postnatal animals showed a higher increase of α5β1 integrin, whereas both integrins were similarly expressed in adult neurons. Therefore, we conclude that motor and sensory axons have a different substrate preference at early postnatal stages but this difference is lost in the adult., (© 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Biosynthetic nerve grafts are developed in order to complement or replace autologous nerve grafts for peripheral nerve reconstruction. Artificial nerve guides currently approved for clinical use are not widely applied in reconstructive surgery as they still have limitations especially when it comes to critical distance repair. Here we report a comprehensive analysis of fine-tuned chitosan nerve guides (CNGs) enhanced by introduction of a longitudinal chitosan film to reconstruct critical length 15 mm sciatic nerve defects in adult healthy Wistar or diabetic Goto-Kakizaki rats. Short and long term investigations demonstrated that the CNGs enhanced by the guiding structure of the introduced chitosan film significantly improved functional and morphological results of nerve regeneration in comparison to simple hollow CNGs. Importantly, this was detectable both in healthy and in diabetic rats (short term) and the regeneration outcome almost reached the outcome after autologous nerve grafting (long term). Hollow CNGs provide properties likely leading to a wider clinical acceptance than other artificial nerve guides and their performance can be increased by simple introduction of a chitosan film with the same advantageous properties. Therefore, the chitosan film enhanced CNGs represent a new generation medical device for peripheral nerve reconstruction., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The proteasome inhibitor bortezomib is nowadays first line treatment for multiple myeloma. One of the most significant adverse events is peripheral neuropathy, mainly involving sensory nerve fibers that can lead to withdrawal of treatment. Here we develop an in vitro model to compare the effects of bortezomib on primary sensory neurons and Schwann cells of adult mice. We observed that sensory neurons were more susceptible to bortezomib, and their viability was reduced at a concentration of 6 nM, that only affected Schwann cell proliferation but not survival. At concentration higher than 8 nM Schwann cell viability was also compromised. Already at low concentrations, surviving neurons presented alterations in neurite outgrowth. Neurites were shorter and had dystrophic appearance, with alterations in neurofilament staining. However, neurites were able to regrow after removing bortezomib from the medium, thus indicating reversibility of the neurotoxicity. We confirmed in vivo that bortezomib produced alterations in neurofilaments at early stages of the treatment. After an accumulated dose of 2 mg/kg bortezomib, dorsal root ganglia neurons of treated animals showed accumulation of neurofilament in the soma. To evaluate if this accumulation was related with alterations in axonal transport, we tested the ability of sensory neurons to retrogradely transport a retrotracer applied at the distal nerve. Treated animals showed a lower amount of retrotracer in the soma 24 h after its application to the tibial nerve, therefore suggesting that axonal transport was affected by bortezomib.

Injury of a peripheral nerve not only leads to target denervation, but also induces massive stripping of spinal synapses on axotomized motoneurons, with disruption of spinal circuits. Even when regeneration is successful, unspecific reinnervation and the limited reconnection of the spinal circuits impair functional recovery. The aim of this study was to describe the changes that axotomized motoneurons suffer after peripheral nerve injury and how activity-dependent therapies and neurotrophic factors can modulate these events. We observed a marked decrease in glutamatergic synapses, with a maximum peak at two weeks post-axotomy, which was only partially reversed with time. This decrease was accompanied by an increase in gephyrin immunoreactivity and a disintegration of perineuronal nets (PNNs) surrounding the motoneurons. Direct application of neurotrophins at the proximal stump was not able to reverse these effects. In contrast, activity-dependent treatment, in the form of treadmill running, reduced the observed destructuring of perineuronal nets and the loss of glutamatergic synapses two weeks after injury. These changes were proportional to the intensity of the exercise protocol. Blockade of sensory inputs from the homolateral hindlimb also reduced PNN immunoreactivity around intact motoneurons, and in that case treadmill running did not reverse that loss, suggesting that the effects of exercise on motoneuron PNN depend on increased sensory activity. Preservation of motoneuron PNN and reduction of synaptic stripping by exercise could facilitate the maintenance of the spinal circuitry and benefit functional recovery after peripheral nerve injury., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Fibroblast growth factor 2 (FGF-2) is a trophic factor expressed by glial cells and different neuronal populations. Addition of FGF-2 to spinal cord and dorsal root ganglia (DRG) explants demonstrated that FGF-2 specifically increases motor neuron axonal growth. To further explore the potential capability of FGF-2 to promote axon regeneration, we produced a lentiviral vector (LV) to overexpress FGF-2 (LV-FGF2) in the injured rat peripheral nerve. Cultured Schwann cells transduced with FGF-2 and added to collagen matrix embedding spinal cord or DRG explants significantly increased motor but not sensory neurite outgrowth. LV-FGF2 was as effective as direct addition of the trophic factor to promote motor axon growth in vitro. Direct injection of LV-FGF2 into the rat sciatic nerve resulted in increased expression of FGF-2, which was localized in the basal lamina of Schwann cells. To investigate the in vivo effect of FGF-2 overexpression on axonal regeneration after nerve injury, Schwann cells transduced with LV-FGF2 were grafted in a silicone tube used to repair the resected rat sciatic nerve. Electrophysiological tests conducted for up to 2 months after injury revealed accelerated and more marked reinnervation of hindlimb muscles in the animals treated with LV-FGF2, with an increase in the number of motor and sensory neurons that reached the distal tibial nerve at the end of follow-up., (© 2014 Wiley Periodicals, Inc.)

In the last ten years, the proteasome has become one of the most attractive targets for the treatment of several cancer malignancies. Like other types of antineoplastic agents, proteasome inhibitors cause toxic peripheral neuropathy, which indeed is one of the limiting side effects of these treatments, and which thus curtails its potential effectiveness. Bortezomib was the first proteasome inhibitor approved for clinical use and is currently the first line treatment for multiple myeloma. The incidence of neuropathy induced by bortezomib is around 30-60%. Although the neurotoxic mechanisms are not completely understood, experimental studies suggest that aggresome formation, endoplasmic reticulum stress, mitotoxicity, inflammatory response, and DNA damage could contribute to this neurotoxicity. Additionally, the second generation of proteasome inhibitors, headed by carfilzomib, is currently being developed in order to reduce the toxic profile, with promising results. However, more extensive clinical experience and further experimental research are needed in order to determine the potential benefits of the second generation over bortezomib. The present review summarizes the main clinical features and mechanistic events related to the neuropathy induced by proteasome-inhibitors., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Bortezomib (BTZ), a proteasome inhibitor, is an effective anti-neoplastic drug used in the treatment of multiple myeloma and mantle cell lymphoma. However, it can induce a reversible peripheral neuropathy that may lead to treatment discontinuation. The mechanism through which BTZ exerts toxic effects in peripheral neurons is not clear. Release of proinflammatory cytokines after nerve damage can induce neurodegeneration, but the effects of BTZ on cytokine expression in neurons are unknown, although BTZ modulates the expression of cytokines, such as TNF-α and IL-6, in tumor cells. The aim of this study was to evaluate the expression and the role of these cytokines on the course of BTZ induced neuropathy in mice. IL-6, TNF-α, TGF-β1 and IL-1β were up-regulated in dorsal root ganglia but TNF-α and IL-6 increased faster and higher. Then, we studied the potential neuroprotective effect of selective antibodies anti-TNF-α and anti-IL-6 on the evolution of the neuropathy. Treatment with anti-TNF-α but not with anti-IL-6 significantly prevented the decrease of sensory nerve action potentials amplitude and the loss of myelinated and unmyelinated fibers. We conclude that monoclonal antibodies directed against TNF-α may be a suitable neuroprotective therapy against the neurotoxicity induced by BTZ., (Copyright © 2013 Elsevier Inc. All rights reserved.)