Axonal damage is a common feature of traumatic injury and neurodegenerative disease. The capacity for axons to regenerate and to recover functionality after injury is a phenomenon that is seen readily in the peripheral nervous system, especially in rodent models, but human axonal regeneration is limited and does not lead to full functional recovery. Here we describe a system where dynamics of human axonal outgrowth and regeneration can be evaluated via live imaging of human-induced pluripotent stem cell (hiPSC)-derived neurons cultured in microfluidic systems, in which cell bodies are isolated from their axons. This system could aid in studying axonal outgrowth dynamics and could be useful for testing potential drugs that encourage regeneration and repair of the nervous system.

Peripheral nerve damage often leads to the onset of neuropathic pain (NeuP). This condition afflicts millions of people, significantly burdening healthcare systems and putting strain on families\' financial well-being. Here, we will focus on the role of peripheral sensory neurons, specifically the Dorsal Root Ganglia neurons (DRG neurons) in the development of NeuP. After axotomy, DRG neurons activate regenerative signals of axons-soma communication to promote a gene program that activates an axonal branching and elongation processes. The results of a neuronal morphological cytoskeleton change are not always associated with functional recovery. Moreover, any axonal miss-targeting may contribute to NeuP development. In this review, we will explore the epidemiology of NeuP and its molecular causes at the level of the peripheral nervous system and the target organs, with major focus on the neuronal cross-talk between intrinsic and extrinsic factors. Specifically, we will describe how failures in the neuronal regenerative program can exacerbate NeuP.

Nerve axons grow from proximal to distal after axonometric injury; however, they have been seen to regenerate via alternate routes, with some also demonstrating retrograde growth in neuromas. We present the case of a 33-year-old male with a 16-year-old traumatic brachial plexus injury presenting with neuropathic pain and isolated spontaneous recovery. Following a successful pre-operative anaesthetic block, a neurectomy of the median and ulnar nerves was planned for pain relief. Intraoperatively, median nerve stimulation resulted in muscle contractions in the pectoralis major (PM) and extensor carpi radialis brevis (ECRB). This was confirmed by electrical and mechanical stimuli. Histological analysis confirmed the presence of viable axons in the median nerve despite no distal nerve function. Post-surgery motor activity was preserved. A plausible explanation for the intraoperative observations, suggesting neural connectivity between the median nerve and PM and ECRB, would be retrograde growth into various nerve pathways. Alternative explanations such as axonal bifurcation, light anaesthesia, or anatomical variations were considered but the evidence favoured retrograde axonal regrowth. These findings challenge conventional understanding and offer potential new approaches to nerve reconstruction.

UNASSIGNED: For nerve injuries, not amendable to tensionless epineural coaptation of the nerve, autografts are the preferred treatment. Although absorbable sutures are not recommended for nerve repair, there is no evidence that non-absorbable sutures are superior to absorbable sutures. This study aims to assess the effectiveness of non-absorbable monofilament nylon sutures, absorbable monofilament vicryl sutures, and fibrin glue when used for nerve grafting.
UNASSIGNED: Lewis rats (N = 32) were subjected to a sciatic nerve transection and randomly assigned to a group: graft with Nylon, graft with Vicryl, graft with Fibrin Glue, or no graft. Motor function, sensory function, and thermal pain were assessed during a 12-week recovery period, and immunohistochemistry was used to assess macrophage response.
UNASSIGNED: At 12 weeks, the Vicryl and Nylon groups had significantly larger ankle angles at to lift off, which is a measure of motor function, compared to injured controls (p < 0.05). Grafted rats displayed no difference in thermal response but hypersensitivity to mechanical stimuli compared to the uninjured hindlimb. The Nylon, Vicryl, and Fibrin Glue groups all had significantly less atrophy of the gastrocnemius muscle compared to injured controls (p < 0.0001). In the Fibrin Glue group, 3/9 grafts did not incorporate. The Nylon group had significantly less (p = 0.0004) axon growth surrounding the suture holes compared to the Vicryl group. There were no differences in the axon counts, motor neurons, or sensory neurons between all grafted rats.
UNASSIGNED: These results demonstrate that vicryl sutures work just as well as nylon for nerve recovery after injury and grafting.

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

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Microtubule stabilization is critical for axonal growth and regeneration, and many microtubule-associated proteins are involved in this process. In this study, we found that the knockdown of echinoderm microtubule-associated protein-like 1 (EML1) hindered axonal growth in cultured cortical and dorsal root ganglion neurons. We further revealed that EML1 facilitated the acetylation of microtubules and that the impairment of axonal growth due to EML1 inhibition could be restored by treatment with deacetylase inhibitors, suggesting that EML1 affected tubulin acetylation. Moreover, we verified an interaction between EML1 and the alpha-tubulin acetyltransferase 1, which is responsible for the acetylation of alpha-tubulin. We thus proposed that EML1 might regulate microtubule acetylation and stabilization via alpha-tubulin acetyltransferase 1 and then promote axon growth. Finally, we verified that the knockdown of EML1 in vivo also inhibited sciatic nerve regeneration. Our findings revealed a novel effect of EML1 on microtubule acetylation during axonal regeneration.

Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen-activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post-SCI. Modulating this pathway post-injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway\'s characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies.

BACKGROUND: This study aimed to investigate whether moxibustion could affect PI3K/Akt pathway to regulate Transforming acidic coiled-coil containing protein 3 (TACC3) and promote axonal regeneration to improve learning and memory function in middle cerebral artery occlusion (MCAO) rats.
METHODS: Sixty SD rats were randomly divided into 4 groups: sham-operated control group (SC), model control group (MC), model + moxibustion group (MM), and model + inhibitor + moxibustion group (MIM). The rats in MC, MM, and MIM groups were made into MCAO models, and PI3K inhibitor LY294002 was injected into the rats in MIM group before modeling; while the rats in SC group were only treated with artery separation without monofilament inserting. After that, the rats in MM and MIM groups were intervented with moxibustion. We used the Zea-Longa scale, micro-Magnetic Resonance Imaging (micro-MRI), Morris water maze (MWM), TUNEL, western blot (WB), immunofluorescence and immunohistochemistry to evaluate the neurological deficits, cerebral infarct volume, learning and memory, apoptotic cell percentage in the hippocampal, the expression level of axonal regeneration and PI3K/AKt related proteins, the expression level of TACC3. The detection of 2 h after surgery showed the result before moxibustion and 7 days after the intervention showed the results after moxibustion.
RESULTS: After 7 d of intervention, the scores of Zea-Longa and the cerebral infarct volume, the escape latency, the percentage of apoptosis cells of MM group were lower than that of MC and MIM groups; the frequency of rats crossed the previous platform location, PI3K, p-Akt/t-Akt and TACC3, the level of GAP-43 in MM group was more than MC and MIM groups (P < 0.05). While no statistical difference existed between MIM group and MC group (P > 0.05).
CONCLUSIONS: Moxibustion can promote axonal regeneration and improve learning and memory of Post-stroke cognitive impairment via activating the PI3K/AKT signaling pathway and TACC3.

Axonal regeneration is restricted in adults and causes irreversible motor dysfunction following spinal cord injury (SCI). In contrast, neonates have prominent regenerative potential and can restore their neural function. Although the distinct cellular responses in neonates have been studied, how they contribute to neural recovery remains unclear. To assess whether the secreted molecules in neonatal SCI can enhance neural regeneration, we re-analyzed the previously performed single-nucleus RNA-seq (snRNA-seq) and focused on Asporin and Cd109, the highly expressed genes in the injured neonatal spinal cord. In the present study, we showed that both these molecules were expressed in the injured spinal cords of adults and neonates. We treated the cortical neurons with recombinant Asporin or CD109 to observe their direct effects on neurons in vitro. We demonstrated that these molecules enhance neurite outgrowth in neurons. However, these molecules did not enhance re-growth of severed axons. Our results suggest that Asporin and CD109 influence neurites at the lesion site, rather than promoting axon regeneration, to restore neural function in neonates after SCI.