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... more
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 ...
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Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective,... more
Although amyotrophic lateral sclerosis (ALS) is pre-eminently a motor disease, the existence of non-motor manifestations, including sensory involvement, has been described in the last few years. Although from a clinical perspective, sensory symptoms are overshadowed by their motor manifestations, this does not mean that their pathological significance is not relevant. In this review, we have made an extensive description of the involvement of sensory and autonomic systems described to date in ALS, from clinical, neurophysiological, neuroimaging, neuropathological, functional, and molecular perspectives.
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No hi ha un tractament eficaç per vèncer l'Esclerosi Lateral Amiotròfica (ELA); tanmateix; el grup de Neuroplasticitat i Regeneració de l'Institut de Neurociències de la UAB ha assajat dos protocols de teràpia cel·lular amb... more
No hi ha un tractament eficaç per vèncer l'Esclerosi Lateral Amiotròfica (ELA); tanmateix; el grup de Neuroplasticitat i Regeneració de l'Institut de Neurociències de la UAB ha assajat dos protocols de teràpia cel·lular amb ratolins model d'ELA per estudiar, a partir d'una estratègia multifocal, com protegir les neurones motores de la medul·la espinal i les seves connexions als músculs, les dianes de la malaltia.No hay un tratamiento eficaz para vencer la Esclerosis Lateral Amiotrófica (ELA); sin embargo; el grupo de Neuroplasticidad y Regeneración del Instituto de Neurociencias de la UAB ha ensayado dos protocolos de terapia celular con ratones modelo de ELA para estudiar, a partir de una estrategia multifocal, cómo proteger las neuronas motores de la médula espinal y sus conexiones con los músculos, las dianas de la enfermedad.There is no effective treatment to overcome Amyotrophic Lateral Sclerosis (ALS); nevertheless; the Neuroplasticity and Regeneration group of...
Un equip coordinat pel professor Xavier Navarro, del Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia, i de l'Institut de Neurociències, ha observat que incrementar l'expressió de la proteïna Neuregulina 1... more
Un equip coordinat pel professor Xavier Navarro, del Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia, i de l'Institut de Neurociències, ha observat que incrementar l'expressió de la proteïna Neuregulina 1 tipus I en ratolins utilitzats com a model per a l'estudi de l'Esclerosi Lateral Amiotròfica (ELA) alenteix l'evolució de la malaltia. Els resultats apunten a una possible futura teràpia gènica per al tractament de l'ELA.Un equipo coordinado por el profesor Xavier Navarro, del Departamento de Biología Celular, Fisiología e Inmunología y del Instituto de Neurociencias ha observado que incrementar la expresión de la proteína neuregulina 1 tipo I en ratones utilizados como modelo para el estudio de la Esclerosis Lateral Amiotrófica (ELA) ralentiza la evolución de la enfermedad. Los resultados apuntan a una posible futura terapia génica para el tratamiento de la ELA.A team coordinated by Professor Xavier Navarro, of the Department of Cellula...
Despres d'una lesio de nervi periferic les neurones posen en marxa mecanismes que permeten regenerar els axons sensorials, per tal d'intentar recuperar la seva funcio. Malgrat tot, en la majoria dels casos la recuperacio funcional... more
Despres d'una lesio de nervi periferic les neurones posen en marxa mecanismes que permeten regenerar els axons sensorials, per tal d'intentar recuperar la seva funcio. Malgrat tot, en la majoria dels casos la recuperacio funcional es insuficient i es produeixen alteracions en el processament de la informacio. Aquesta recerca demostra que l'alteracio dels nivells de clor intracel·lular afecta la regeneracio de les fibres responsables de conduir sensacions de tacte i de posicio, sense afectar la regeneracio de les que condueixen sensacions de dolor i temperatura.
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For chronic stimulation of nerve fibers, only charge balanced waveforms should be used. However, if the charge recuperation phase comes right after the stimulation phase, it might abolish activation of the nerve fibers that are close to... more
For chronic stimulation of nerve fibers, only charge balanced waveforms should be used. However, if the charge recuperation phase comes right after the stimulation phase, it might abolish activation of the nerve fibers that are close to the threshold level. Delaying the charge recuperation phase may eliminate this abolition effect, and thus reduce the charge required to activate nerve fibers. The objective of this in vivo study, was to determine to which extent the required stimulation charge might be decreased by delaying the discharge phase, depending on the pulse duration and the way the discharge is performed. The results demonstrated that delaying the discharge phase allows to gain more charge for shorter pulses. The difference in the gain between the waveforms with passive and active discharge is less striking. The delayed discharge does not affect much stimulation selectivity.
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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... more
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.
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Research on microglia has established the differentiation between the so-called M1 and M2 phenotypes. However, new frameworks have been proposed attempting to discern between meaningful microglia profiles. We have set up an in vitro... more
Research on microglia has established the differentiation between the so-called M1 and M2 phenotypes. However, new frameworks have been proposed attempting to discern between meaningful microglia profiles. We have set up an in vitro microglial activation model by adding an injured spinal cord (SCI) lysate to microglial cultures, obtained from postnatal rats, in order to mimic the environment of the spinal cord after injury. We found that under the presence of the SCI lysate microglial cells changed their phenotype, developing less ramified but longer processes, and proliferated. The SCI lysate also led to upregulation of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, downregulation of the anti-inflammatory cytokines IL-10 and IL-4, and a biphasic profile of iNOS. In addition, a latex beads phagocytosis assay revealed the SCI lysate stimulated the phagocytic capacity of microglia. Flow cytometry analysis indicated that microglial cells showed a pro-inflammatory profile i...
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Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the... more
Background Vafidemstat (ORY-2001) is a clinical stage inhibitor of the Lysine Specific Demethylase KDM1A in development for treatment of neurodegenerative and psychiatric diseases. KDM1A demethylates H3K4me1/2 and together with the histone deacetylases HDAC1/2, it forms part of co-repressor complexes recruited by zinc finger factors to control transcription. The exact role of KDM1A in neuroinflammation remained to be explored. Methods Compounds were administered p.o. gavage to mice with MOG35-55 induced experimental autoimmune encephalomyelitis or mice infected with Theiler’s murine encephalomyelitis virus. Immune cell infiltration was analyzed by immunohistochemistry. Cytokine and chemokine levels were analyzed by ELISA. Genome wide gene expression in spinal cord and brain were analyzed by two-color microarray analysis and qRT-PCR.Results ORY-2001 improved the clinical score in mouse experimental autoimmune encephalomyelitis and in mice infected with the Theiler’s murine encephalom...
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Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead... more
Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury...
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Els dispositius neuroprostetics han anat evolucionant en els darrers anys amb l’objectiu de substituir o recuperar les funcions de extremitats en pacients amputats. No obstant, segons la literatura mes actual, els avencos en tecnologies... more
Els dispositius neuroprostetics han anat evolucionant en els darrers anys amb l’objectiu de substituir o recuperar les funcions de extremitats en pacients amputats. No obstant, segons la literatura mes actual, els avencos en tecnologies robotiques van un pas endavant en comparacio amb els encara limitats avencos en el mon de les interficies neurals com per poder fer un us mes fiable, generalitzat i assequible. Aixo, requereix principalment una millora dels “closed loops commands” per executar moviments en resposta a la percepcio d’estimuls sensorials mitjancant la incorporacio funcions motores i sensorials a la interficie. Un altre problema es la manca de tecniques que ens permetin l’acces a senyals sensorials i motores a alta resolucio dirigides a maquines connectades a humans com ara bracos robotics. Per tant, com en estudis previs han descrit que els axons en regeneracio poden ser guiats per diferents factors, ens vam centrar en el desenvolupament d’un electrode regeneratiu de do...
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SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further... more
SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further define peripheral sensory involvement, analyzing at the same time points the neuronal bodies located in the dorsal root ganglia (DRG) and the distal part of their axons in the skin, in order to shed light in the mechanisms of sensory involvement in ALS. We performed immunohistochemical analysis of peptidergic (CGRP), non-peptidergic (IB4) fibers in epidermis, as well as sympathetic sudomotor fibers (VIP) in the footpads of SOD1G93A mice and wild type littermates at 4, 8, 12 and 16 weeks of age. We also immunolabeled and quantified neuronal bodies of IB4, CGRP and parvalbumin (PV) positive sensory neurons in lumbar DRG. We detected a reduction of intraepidermal nerve fiber density in the SOD1G93A mice of both peptidergic and non-peptidergic axons, compa...
SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further... more
SOD1G93A mice show loss of cutaneous small fibers, as in ALS patients. Our objective is to characterize the involvement of different somatosensory neuron populations and its temporal progression in the SOD1G93A mice. We aim to further define peripheral sensory involvement, analyzing at the same time points the neuronal bodies located in the dorsal root ganglia (DRG) and the distal part of their axons in the skin, in order to shed light in the mechanisms of sensory involvement in ALS. We performed immunohistochemical analysis of peptidergic (CGRP), non-peptidergic (IB4) fibers in epidermis, as well as sympathetic sudomotor fibers (VIP) in the footpads of SOD1G93A mice and wild type littermates at 4, 8, 12 and 16 weeks of age. We also immunolabeled and quantified neuronal bodies of IB4, CGRP and parvalbumin (PV) positive sensory neurons in lumbar DRG. We detected a reduction of intraepidermal nerve fiber density in the SOD1G93A mice of both peptidergic and non-peptidergic axons, compa...
Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous... more
Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson’s disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800–0.935) showed that detectio...
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Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous... more
Diagnosis of ALS is based on clinical symptoms when motoneuron degeneration is significant. Therefore, new approaches for early diagnosis are needed. We aimed to assess if alterations in appearance and cellular localization of cutaneous TDP-43 may represent a biomarker for ALS. Skin biopsies from 64 subjects were analyzed: 44 ALS patients, 10 healthy controls (HC) and 10 neurological controls (NC) (Parkinson’s disease and multiple sclerosis). TDP-43 immunoreactivity in epidermis and dermis was analyzed, as well as the percentage of cells with TDP-43 cytoplasmic localization. We detected a higher amount of TDP-43 in epidermis (p < 0.001) and in both layers of dermis (p < 0.001), as well as a higher percentage of TDP-43 cytoplasmic positive cells (p < 0.001) in the ALS group compared to HC and NC groups. Dermal cells containing TDP-43 were fibroblasts as identified by co-labeling against vimentin. ROC analyses (AUC 0.867, p < 0.001; CI 95% 0.800–0.935) showed that detectio...
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Research Interests:
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... more
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...
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This paper reports on the design, in vitro and in vivo investigation of a flexible, lightweight, polyimide based implantable sieve electrode with a hybrid assembly of multiplexers and polymer encapsulation. The integration of multiplexers... more
This paper reports on the design, in vitro and in vivo investigation of a flexible, lightweight, polyimide based implantable sieve electrode with a hybrid assembly of multiplexers and polymer encapsulation. The integration of multiplexers enables us to connect a large number of electrodes on the sieve using few input connections. The implant assembly of the sieve electrode with the electronic circuitry was verified by impedance measurement. The 27 platinum electrodes of the sieve were coated with platinum black to reduce the electrode impedance. The impedance magnitude of the electrode sites on the sieve (geometric surface area 2,200 microm(2)) was |Z(f=1kHz)| = 5.7 kOmega. The sieve electrodes, encased in silicone, have been implanted in the transected sciatic nerve of rats. Initial experiments showed that axons regenerated through the holes of the sieve and reinnervated distal target organs. Nerve signals were recorded in preliminary tests after 3-7 months post-implantation.
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Research Interests: Computer Science, Algorithms, Biophysics, Biomedical Engineering, Computational Modelling, and 15 moreComputational Neuroscience, Finite element method, Finite Element Analysis, Computer Simulation, Computer Model, Animals, Active site, Data Model, Indexation, Experimental Validation, Biological System Modeling, Equipment Design, Electrical And Electronic Engineering, Hybrid Model, and Electric stimulation
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Significant strides have been recently made to develop highly sensorized cybernetic prostheses aimed at restoring sensorimotor limb functions to those who have lost them because of a traumatic event (amputation). In these cases, one of... more
Significant strides have been recently made to develop highly sensorized cybernetic prostheses aimed at restoring sensorimotor limb functions to those who have lost them because of a traumatic event (amputation). In these cases, one of the main goals is to create a bidirectional link between the artificial devices (e.g., robotic hands, arms, or legs) and the nervous system. Several human-machine interfaces (HMIs) are currently used to this aim. Among them, interfaces with the peripheral nervous system and in particular longitudinal intrafascicular electrodes can be a promising solution able to improve the current situation. In this paper, the potentials and limits of the use of this interface to control robotic devices are presented. Specific information is provided on: 1) the neurophysiological bases for the use peripheral nerve interfaces; 2) a comparison of the potentials of the different peripheral neural interfaces; 3) the possibility of extracting and appropriately interpreting the neural code for motor commands and of delivering sensory feedback by stimulating afferent fibers by using longitudinal intrafascicular electrodes; 4) a preliminary comparative analysis of the performance of this approach with the ones of others HMIs; 5) the open issues which have to be addressed for a chronic usability of this approach.
Research Interests: Engineering, Robotics, Biomedical Engineering, Cybernetics, Medicine, and 15 moreHumans, Peripheral Nervous System, Comparative Analysis, Human Machine Interface, Electromyography, Amputees, Peripheral nerves, Hand, Peripheral Nerve, Nervous System, Equipment Design, Equipment Failure Analysis, Electrical And Electronic Engineering, neural code, and neural systems
Pain is a physiological experience, designed to alert us from potential damages to our body, so it has a clear protective role. Pain is defined by the IASP (International Association for the Study of Pain) as an unpleasant sensory and... more
Pain is a physiological experience, designed to alert us from potential damages to our body, so it has a clear protective role. Pain is defined by the IASP (International Association for the Study of Pain) as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. When the pain circuits are correctly working they aware us from external (abnormal heating, pinch stimuli, etc.) or internal stimuli (cardiac ischemia) that would potentially hurt the tissues. Ideally, the sensation we perceive should be unpleasant enough, so it cannot be ignored, and the sensation should continue as long as the stimulus is present. Different types of “normal” pain can be distinguished depending on their origin and characteristics: acute (or pricking), chronic (or burning), and continuous or visceral.
Micro-fabricated neural interfaces based on polyimide (PI) are achieving increasing importance in translational research. The ability to produce well-defined micro-structures with properties that include chemical inertness, mechanical... more
Micro-fabricated neural interfaces based on polyimide (PI) are achieving increasing importance in translational research. The ability to produce well-defined micro-structures with properties that include chemical inertness, mechanical flexibility and low water uptake are key advantages for these devices. This paper reports the development of the transverse intrafascicular multichannel electrode (TIME) used to deliver intraneural sensory feedback to an upper-limb amputee in combination with a sensorized hand prosthesis. A first-in-human study limited to 30 days was performed. About 90 % of the stimulation contact sites of the TIMEs maintained electrical functionality and stability during the full implant period. However, optical analysis post-explantation revealed that 62.5 % of the stimulation contacts showed signs of mechanical damage at the metallization-PI interface. Such damage likely occurred due to handling during explantation and subsequent analysis, since a significant chang...
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Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2)... more
Neuropathic pain after peripheral nerve injury is characterized by loss of inhibition in both peripheral and central pain pathways. In the adult nervous system, the Na(+)-K(+)-2Cl(-) (NKCC1) and neuron-specific K(+)-Cl(-) (KCC2) cotransporters are involved in setting the strength and polarity of GABAergic/glycinergic transmission. After nerve injury, the balance between these cotransporters changes, leading to a decrease in the inhibitory tone. However, the role that NKCC1 and KCC2 play in pain-processing brain areas is unknown. Our goal was to study the effects of peripheral nerve injury on NKCC1 and KCC2 expression in dorsal root ganglia (DRG), spinal cord, ventral posterolateral (VPL) nucleus of the thalamus, and primary somatosensory (S1) cortex. After sciatic nerve section and suture in adult rats, assessment of mechanical and thermal pain thresholds showed evidence of hyperalgesia during the following 2 months. We also found an increase in NKCC1 expression in the DRG and a downregulation of KCC2 in spinal cord after injury, accompanied by later decrease of KCC2 levels in higher projection areas (VPL and S1) from 2 weeks postinjury, correlating with neuropathic pain signs. Administration of bumetanide (30 mg/kg) during 2 weeks following sciatic nerve lesion prevented the previously observed changes in the spinothalamic tract projecting areas and the appearance of hyperalgesia. In conclusion, the present results indicate that changes in NKCC1 and KCC2 in DRG, spinal cord, and central pain areas may contribute to development of neuropathic pain.
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Peripheral nerve injuries lead to the loss of motor, sensory and autonomic functions in the territories supplied by the injured nerve. Currently, nerve injuries are managed by surgical repair procedures, and there are no effective drugs... more
Peripheral nerve injuries lead to the loss of motor, sensory and autonomic functions in the territories supplied by the injured nerve. Currently, nerve injuries are managed by surgical repair procedures, and there are no effective drugs in the clinic for improving the capacity of axonal regeneration. Sigma-1 receptor (Sig-1R) is an endoplasmic reticulum chaperon protein involved in many functions, including neuroprotection and neuroplasticity. A few previous studies using Sig-1R ligands reported results that suggest this receptor as a putative target to enhance regeneration. The aim of this study was to evaluate the possible effects of Sig-1R ligands on axonal regeneration in a sciatic nerve section and repair model in mice. To this end, mice were treated either with the Sig-1R agonist PRE-084 or the antagonist BD1063, and a Sig-1R knock-out (KO) mice group was also studied. The electrophysiological and histological data showed that treatment with Sig-1R ligands, or the lack of this...
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Research Interests:
We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced... more
We currently lack effective treatments for the devastating loss of neural function associated with spinal cord injury (SCI). In this study, we evaluated a combination therapy comprising human neural stem cells derived from induced pluripotent stem cells (iPSC-NSC), human mesenchymal stem cells (MSC), and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allows the sustained release of curcumin. In vitro analysis demonstrated that PA-C treatment protected iPSC-NSC from oxidative damage in vitro, while MSC co-culture prevented lipopolysaccharide-induced activation of nuclear factor-κB (NF-κB) in iPSC-NSC. Then, we evaluated the combination of PA-C delivery into the intrathecal space in a rat model of contusive SCI with stem cell transplantation. While we failed to observe significant improvements in locomotor function (BBB scale) in treated animals, histological analysis revealed that PA-C-treated or PA-C and iPSC-NSC + MSC-treated animals displayed significantly smaller s...
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Jordi Badia1,2, Aritra Kundu3, Kristian R. Harreby3, Tim Boretius4,5, Thomas Stieglitz5,6,7, Winnie Jensen3,* and Xavier Navarro1,2,* 1Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat... more
Jordi Badia1,2, Aritra Kundu3, Kristian R. Harreby3, Tim Boretius4,5, Thomas Stieglitz5,6,7, Winnie Jensen3,* and Xavier Navarro1,2,* 1Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain 2Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain 3Department of Health Science and Technology, Aalborg University, Denmark 4Neuroloop GmbH, Freiburg, Germany 5Laboratory for Biomedical Microsystems, Department of Microsystems Engineering-IMTEK, Albert-Ludwig-University of Freiburg, Freiburg, Germany 6BrainLinks-BrainTools, Albert-Ludwig-University of Freiburg, Freiburg, Germany 7Bernstein Center Freiburg, Albert-Ludwig-University of Freiburg, Freiburg, Germany E-mail: xavier.navarro@uab.cat ∗Corresponding Authors
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Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation offers promise in improving hand function. However, it is still unknown which stimulus intensity or which muscle force level could be better for this... more
Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation offers promise in improving hand function. However, it is still unknown which stimulus intensity or which muscle force level could be better for this improvement. Nine healthy individuals received the following interventions: (i) eEmc intensities at 80%, 90% and 110% of abductor pollicis brevis motor threshold combined with hand training consisting in 100% handgrip strength; (ii) hand training consisting in 100% and 50% of maximal handgrip strength combined with 90% eEmc intensity. The evaluations included box and blocks test (BBT), maximal voluntary contraction (MVC), F wave persistency, F/M ratio, spinal and cortical motor evoked potentials (MEP), recruitment curves of spinal MEP and cortical MEP and short-interval intracortical inhibition. The results showed that: (i) 90% eEmc intensity increased BBT, MVC, F wave persistency, F/M ratio and cortical MEP recruitment curve; 110% eEmc intensity in...
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Peripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial... more
Peripheral Nerve Stimulation (PNS) is a promising approach in functional restoration following neural impairments. Although it proves to be advantageous in the number of implantation sites provided compared with intramuscular or epimysial stimulation and the fact that it does not require daily placement, as is the case with surface electrodes, the further advancement of PNS paradigms is hampered by the limitation of spatial selectivity due to the current spread and variations of nerve physiology. New electrode designs such as the Transverse Intrafascicular Multichannel Electrode (TIME) were proposed to resolve this issue, but their use was limited by a lack of innovative multichannel stimulation devices. In this study, we introduce a new portable multichannel stimulator—called STIMEP—and implement different stimulation protocols in rats to test its versatility and unveil the potential of its combined use with TIME electrodes in rehabilitation protocols. We developed and tested vario...
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Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery... more
Loss of motor neurons (MNs) after spinal root injury is a drawback limiting the recovery after palliative surgery by nerve or muscle transfers. Research based on preventing MN death is a hallmark to improve the perspectives of recovery following severe nerve injuries. Sigma-1 receptor (Sig-1R) is a protein highly expressed in MNs, proposed as neuroprotective target for ameliorating MN degenerative conditions. Here, we used a model of L4–L5 rhizotomy in adult mice to induce MN degeneration and to evaluate the neuroprotective role of Sig-1R ligands (PRE-084, SA4503 and BD1063). Lumbar spinal cord was collected at 7, 14, 28 and 42 days post-injury (dpi) for immunohistochemistry, immunofluorescence and Western blot analyses. This proximal axotomy at the immediate postganglionic level resulted in significant death, up to 40% of spinal MNs at 42 days after injury and showed markedly increased glial reactivity. Sig-1R ligands PRE-084, SA4503 and BD1063 reduced MN loss by about 20%, associa...
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Research Interests:
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including... more
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the neuromuscular system for which currently there is no effective therapy. Motoneuron (MN) degeneration involves several complex mechanisms, including surrounding glial cells and skeletal muscle contributions. Neuregulin 1 (NRG1) is a trophic factor present particularly in MNs and neuromuscular junctions. Our previous studies revealed that gene therapy overexpressing the isoform I (NRG1-I) in skeletal muscles as well as overexpressing the isoform III (NRG1-III) directly in the central nervous system are both effective in preserving MNs in the spinal cord of ALS mice, opening novel therapeutic approaches. In this study, we combined administration of both viral vectors overexpressing NRG1-I in skeletal muscles and NRG1-III in spinal cord of the SOD1G93A mice in order to obtain a synergistic effect. The results showed that the combinatorial gene therapy increased preservation of MNs and of innervated ne...
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The foreign body reaction is a complex biological process leading to the insulation of implanted artificial materials through a capsule of scar tissue. In particular, in chronic implantations of neural electrodes, the prediction of the... more
The foreign body reaction is a complex biological process leading to the insulation of implanted artificial materials through a capsule of scar tissue. In particular, in chronic implantations of neural electrodes, the prediction of the scar tissue evolution is crucial to assess the implant reliability over time. Indeed, the capsule behaves like an increasing insulating barrier between electrodes and nerve fibers. However, no explicit and physically based rules are available to computationally reproduce the capsule evolution. In addition, standard approaches to this problem (i.e., Vandermonde-based and Lagrange interpolation) fail for the onset of the Runge phenomenon. More specifically, numerical oscillations arise, thus standard procedures are only able to reproduce experimental detections while they result in non physical values for inter-interval times (i.e., times before and after experimental detections). As a consequence, in this work, a novel framework is described to model t...
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Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation is a non-invasive method that can modify the functional state of the sensory-motor system. We hypothesize that eEmc delivery, together with hand... more
Electrical enabling motor control (eEmc) through transcutaneous spinal cord stimulation is a non-invasive method that can modify the functional state of the sensory-motor system. We hypothesize that eEmc delivery, together with hand training, improves hand function in healthy subjects more than either intervention alone by inducing plastic changes at spinal and cortical levels. Ten voluntary participants were included in the following three interventions: (i) hand grip training, (ii) eEmc, and (iii) eEmc with hand training. Functional evaluation included the box and blocks test (BBT) and hand grip maximum voluntary contraction (MVC), spinal and cortical motor evoked potential (sMEP and cMEP), and resting motor thresholds (RMT), short interval intracortical inhibition (SICI), and F wave in the abductor pollicis brevis muscle. eEmc combined with hand training retained MVC and increased F wave amplitude and persistency, reduced cortical RMT and facilitated cMEP amplitude. In contrast, ...
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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... more
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 dener...
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Research Interests:
Research Interests:
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic... more
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1 mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied wit...
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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... more
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 re...
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Amyotrophic Lateral Sclerosis (ALS ) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS ,... more
Amyotrophic Lateral Sclerosis (ALS ) is a neurodegenerative disease affecting spinal cord and brain motoneurons , leading to paralysis and early death. Multiple etiopathogenic mechanisms appear to contribute in the development of ALS , including glutamate excitotoxicity, oxidative stress , protein misfolding, mitochondrial defects, impaired axonal transport, inflammation and glial cell alterations. The Sigma-1 receptor is highly expressed in motoneurons of the spinal cord, particularly enriched in the endoplasmic reticulum (ER) at postsynaptic cisternae of cholinergic C-terminals. Several evidences point to participation of Sigma-1R alterations in motoneuron degeneration. Thus, mutations of the transmembrane domain of the Sigma-1R have been described in familial ALS cases. Interestingly, Sigma-1R KO mice display muscle weakness and motoneuron loss. On the other hand, Sigma-1R agonists promote neuroprotection and neurite elongation through activation of protein kinase C on motoneuron...
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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... more
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) (PL...