Mitochondrial dysfunction as a target in spinal cord injury: intimate correlation between pathological processes and therapeutic approaches.

Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves: (1) resealing injured axons; (2) reconstructing the cytoskeletal structure inside axons; (3) re-establishing healthy growth cones; and (4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regeneration-reconnection after spinal cord injury.

The Combined Use of Curcumin and Platelet-Rich Plasma Enhances Axonal Regeneration in Acute Nerve Injuries: An Experimental Study in a Rat Model.

Introduction The aim of this study was to determine if the combined use of curcumin and platelet-rich plasma (PRP) improves the axonal regeneration process in acutely repaired nerve injuries. Materials and Methods The right sciatic nerves of 32 Holtzman albino rats were transected and immediately repaired. Four treatments were randomly allocated: (1) nerve repair only; (2) nerve repair + local PRP; (3) nerve repair + intraperitoneal curcumin; and (4) nerve repair + local PRP + intraperitoneal curcumin. Clinical (estimation of sciatic functional index) and electrophysiological outcomes were assessed 4 and 12 weeks after surgery, and histologic evaluations performed 12 weeks after surgery. Results Group IV (PRP + curcumin) resulted in significantly better outcomes across all the evaluation parameters, compared with the other three groups ( p < 0.05). Additionally, when used as single adjuvants, both the curcumin (group III) and PRP (group II) groups showed significant improvement over the control group ( p < 0.05). No significant differences were found between PRP and curcumin when used as sole adjuvants. Conclusion The combined administration of curcumin + PRP as adjuvants to nerve repair could enhance axonal regeneration in terms of clinical, electrophysiological, and histological parameters in a rat model of acute sciatic nerve injury.

Neuronal activity-dependent ATP enhances the pro-growth effect of repair Schwann cell extracellular vesicles by increasing their miRNA-21 loading.

Functional recovery after peripheral nerve injuries is critically dependent on axonal regeneration. Several autonomous and non-cell autonomous processes regulate axonal regeneration, including the activation of a growth-associated transcriptional program in neurons and the reprogramming of differentiated Schwann cells (dSCs) into repair SCs (rSCs), triggering the secretion of neurotrophic factors and the activation of an inflammatory response. Repair Schwann cells also release pro-regenerative extracellular vesicles (EVs), but is still unknown whether EV secretion is regulated non-cell autonomously by the regenerating neuron. Interestingly, it has been described that nerve activity enhances axonal regeneration by increasing the secretion of neurotrophic factors by rSC, but whether this activity modulates pro-regenerative EV secretion by rSC has not yet been explored. Here, we demonstrate that neuronal activity enhances the release of rSC-derived EVs and their transfer to neurons. This effect is mediated by activation of P2Y receptors in SCs after activity-dependent ATP release from sensory neurons. Importantly, activation of P2Y in rSCs also increases the amount of miRNA-21 present in rSC-EVs. Taken together, our results demonstrate that neuron to glia communication by ATP-P2Y signaling regulates the content of SC-derived EVs and their transfer to axons, modulating axonal elongation in a non-cell autonomous manner.

The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection.

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.

Current Advances in Comprehending Dynamics of Regenerating Axons and Axon-Glia Interactions after Peripheral Nerve Injury in Zebrafish.

Following an injury, axons of both the central nervous system (CNS) and peripheral nervous system (PNS) degenerate through a coordinated and genetically conserved mechanism known as Wallerian degeneration (WD). Unlike central axons, severed peripheral axons have a higher capacity to regenerate and reinnervate their original targets, mainly because of the favorable environment that they inhabit and the presence of different cell types. Even though many aspects of regeneration in peripheral nerves have been studied, there is still a lack of understanding regarding the dynamics of axonal degeneration and regeneration, mostly due to the inherent limitations of most animal models. In this scenario, the use of zebrafish (Danio rerio) larvae combined with time-lapse microscopy currently offers a unique experimental opportunity to monitor the dynamics of the regenerative process in the PNS in vivo. This review summarizes the current knowledge and advances made in understanding the dynamics of the regenerative process of PNS axons. By using different tools available in zebrafish such as electroablation of the posterior lateral line nerve (pLLn), and laser-mediated transection of motor and sensory axons followed by time-lapse microscopy, researchers are beginning to unravel the complexity of the spatiotemporal interactions among different cell types during the regenerative process. Thus, understanding the cellular and molecular mechanisms underlying the degeneration and regeneration of peripheral nerves will open new avenues in the treatment of acute nerve trauma or chronic conditions such as neurodegenerative diseases.

Intraspinal Administration of Netrin-1 Promotes Locomotor Recovery after Complete Spinal Cord Transection.

Complete spinal cord lesions interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. In particular, the interruption of connections with the neurons at lumbar segments after thoracic injuries impairs voluntary body control below the injury. The failure of spontaneous regrowth of transected axons across the lesion prevents the reconnection and reinnervation of the neuronal targets. At present, the only treatment in humans that has proven to promote some degree of locomotor recovery is physical therapy. The success of these strategies, however, depends greatly on the type of lesion and the level of preservation of neural tissue in the spinal cord after injury. That is the reason it is key to design strategies to promote axonal regrowth and neuronal reconnection. Here, we test the use of a developmental axon guidance molecule as a biological agent to promote axonal regrowth, axonal reconnection, and recovery of locomotor activity after spinal cord injury (SCI). This molecule, netrin-1, guides the growth of the corticospinal tract (CST) during the development of the central nervous system. To assess the potential of this molecule, we used a model of complete spinal cord transection in rats, at thoracic level 10-11. We show that in situ delivery of netrin-1 at the epicenter of the lesion: (1) promotes regrowth of CST through the lesion and prevents CST dieback, (2) promotes synaptic reconnection of regenerated motor and sensory axons, and (3) preserves the polymerization of the neurofilaments in the sciatic nerve axons. These anatomical findings correlate with a significant recovery of locomotor function. Our work identifies netrin-1 as a biological agent with the capacity to promote the functional repair and recovery of locomotor function after SCI. These findings support the use of netrin-1 as a therapeutic intervention to be tested in humans.

PDCD4 regulates axonal growth by translational repression of neurite growth-related genes and is modulated during nerve injury responses.

Programmed cell death 4 (PDCD4) protein is a tumor suppressor that inhibits translation through the mTOR-dependent initiation factor EIF4A, but its functional role and mRNA targets in neurons remain largely unknown. Our work identified that PDCD4 is highly expressed in axons and dendrites of CNS and PNS neurons. Using loss- and gain-of-function experiments in cortical and dorsal root ganglia primary neurons, we demonstrated the capacity of PDCD4 to negatively control axonal growth. To explore PDCD4 transcriptome and translatome targets, we used Ribo-seq and uncovered a list of potential targets with known functions as axon/neurite outgrowth regulators. In addition, we observed that PDCD4 can be locally synthesized in adult axons in vivo, and its levels decrease at the site of peripheral nerve injury and before nerve regeneration. Overall, our findings demonstrate that PDCD4 can act as a new regulator of axonal growth via the selective control of translation, providing a target mechanism for axon regeneration and neuronal plasticity processes in neurons.

Collateral Sprouting of Peripheral Sensory Neurons Exhibits a Unique Transcriptomic Profile.

Peripheral nerve injuries result in motor and sensory dysfunction which can be recovered by compensatory or regenerative processes. In situations where axonal regeneration of injured neurons is hampered, compensation by collateral sprouting from uninjured neurons contributes to target reinnervation and functional recovery. Interestingly, this process of collateral sprouting from uninjured neurons has been associated with the activation of growth-associated programs triggered by Wallerian degeneration. Nevertheless, the molecular alterations at the transcriptomic level associated with these compensatory growth mechanisms remain to be fully elucidated. We generated a surgical model of partial sciatic nerve injury in mice to mechanistically study degeneration-induced collateral sprouting from spared fibers in the peripheral nervous system. Using next-generation sequencing and Ingenuity Pathway Analysis, we described the sprouting-associated transcriptome of uninjured sensory neurons and compare it with the activated by regenerating neurons. In vitro approaches were used to functionally assess sprouting gene candidates in the mechanisms of axonal growth. Using a novel animal model, we provide the first description of the sprouting transcriptome observed in uninjured sensory neurons after nerve injury. This collateral sprouting-associated transcriptome differs from that seen in regenerating neurons, suggesting a molecular program distinct from axonal growth. We further demonstrate that genetic upregulation of novel sprouting-associated genes activates a specific growth program in vitro, leading to increased neuronal branching. These results contribute to our understanding of the molecular mechanisms associated with collateral sprouting in vivo. The data provided here will therefore be instrumental in developing therapeutic strategies aimed at promoting functional recovery after injury to the nervous system.

Schwann cell reprogramming into repair cells increases miRNA-21 expression in exosomes promoting axonal growth.

Functional recovery after peripheral nerve damage is dependent on the reprogramming of differentiated Schwann cells (dSCs) into repair Schwann cells (rSCs), which promotes axonal regeneration and tissue homeostasis. Transition into a repair phenotype requires expression of c-Jun and Sox2, which transcriptionally mediates inhibition of the dSC program of myelination and activates a non-cell-autonomous repair program, characterized by the secretion of neuronal survival and regenerative molecules, formation of a cellular scaffold to guide regenerating axons and activation of an innate immune response. Moreover, rSCs release exosomes that are internalized by peripheral neurons, promoting axonal regeneration. Here, we demonstrate that reprogramming of Schwann cells (SCs) is accompanied by a shift in the capacity of their secreted exosomes to promote neurite growth, which is dependent on the expression of c-Jun (also known as Jun) and Sox2 by rSCs. Furthermore, increased expression of miRNA-21 is responsible for the pro-regenerative capacity of rSC exosomes, which is associated with PTEN downregulation and PI3-kinase activation in neurons. We propose that modification of exosomal cargo constitutes another important feature of the repair program of SCs, contributing to axonal regeneration and functional recovery after nerve injury.

Single vs. Combined Therapeutic Approaches in Rats With Chronic Spinal Cord Injury.

The regenerative capability of the central nervous system is limited after traumatic spinal cord injury (SCI) due to intrinsic and extrinsic factors that inhibit spinal cord regeneration, resulting in deficient functional recovery. It has been shown that strategies, such as pre-degenerated peripheral nerve (PPN) grafts or the use of bone marrow stromal cells (BMSCs) or exogenous molecules, such as chondroitinase ABC (ChABC) promote axonal growth and remyelination, resulting in an improvement in locomotor function. These treatments have been primarily assessed in acute injury models. The aim of the present study is to evaluate the ability of several single and combined treatments in order to modify the course of chronic complete SCI in rats. A complete cord transection was performed at the T9 level. One month later, animals were divided into five groups: original injury only (control group), and original injury plus spinal cord re-transection to create a gap to accommodate BMSCs, PPN, PPN + BMSCs, and PPN + BMSCs + ChABC. In comparison with control and single-treatment groups (PPN and BMSCs), combined treatment groups (PPN + BMSCs and PPN + BMSCs + ChABC) showed significative axonal regrowth, as revealed by an increase in GAP-43 and MAP-1B expression in axonal fibers, which correlated with an improvement in locomotor function. In conclusion, the combined therapies tested here improve locomotor function by enhancing axonal regeneration in rats with chronic SCI. Further studies are warranted to refine this promising line of research for clinical purposes.

A Synthetic Snake-Venom-Based Tripeptide Protects PC12 Cells from the Neurotoxicity of Acrolein by Improving Axonal Plasticity and Bioenergetics.

The synthetic peptide p-BTX-I is based on the native peptide (formed by glutamic acid, valine and tryptophan) isolated from Bothrops atrox venom. We have previously demonstrated its neuroprotective and neurotrophic properties in PC12 cells treated with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Now, we have investigated the neuroprotective effects and mechanisms of p-BTX-I against the toxicity of acrolein in PC12 cells. Studies have demonstrated that acrolein might play an important role in the etiology of Alzheimer's disease (AD), which is characterized by neuronal and synaptic loss. Our results showed that not only acrolein reduced cell differentiation and cell viability, but also altered the expression of markers of synaptic communication (synapsin I), energy metabolism (AMPK-α, Sirt I and glucose uptake), and cytoskeleton (ß-III-tubulin). Treatment with p-BTX-I increased the percentage of differentiation in cells treated with acrolein and significantly attenuated cell viability loss, besides counteracting the negative effects of acrolein on synapsin I, AMPK-α, Sirt I, glucose uptake, and ß-III-tubulin. Additionally, p-BTX-I alone increased the expression of apolipoprotein E (apoE) gene, associated with the proteolytic degradation of ß-amyloid peptide aggregates, a hallmark of AD. Taken together, these findings demonstrate that p-BTX-I protects against acrolein-induced neurotoxicity and might be a tool for the development of novel drugs for the treatment of neurodegenerative diseases.

Caffeic Acid Phenethyl Ester (CAPE) Protects PC12 Cells Against Cisplatin-Induced Neurotoxicity by Activating the AMPK/SIRT1, MAPK/Erk, and PI3k/Akt Signaling Pathways.

Peripheral sensory neuropathy (PSN) is a well-known side effect of cisplatin characterized by axonal damage. In the early stage of neurotoxicity, cisplatin affects proteins that modulate neurite outgrowth and neuroplasticity, without inducing mitochondrial damage or apoptosis. There are no preventive therapies for cisplatin-induced peripheral neuropathy; therefore, measures to improve axonal growth and connectivity would be beneficial. Caffeic acid phenethyl ester (CAPE) is a bioactive component of propolis with neurotrophic and neuroprotective activities. We have recently showed that CAPE protects against cisplatin-induced neurotoxicity by activating NGF high-affinity receptors (trkA) and inducing neuroplasticity. We have now assessed other potential early targets of cisplatin and additional mechanisms involved in the neuroprotection of CAPE. Cisplatin reduced axonal cytoskeletal proteins (F-actin and ß-III-tubulin) without inducing oxidative damage in PC12 cells. It also reduced energy-related proteins (AMPK α, p-AMPK α, and SIRT1) and glucose uptake. At this stage of neurotoxicity, glutamate excitotoxicity is not involved in the toxicity of cisplatin. CAPE attenuated the downregulation of the cytoskeleton and energy-related markers as well as SIRT1 and phosphorylated AMPK α. Moreover, the neuroprotective mechanism of CAPE also involves the activation of the neurotrophic signaling pathways MAPK/Erk and PI3k/Akt. The PI3K/Akt pathway is involved in the upregulation of SIRT1 induced by CAPE, but not in the upregulation of cytoskeletal proteins. Altogether, these findings suggest that the neuroprotective effect of CAPE against cisplatin-induced neurotoxicity involves both (a) a neurotrophic mechanism that mimics the mechanism triggered by the NGF itself and (b) a non-neurotrophic mechanism that upregulates the cytoskeletal proteins.

In Vitro Analysis of the Role of Schwann Cells on Axonal Degeneration and Regeneration Using Sensory Neurons from Dorsal Root Ganglia.

Sensory neurons from dorsal root ganglion efficiently regenerate after peripheral nerve injuries. These neurons are widely used as a model system to study degenerative mechanisms of the soma and axons, as well as regenerative axonal growth in the peripheral nervous system. This chapter describes techniques associated to the study of axonal degeneration and regeneration using explant cultures of dorsal root ganglion sensory neurons in vitro in the presence or absence of Schwann cells. Schwann cells are extremely important due to their involvement in tissue clearance during axonal degeneration as well as their known pro-regenerative effect during regeneration in the peripheral nervous system. We describe methods to induce and study axonal degeneration triggered by axotomy (mechanical separation of the axon from its soma) and treatment with vinblastine (which blocks axonal transport), which constitute clinically relevant mechanical and toxic models of axonal degeneration. In addition, we describe three different methods to evaluate axonal regeneration using quantitative methods. These protocols constitute a valuable tool to analyze in vitro mechanisms associated to axonal degeneration and regeneration of sensory neurons and the role of Schwann cells in these processes.

PPE tube filled with autologous fat in the repair of peripheral nerve: a new proposal / Tubo PPE relleno con grasa autóloga en la reparación de los nervios periféricos: una nueva propuesta

This study proposes the use of a porous polyethylene (PPE) tube as the conductive element in the regeneration in the sciatic nerve sectioning and evaluates the use of fill with autologous fat. The subject was divided randomly into five groups, 3 control and 2 experimental (PPE tube graft with/ without autologous fat). Each group was selected for functional, histological and morphometric evaluation of the sciatic nerve. Functional analysis of the sciatic nerve occurred through the "footprint" values near -100 refer sectioned sciatic nerve, near 0 (zero) refer to control group. On histological analysis of the experimental groups lots of dense connective tissue replacing nerve tissue was observed. In morphometric analysis the group EGPGf got higher performance in all of variables. The use of PPE has shown promise in nerve regeneration with favorable results when associate with fat as a trophic factor in the regeneration.

Este estudio propone el uso de un tubo de polietileno poroso (PPE) como elemento conductor en la regeneración del nervio ciático seccionado y evaluar el uso de relleno con grasa autóloga. Al azar se formaron cinco grupos, 3 y 2 de control experimental (PPE prótesis tubular con / sin grasa autóloga). Cada grupo fue seleccionado para estudiar la forma funcional, histológica y evaluación morfométrica del nervio ciático. Un análisis funcional del nervio ciático se produjo a través de los valores de "huella", cerca de -100 se refiere al nervio ciático seccionado; cerca de 0 (cero) se refiere al grupo control. En el análisis histológico de los grupos experimentales se observó una gran cantidad de tejido conjuntivo denso que sustituye el tejido nervioso. En el análisis morfométrico, el grupo experimental de injerto de polietileno lleno de grasa (EGPGf) obtuvo un mayor rendimiento en todas las variables. El uso de PPE ha mostrado ser prometedor en la regeneración del nervio, con resultados favorables cuando se asocia con la grasa como un factor trófico en la regeneración.

Enhanced Immune Response in Immunodeficient Mice Improves Peripheral Nerve Regeneration Following Axotomy.

Injuries to peripheral nerves cause loss of motor and sensory function, greatly affecting life quality. Successful repair of the lesioned nerve requires efficient cell debris removal, followed by axon regeneration and reinnervation of target organs. Such process is orchestrated by several cellular and molecular events in which glial and immune cells actively participate. It is known that tissue clearance is largely improved by macrophages, which activation is potentiated by cells and molecules of the acquired immune system, such as T helper lymphocytes and antibodies, respectively. In the present work, we evaluated the contribution of lymphocytes in the regenerative process of crushed sciatic nerves of immunocompetent (wild-type, WT) and T and B-deficient (RAG-KO) mice. In Knockout animals, we found increased amount of macrophages under basal conditions and during the initial phase of the regenerative process, that was evaluated at 2, 4, and 8 weeks after lesion (wal). That parallels with faster axonal regeneration evidenced by the quantification of neurofilament and a growth associated protein immunolabeling. The motor function, evaluated by the sciatic function index, was fully recovered in both mouse strains within 4 wal, either in a progressive fashion, as observed for RAG-KO mice, or presenting a subtle regression, as seen in WT mice between 2 and 3 wal. Interestingly, boosting the immune response by early adoptive transference of activated WT lymphocytes at 3 days after lesion improved motor recovery in WT and RAG-KO mice, which was not ameliorated when cells were transferred at 2 wal. When monitoring lymphocytes by in vivo imaging, in both mouse strains, cells migrated to the lesion site shortly after transference, remaining in the injured limb up to its complete motor recovery. Moreover, a first peak of hyperalgesia, determined by von-Frey test, was coincident with increased lymphocyte infiltration in the damaged paw. Overall, the present results suggest that a wave of immune cell infiltration takes place during subacute phase of axonal regeneration, resulting in transient set back of motor recovery following peripheral axonal injury. Moreover, modulation of the immune response can be an efficient approach to speed up nerve regeneration.

Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system.

Axonal regeneration in the peripheral nervous system is greatly supported by Schwann cells (SCs). After nerve injury, SCs dedifferentiate to a progenitor-like state and efficiently guide axons to their original target tissues. Contact and soluble factors participate in the crosstalk between SCs and axons during axonal regeneration. Here we show that dedifferentiated SCs secrete nano-vesicles known as exosomes which are specifically internalized by axons. Surprisingly, SC-derived exosomes markedly increase axonal regeneration in vitro and enhance regeneration after sciatic nerve injury in vivo. Exosomes shift the growth cone morphology to a pro-regenerating phenotype and decrease the activity of the GTPase RhoA, involved in growth cone collapse and axon retraction. Altogether, our work identifies a novel mechanism by which SCs communicate with neighboring axons during regenerative processes. We propose that SC exosomes represent an important mechanism by which these cells locally support axonal maintenance and regeneration after nerve damage.

Spinal cord regeneration: lessons for mammals from non-mammalian vertebrates.

Unlike mammals, regenerative model organisms such as amphibians and fish are capable of spinal cord regeneration after injury. Certain key differences between regenerative and nonregenerative organisms have been suggested as involved in promoting this process, such as the capacity for neurogenesis and axonal regeneration, which appear to be facilitated by favorable astroglial, inflammatory and immune responses. These traits provide a regenerative-permissive environment that the mammalian spinal cord appears to be lacking. Evidence for the regenerative nonpermissive environment in mammals is given by the fact that they possess neural stem/progenitor cells, which transplanted into permissive environments are able to give rise to new neurons, whereas in the nonpermissive spinal cord they are unable to do so. We discuss the traits that are favorable for regeneration, comparing what happens in mammals with each regenerative organism, aiming to describe and identify the key differences that allow regeneration. This comparison should lead us toward finding how to promote regeneration in organisms that are unable to do so.

Transfer of vesicles from schwann cells to axons: a novel mechanism of communication in the peripheral nervous system.

Schwann cells (SCs) are the glial component of the peripheral nervous system, with essential roles during development and maintenance of axons, as well as during regenerative processes after nerve injury. SCs increase conduction velocities by myelinating axons, regulate synaptic activity at presynaptic nerve terminals and are a source of trophic factors to neurons. Thus, development and maintenance of peripheral nerves are crucially dependent on local signaling between SCs and axons. In addition to the classic mechanisms of intercellular signaling, the possibility of communication through secreted vesicles has been poorly explored to date. Interesting recent findings suggest the occurrence of lateral transfer mediated by vesicles from glial cells to axons that could have important roles in axonal growth and axonal regeneration. Here, we review the role of vesicular transfer from SCs to axons and propose the advantages of this means in supporting neuronal and axonal maintenance and regeneration after nerve damage.

Enxerto com tubo de polietileno poroso preenchido com gordura autóloga no reparo de nervo periférico: uma nova proposta

Os nervos periféricos são extensões do sistema nervoso central e responsáveis pela interação das atividades das extremidades, em suas funções sensitiva e motora. São vulneráveis aos mesmos tipos de traumas que afetam outros tecidos: contusão, compressão, esmagamento, estiramento, avulsão e laceração. Desta forma, a interrupção de continuidade da estrutura do nervo, por algum tipo de trauma, resulta na interrupção de transmissão dos impulsos nervosos e na desorganização de suas atividades funcionais. Para tanto, em vista da evolução tecnológica e o desenvolvimento de equipamentos mais sofisticados, a microcirurgia vem ganhando cada vez mais espaço no campo da investigação experimental referente a recuperação de nervos periféricos lesionados. Em uma secção simples, sem perda tecidual, a neurorrafia denominada término-terminal apresenta bons resultados, contudo, quando ocorre perda de tecido nervoso ou, não se têm mais os cotos distais do nervo, outras técnicas devem ser empregadas, até porque, não se pode de modo algum tencionar o nervo numa tentativa de coaptá-lo novamente. Várias técnicas de tubulização utilizando-se materiais biológicos e não biológicos, para criar um meio por onde ocorrerá a regeneração nervosa já foram ou ainda estão sendo testados com resultados insatisfatórios sob o aspecto funcional.É sabido que em um trauma sem perda tecidual, numa neuropraxia, por exemplo, o nervo recupera espontaneamente de forma satisfatória. É sabido também que em um feixe vásculo-nervoso, o nervo periférico encontra-se em íntimo contato com a adventícia de artérias e veias. A adventícia dos vasos é constituída por tecido conjuntivo frouxo, rico em adipócitos. Assim, em um trauma, os neuritos oriundos do coto proximal do nervo lesado, ficam diretamente em contato com esses adipócitos. Seguindo este raciocínio, e com base em trabalhos anteriores onde foi usada veia preenchida com músculo esquelético a fresco como enxerto...

Peripheral nerves are extensions of the central nervous system and are responsible for the interaction of the activities of the extremities in their sensory and motor function. They are vulnerable to these types of injuries that affect other tissues: contusion, compression, crush, stretch, tear and avulsion. Thus, the interruption of continuity of the nerve structure, due to some sort of trauma, results in the interruption of transmission of nerve impulses and disruption of their functional activities. Therefore, in view of technological evolution and development of more sophisticated equipment, microsurgery is gaining more space in the field of experimental research concerning the recovery of injured peripheral nerves. In a single section, without loss of tissue, called the end-terminal neurorrhaphy was also good, however, when there is loss of nervous tissue or, if not longer have the distal nerve stumps, other techniques must be employed, because, in any circumstance the nerve should be tensioned as an attempt to coaptation again. Several techniques of tubing, using biological materials and non-biological means to create a place where nerve regeneration have been or are still being tested with unsatisfactory results in the functional aspect. It is known that in a trauma without loss of tissue, a neuropraxia, for example, the nerve recovers spontaneously and satisfactorily. It is also known that in a neurovascular bundle, the peripheral nerve is in close contact with the adventitia of arteries and veins. The adventitia of the vessels is composed of loose connective tissue rich in adipocytes. Thus, in trauma, the neurites from the proximal stump of injured nerve, are directly in contact with these adipocytes. Following this reasoning, and based on previous work where it was used vein filled with fresh skeletal muscle as a graft, decided to test the possibility of axonal growth by grafting polyethylene tube filled with autologous adipose tissue...

Strategies to promote optic nerve regeneration

Damage to the adult mammalian optic nerve (ON) usually results in the degeneration of the ON and death of retinal ganglion cells (RGCs), leading to permanent loss of visual functions. New strategies, especially the transplantation of a peripheral nerve (PN) to the retina or transected ON, have been created to promote the neuronal survival and axonal regeneration of axotomized RGCs. In this review, we focus on how a PN and other factors are used to overcome the unfavorable extrinsic CNS environment and the lack of trophic factors, and upregulate the intrinsic growth potential of the axotomized neurons since recent studies suggest that the lack of intrinsic growth potential in the CNS neurons is also an important factor contributing to the failure of CNS regeneration.