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As a commonly used physical intervention, electrical stimulation (ES) has been demonstrated to be effective in the treatment of central nervous system disorders. Currently, researchers are studying the effects of electrical stimulation on individual neurons and neural networks, which are dependent on factors such as stimulation intensity, duration, location, and neuronal properties. However, the exact mechanism of action of electrical stimulation remains unclear. In some cases, repeated or prolonged electrical stimulation can lead to changes in the morphology or function of the neuron. In this study, immunofluorescence staining and Sholl analysis are used to assess changes in the neurite number and axon length to determine the optimal pattern and stimulation parameters of ES for neurons. Neuronal death and plasticity are detected by TUNEL staining and microelectrode array assays, respectively. mRNA sequencing and bioinformatics analysis are applied to predict the key targets of the action of ES on neurons, and the identified targets are validated by western blot analysis and qRT-PCR. The effects of alternating current stimulation (ACS) on neurons are more significant than those of direct current stimulation (DCS), and the optimal parameters are 3 μA and 20 min. ACS stimulation significantly increases the number of neurites, the length of axons and the spontaneous electrical activity of neurons, significantly elevates the expression of growth-associated protein-43 (GAP-43) without significant changes in the expression of neurotrophic factors. Furthermore, application of PI3K/AKT-specific inhibitors significantly abolishes the beneficial effects of ACS on neurons, confirming that the PI3K/AKT pathway is an important potential signaling pathway in the action of ACS.

This study aimed to assess the effects of the timing of administering botulinum neurotoxin A (BoNT/A) on nerve regeneration in rats. Sixty 6-week-old rats with a sciatic nerve injury were randomly divided into four groups: the immediately treated (IT) group (BoNT/A injection administered immediately post-injury), the delay-treated (DT) group (BoNT/A injection administered one week post-injury), the control group (saline administered one week post-injury), and the sham group (only skin and muscle incisions made). Nerve regeneration was assessed 3, 6, and 9 weeks post-injury using various techniques. The levels of glial fibrillary acid protein (GFAP), astroglial calcium-binding protein S100β (S100β), growth-associated protein 43 (GAP43), neurofilament 200 (NF200), and brain-derived neurotrophic factor (BDNF) in the IT and DT groups were higher. ELISA revealed the highest levels of these proteins in the IT group, followed by the DT and control groups. Toluidine blue staining revealed that the average area and myelin thickness were higher in the IT group. Electrophysiological studies revealed that the CMAP in the IT group was significantly higher than that in the control group, with the DT group exhibiting significant differences starting from week 8. The findings of the sciatic functional index analysis mirrored these results. Thus, administering BoNT/A injections immediately after a nerve injury is most effective for neural recovery. However, injections administered one week post-injury also significantly enhanced recovery. BoNT/A should be administered promptly after nerve damage; however, its administration during the non-acute phase is also beneficial.

More than three decades ago, we embarked on a number of bioengineering explorations using the most advanced materials and fabrication methods. In every area we ventured into, it was our intention to ensure fundamental discoveries were deployed into the clinic to benefit patients. When we embarked on this journey, we did so without a road map, not even a compass, and so the path was arduous, sometimes tedious. Now, we can see the doorway to deployment on the near horizon. We now appreciate that overcoming the challenges has made this a rewarding and exciting journey. However, maybe we could have been here a lot sooner, and so maybe the lessons we have learned could benefit others and accelerate progress in clinical translation. Through a number of case studies, including neural regeneration, cartilage regeneration, skin regeneration, the 3D printing of capsules for islet cell transplantation, and the bioengineered cornea, here, we retrace our steps. We will summarise the journey to date, point out the obstacles encountered, and celebrate the translational impact. Then, we will provide a framework for project design with the clinical deployment of bioengineered products as the goal.

Abstract Current therapies for the devastating damage caused by traumatic brain injuries (TBI) are limited. This is in part due to poor drug efficacy to modulate neuroinflammation, angiogenesis and/or promoting neuroprotection and is the combined result of challenges in getting drugs across the blood brain barrier, in a targeted approach. The negative impact of the injured extracellular matrix (ECM) has been identified as a factor in restricting post‐injury plasticity of residual neurons and is shown to reduce the functional integration of grafted cells. Therefore, new strategies are needed to manipulate the extracellular environment at the subacute phase to enhance brain regeneration. In this review, potential strategies are to be discussed for the treatment of TBI by using self‐assembling peptide (SAP) hydrogels, fabricated via the rational design of supramolecular peptide scaffolds, as an artificial ECM which under the appropriate conditions yields a supramolecular hydrogel. Sequence selection of the peptides allows the tuning of these hydrogels' physical and biochemical properties such as charge, hydrophobicity, cell adhesiveness, stiffness, factor presentation, degradation profile and responsiveness to (external) stimuli. This review aims to facilitate the development of more intelligent biomaterials in the future to satisfy the parameters, requirements, and opportunities for the effective treatment of TBI.

Hypoxic-ischemic brain injury poses a significant threat to the neural niche within the central nervous system. In response to this pathological process, microglia, as innate immune cells in the central nervous system, undergo rapid morphological, molecular and functional changes. Here, we comprehensively review these dynamic changes in microglial response to hypoxic-ischemic brain injury under pathological conditions, including stroke, chronic intermittent hypoxia and neonatal hypoxic-ischemic brain injury. We focus on the regulation of signaling pathways under hypoxic-ischemic brain injury and further describe the process of microenvironment remodeling and neural tissue regeneration mediated by microglia after hypoxic-ischemic injury. [ABSTRACT FROM AUTHOR]

This study was designed to compare the effects of various doses of botulinum neurotoxin A (BoNT/A) on nerve regeneration. Sixty-five six-week-old rats with sciatic nerve injury were randomly allocated to three experimental groups, a control group, and a sham group. The experimental groups received a single session of intraneural BoNT/A (3.5, 7.0, or 14 U/kg) injection immediately after nerve-crushing injury. The control group received normal intraneural saline injections after sciatic nerve injury. At three, six, and nine weeks after nerve damage, immunofluorescence staining, an ELISA, and toluidine blue staining was used to evaluate the regenerated nerves. Serial sciatic functional index analyses and electrophysiological tests were performed every week for nine weeks. A higher expression of GFAP, S100β, GAP43, NF200, BDNF, and NGF was seen in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The average area and myelin thickness were significantly greater in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The sciatic functional index and compound muscle action potential amplitudes exhibited similar trends. These findings indicate that the 3.5 U/kg and 7.0 U/kg BoNT/A groups exhibited better nerve regeneration than the 14 U/kg BoNT/A and control group. As the 3.5 U/kg and the 7.0 U/kg BoNT/A groups exhibited no statistical difference, we recommend using 3.5 U/kg BoNT/A for its cost-effectiveness. [ABSTRACT FROM AUTHOR]

Background: Traumatic spinal cord injury (SCI) is a disabling condition that affects millions of people around the world. Currently, no clinical treatment can restore spinal cord function. Comparison of molecular responses in regenerating to non-regenerating vertebrates can shed light on neural restoration. The axolotl (Ambystoma mexicanum) is an amphibian that regenerates regions of the brain or spinal cord after damage. Methods: In this study, we compared the transcriptomes after SCI at acute (1–2 days after SCI) and sub-acute (6–7 days post-SCI) periods through the analysis of RNA-seq public datasets from axolotl and non-regenerating rodents. Results: Genes related to wound healing and immune responses were upregulated in axolotls, rats, and mice after SCI; however, the immune-related processes were more prevalent in rodents. In the acute phase of SCI in the axolotl, the molecular pathways and genes associated with early development were upregulated, while processes related to neuronal function were downregulated. Importantly, the downregulation of processes related to sensorial and motor functions was observed only in rodents. This analysis also revealed that genes related to pluripotency, cytoskeleton rearrangement, and transposable elements (e.g., Sox2, Krt5, and LOC100130764) were among the most upregulated in the axolotl. Finally, gene regulatory networks in axolotls revealed the early activation of genes related to neurogenesis, including Atf3/4 and Foxa2. Conclusions: Immune-related processes are upregulated shortly after SCI in axolotls and rodents; however, a strong immune response is more noticeable in rodents. Genes related to early development and neurogenesis are upregulated beginning in the acute stage of SCI in axolotls, while the loss of motor and sensory functions is detected only in rodents during the sub-acute period of SCI. The approach employed in this study might be useful for designing and establishing regenerative therapies after SCI in mammals, including humans. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase 3 (GSK3) signaling plays important and broad roles in regulating neural development in vitro and in vivo. Here, we reviewed recent findings of GSK3-regulated axon regeneration in vivo in both the peripheral and central nervous systems and discussed a few controversial findings in the field. Overall, current evidence indicates that GSK3β signaling serves as an important downstream mediator of the PI3K–AKT pathway to regulate axon regeneration in parallel with the mTORC1 pathway. Specifically, the mTORC1 pathway supports axon regeneration mainly through its role in regulating cap-dependent protein translation, whereas GSK3β signaling might be involved in regulating N 6-methyladenosine mRNA methylation-mediated, cap-independent protein translation. In addition, GSK3 signaling also plays a key role in reshaping the neuronal transcriptomic landscape during neural regeneration. Finally, we proposed some research directions to further elucidate the molecular mechanisms underlying the regulatory function of GSK3 signaling and discover novel GSK3 signaling-related therapeutic targets. Together, we hope to provide an updated and insightful overview of how GSK3 signaling regulates neural regeneration in vivo. [ABSTRACT FROM AUTHOR]

Background: Low-level laser therapy (LLLT) has been clinically accepted to accelerate the nerve regeneration process after a nerve injury or transection. We aimed to investigate the neuronal basis and the influence of LLLT on brain functional networks in traumatic patients with olfactory dysfunction. Methods: Twenty-four Patients with traumatic anosmia/hyposmia were exposed to pleasant olfactory stimuli during a block-designed fMRI session. After a 10-week period, patients as control group and patients who had completed the sessions of LLLT were invited for follow-up testing using the same fMRI protocol. Two-sample t-tests were conducted to explore group differences in activation responding to odorants (p -FDR-corrected <0.05). Differences of functional connectivity were compared between the two groups and the topological features of the olfactory network were calculated. Correlation analysis was performed between graph parameters and TDI score. Results: Compared to controls, laser-treated patients showed increased activation in the cingulate, rectus gyrus, and some parts of the frontal gyrus. Shorter pathlength (p = 0.047) and increased local efficiency (p = 0.043) within the olfactory network, as well as decreased inter-network connectivity within the whole brain were observed in patients after laser surgery. Moreover, higher clustering and local efficiency were related to higher TDI score, as manifested in increased sensitivity to identify odors. Conclusions: The results support that low-level laser induces neural reorganization process and make new connections in the olfactory structures. Furthermore, the connectivity parameters may serve as potential biomarkers for traumatic anosmia or hyposmia by revealing the underlying neural mechanisms of LLLT. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a leading cause of long‐term disability in young adults and induces complex neuropathological processes. Cellular autonomous and intercellular changes during the subacute phase contribute substantially to the neuropathology of TBI. However, the underlying mechanisms remain elusive. In this study, we explored the dysregulated cellular signaling during the subacute phase of TBI. Methods: Single‐cell RNA‐sequencing data (GSE160763) of TBI were analyzed to explore the cell–cell communication in the subacute phase of TBI. Upregulated neurotrophic factor signaling was validated in a mouse model of TBI. Primary cell cultures and cell lines were used as in vitro models to examine the potential mechanisms affecting signaling. Results: Single‐cell RNA‐sequencing analysis revealed that microglia and astrocytes were the most affected cells during the subacute phase of TBI. Cell–cell communication analysis demonstrated that signaling mediated by the non‐canonical neurotrophic factors midkine (MDK), pleiotrophin (PTN), and prosaposin (PSAP) in the microglia/astrocytes was upregulated in the subacute phase of TBI. Time‐course profiling showed that MDK, PTN, and PSAP expression was primarily upregulated in the subacute phase of TBI, and astrocytes were the major source of MDK and PTN after TBI. In vitro studies revealed that the expression of MDK, PTN, and PSAP in astrocytes was enhanced by activated microglia. Moreover, MDK and PTN promoted the proliferation of neural progenitors derived from human‐induced pluripotent stem cells (iPSCs) and neurite growth in iPSC‐derived neurons, whereas PSAP exclusively stimulated neurite growth. Conclusion: The non‐canonical neurotrophic factors MDK, PTN, and PSAP were upregulated in the subacute phase of TBI and played a crucial role in neuroregeneration. [ABSTRACT FROM AUTHOR]

Therapeutic solutions for injuries in the peripheral nervous system are limited and not existing in the case of the central nervous system. The electrical stimulation of cells through a cell-supporting conductive scaffold may contribute to new therapeutic solutions for nerve regeneration. In this work, biocompatible Polylactic acid (PLA) fibrous scaffolds incorporating Fe(III)Tosylate (FeTos) were produced by electrospinning a mixture of PLA/FeTos solutions towards a rotating cylinder, inducing fiber alignment. Fibers were coated with the conductive polymer Poly(3,4 ethylenedioxythiophene) (PEDOT) formed by vapor-phase polymerization of EDOT at 70 °C for 2 h. Different solvents (ETH, DMF and THF) were used as FeTos solvents to investigate the impact on the scaffold's conductivity. Scaffold conductivity was estimated to be as high as 1.50 × 10−1 S/cm when FeTos was dissolved in DMF. In vitro tests were performed to evaluate possible scaffold cytotoxicity, following ISO 10993-5, revealing no cytotoxic effects. Differentiation and growth of cells from the neural cell line SH-SY5Y seeded on the scaffolds were also assessed, with neuritic extensions observed in cells differentiated in neurons with retinoic acid. These extensions tended to follow the preferential alignment of the scaffold fibers. [ABSTRACT FROM AUTHOR]

Müller cells play an integral role in the development, maintenance, and photopic signal transmission of the retina. While lower vertebrate Müller cells can differentiate into various types of retinal neurons to support retinal repair following damage, there is limited neurogenic potential of mammalian Müller cells. Therefore, it is of great interest to harness the neurogenic potential of mammalian Müller cells to achieve self-repair of the retina. While multiple studies have endeavored to induce neuronal differentiation and proliferation of mammalian Müller cells under defined conditions, the efficiency and feasibility of these methods often fall short, rendering them inadequate for the requisites of retinal repair. As the mechanisms and methodologies of Müller cell reprogramming have been extensively explored, a summary of the reprogramming process of unlocking the neurogenic potential of Müller cells can provide insight into Müller cell fate development and facilitate their therapeutic use in retinal repair. In this review, we comprehensively summarize the progress in reprogramming mammalian Müller cells and discuss strategies for optimizing methods and enhancing efficiency based on the mechanisms of fate regulation.

Spinal cord injury (SCI) is a devastating event that results in a wide range of physical impairments and disabilities. Despite the advances in our understanding of the biological response to injured tissue, no effective treatments are available for SCIs at present. Some studies have addressed this issue by exploring the potential of cell transplantation therapy. However, because of the abnormal microenvironment in injured tissue, the survival rate of transplanted cells is often low, thus limiting the efficacy of such treatments. Many studies have attempted to overcome these obstacles using a variety of cell types and animal models. Recent studies have shown the utility of zebrafish as a model of neural regeneration following SCIs, including the proliferation and migration of various cell types and the involvement of various progenitor cells. In this review, we discuss some of the current challenges in SCI research, including the accurate identification of cell types involved in neural regeneration, the adverse microenvironment created by SCIs, attenuated immune responses that inhibit nerve regeneration, and glial scar formation that prevents axonal regeneration. More in-depth studies are needed to fully understand the neural regeneration mechanisms, proteins, and signaling pathways involved in the complex interactions between the SCI microenvironment and transplanted cells in non-mammals, particularly in the zebrafish model, which could, in turn, lead to new therapeutic approaches to treat SCIs in humans and other mammals. [ABSTRACT FROM AUTHOR]

Magnetic fields play an essential role in material science and biomedical engineering. Magnetic-responsive materials can be arranged orderly in matrix to realize the construction of an aligned scaffold under magnetic induction. However, a single topological cue is insufficient to activate neural tissue regeneration, demanding more cues to promote regeneration synergistically, such as electrical stimulation and a biomimetic matrix. Herein, we propose one-dimensional (1D) magnetoelectric Fe 3 O 4 @BaTiO 3 nanochains with controllable lengths under the regulation of a magnetic field. These nanochains can be oriented in the biomimetic hydrogel under magnetic guidance and induce the hydrogel microfiber to align along the direction of the nanochains, which is beneficial for cell-oriented outgrowth. This aligned hydrogel enabled wireless electrical stimulation mediated by magnetoelectric nanochains under magnetic stimulation, thereby activating the voltage-gated ion channel. Consequently, topological and electrical cues in this multifunctional biomimetic hydrogel synergistically enhanced the expression of neural functional proteins, facilitating synapse remodeling and neural regeneration. Predictably, the construction of multifunctional hydrogels based on low-cost and facile synthesis of magnetoelectric nanochains is an emerging patient-friendly and effective therapeutic strategy for neural or other tissue regeneration. A facile and controllable magnetic strategy is established to manipulate 1D nanomaterial growth, matrix topography, and wireless electrical stimulation of cells. First, the magnetic-assisted interface co-assembly was used to control the length of Fe 3 O 4 @BaTiO 3 nanochains with enhanced magnetoelectric effect. Then, the motion of the magnetic-induced nanochains guided the orientation of nanofibers in a 3D biomimetic hydrogel matrix. Finally, wireless electrical signals and topological cues in the biomimetic matrix synergistically promoted orderly aligned cell outgrowth and membrane depolarization by Ca2+ influx, thus enhancing nerve cell synaptic plasticity and functional expression. Consequently, this work provides a conceptual strategy from material design to extracellular matrix signal manipulation and synergistic induction of tissue regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

The age-dependent loss of neuronal plasticity is a well-known phenomenon that is poorly understood. The loss of this capacity for axonal regeneration is emphasized following traumatic brain injury, which is a major cause of disability and death among adults in the US. We have previously shown the intrinsic capacity of magnocellular neurons within the supraoptic nucleus to undergo axonal regeneration following unilateral axotomization in an age-dependent manner. The aim of this research was to determine the age-dependent molecular mechanisms that may underlie this phenomenon. As such, we characterized the transcriptome and DNA methylome of the supraoptic nucleus in uninjured 35-day old rats and 125-day old rats. Our data indicates the downregulation of a large number of axonogenesis related transcripts in 125-day old rats compared to 35-day old rats. Specifically, several semaphorin and ephrin genes were downregulated, as well as growth factors including FGF's, insulin-like growth factors (IGFs), and brain-derived neurotrophic factor (BDNF). Differential methylation analysis indicates enrichment of biological processes involved in axonogenesis and axon guidance. Conversely, we observed a robust and specific upregulation of MHCI related transcripts. This may involve the activator protein 1 (AP-1) transcription factor complex as motif analysis of differentially methylated regions indicate enrichment of AP-1 binding sites in hypomethylated regions. Together, our data suggests a loss of pro-regenerative capabilities with age which would prevent axonal growth and appropriate innervation following injury. [ABSTRACT FROM AUTHOR]

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in the juvenile brain that was not found in adults. We demonstrate strikingly different stroke-induced neuroimmune responses that are deleterious in adults and protective in juveniles, supporting neural regeneration and plasticity. Understanding age-related differences in neuronal repair and regeneration, restoration of neural network function, and neuroimmune signaling in the stroke-injured brain may offer new insights for the development of novel therapeutic strategies for stroke rehabilitation. [ABSTRACT FROM AUTHOR]

Despite the high prevalence, stroke remains incurable due to the limited regeneration capacity in the central nervous system. Neuronal replacement strategies are highly diverse biomedical fields that attempt to replace lost neurons by utilizing exogenous stem cell transplants, biomaterials, and direct neuronal reprogramming. Although these approaches have achieved encouraging outcomes mostly in the rodent stroke model, further preclinical validation in non-human primates (NHP) is still needed prior to clinical trials. In this paper, we briefly review the recent progress of promising neuronal replacement therapy in NHP stroke studies. Moreover, we summarize the key characteristics of the NHP as highly valuable translational tools and discuss (1) NHP species and their advantages in terms of genetics, physiology, neuroanatomy, immunology, and behavior; (2) various methods for establishing NHP focal ischemic models to study the regenerative and plastic changes associated with motor functional recovery; and (3) a comprehensive analysis of experimentally and clinically accessible outcomes and a potential adaptive mechanism. Our review specifically aims to facilitate the selection of the appropriate NHP cortical ischemic models and efficient prognostic evaluation methods in preclinical stroke research design of neuronal replacement strategies. [ABSTRACT FROM AUTHOR]

We previously demonstrated that neural stem/progenitor cells (NSPCs) were induced within and around the ischemic areas in a mouse model of ischemic stroke. These injury/ischemia-induced NSPCs (iNSPCs) differentiated to electrophysiologically functional neurons in vitro, indicating the presence of a self-repair system following injury. However, during the healing process after stroke, ischemic areas were gradually occupied by inflammatory cells, mainly microglial cells/macrophages (MGs/MΦs), and neurogenesis rarely occurred within and around the ischemic areas. Therefore, to achieve neural regeneration by utilizing endogenous iNSPCs, regulation of MGs/MΦs after an ischemic stroke might be necessary. To test this hypothesis, we used iNSPCs isolated from the ischemic areas after a stroke in our mouse model to investigate the role of MGs/MΦs in iNSPC regulation. In coculture experiments, we show that the presence of MGs/MΦs significantly reduces not only the proliferation but also the differentiation of iNSPCs toward neuronal cells, thereby preventing neurogenesis. These effects, however, are mitigated by MG/MΦ depletion using clodronate encapsulated in liposomes. Additionally, gene ontology analysis reveals that proliferation and neuronal differentiation are negatively regulated in iNSPCs cocultured with MGs/MΦs. These results indicate that MGs/MΦs negatively impact neurogenesis via iNSPCs, suggesting that the regulation of MGs/MΦs is essential to achieve iNSPC-based neural regeneration following an ischemic stroke. [ABSTRACT FROM AUTHOR]

Brain tumors have been proved challenging to treat. Here we established a Multi-Target Neural Differentiation (MTND) therapeutic cocktail to achieve effective and safe treatment of brain malignancies by targeting the important hallmarks in brain cancers: poor cell differentiation and compromised cell cycle. In-vitro and in-vivo experiments confirmed the significant therapeutic effect of our MTND therapy. Significantly improved therapeutic effects over current first-line chemo-drugs have been identified in clinical cells, with great inhibition of the growth and migration of tumor cells. Further in-vivo experiments confirmed that sustained MTND treatment showed a 73% reduction of the tumor area. MTND also induced strong expression of phenotypes associated with cell cycle exit/arrest and rapid neural reprograming from clinical glioma cells to glutamatergic and GABAergic expressing cells, which are two key neuronal types involved in many human brain functions, including learning and memory. Collectively, MTND induced multi-targeted genotypic expression changes to achieve direct neural conversion of glioma cells and controlled the cell cycle/tumorigenesis development, helping control tumor cells' malignant proliferation and making it possible to treat brain malignant tumors effectively and safely. These encouraging results open avenues to developing new therapies for brain malignancies beyond cytotoxic agents, providing more effective medication recommendations with reduced toxicity. [ABSTRACT FROM AUTHOR]

• Electro-, manual, and scalp acupuncturewith physical therapy can improve mobility and functioning of pelvic organs following SCI. • Research on rats shows that electro-acupuncture aids in neural function regeneration by suppressing notch signaling pathways. • Acupuncture is cost effective and easy to perform in hospital settings. • Integrating acupuncture and physical therapy may significantly improve motor and neurological functions for SCI. Spinal cord injury (SCI) is a major problem worldwide, which can result in partial or complete loss of sensory function and motor control. Injured people are 2–5 times more likely to suffer premature death than their uninjured counterparts. This case reports the injuries sustained by a 41-year-old woman who jumped from a building being bombed in Kyiv, Ukraine, and her subsequent treatment and recovery. The patient suffered a complete spinal cord injury (SCI), lower distal paraplegia, and dysfunction of pelvic organs, with orthopedist reporting she would likely never walk again. She substantially recuperated after the integration of acupuncture and physical therapy (PT) in her rehabilitation. Utilizing electrical, manual, and scalp acupuncture along with PT, the patient regained full bowel control, improved bladder function, and gained ability to support orthostatic position. Acupuncture is cost effective and easy to perform in hospital settings. It has an important role to play in the rehabilitation of injuries. The integration of acupuncture and PT may significantly improve motor and neurological functions for SCI patients. [ABSTRACT FROM AUTHOR]

Abstract Background Hyperbaric oxygen (HBO) plays positive roles in the therapy of traumatic brain injury (TBI); however, the mechanism underlying its effects on TBI is largely unknown. The study aims to elucidate the molecular mechanism implicated with the interaction between platelet-derived growth factor-BB (PDGF-BB) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which may play critical roles during HBO treatment both in the astrocyte scratching model in vitro and rat TBI model in vivo. Methods Changes in neurological function and wound healing were evaluated using the neurological severity scores (NSS) scale, immunohistochemistry, western blotting, and qRT-PCR, respectively. Results The results showed that PDGF-BBi (PDGB interfered with small RNA) dramatically improves neuronal viability in vitro when transfected into the scratched astrocytes derived from the cerebral cortex of neonatal rats. Moreover, in vivo experiments revealed that HBO therapy substantially elevated the NSS scores and simultaneously reduced the mortality in TBI rats, as indicated by the NSS scales. Notably, HBO therapy was found to possess the ability to inhibit glial cell proliferation, promote the regeneration of neurons and synapses, and ultimately facilitate the wound healing, as revealed by immunohistochemistry and glial scar formation found in TBI rats. Importantly, HBO markedly decreased the expression levels of PDGF-BB and ERK1/2. It can clearly be seen that downregulated PDGF-BB and ERK1/2 levels were corresponding with the status of significant amelioration of the therapeutic effect of HBO. Conversely, the upregulation of PDGF-BB and ERK1/2 levels was in line with the opposite effect. Conclusion It has been concluded that HBO therapy may play its active role in TBI treatment dependent on astrogliosis inhibition, which may be achieved by downregulating the ERK1/2 signaling pathway mediated by PDGF-BB.

Abstract Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and neuro-regenerative therapeutic effects is essential for effective wound repair. However, most therapeutic systems apply these strategies separately or ineffectively. This study investigates the performance of an all-in-one smart dressing (ASD) that integrates angiogenic functional materials and multiple biological factors within a light crosslinked hydrogel, forming a multi-functional dressing capable of facilitating simultaneous micro-vascularization and neural regeneration. The ASD uses a zeolite-imidazolate framework 67 with anchored vanadium oxide (VO2@ZIF-67) that allows for the on-demand release of Co2+ with fluctuations in pH at the wound site to stimulate angiogenesis. It can simultaneously release CXCL12, ligustroflavone, and ginsenoside Rg1 in a sustained manner to enhance the recruitment of endogenous mesenchymal stem cells, inhibit senescence, and induce neural differentiation to achieve in situ nerve regeneration. The ASD can stimulate rapid angiogenesis and nerve regeneration within 17 days through multiple angiogenic and neuro-regenerative cues within one dressing. This study provides a proof-of-concept for integrating functional nanomaterials and multiple complementary drugs within a smart dressing for simultaneous angiogenesis and neural regeneration.

Purpose Spinal cord injury (SCI) destroys the sensorimotor pathway and induces brain plasticity. However, the effect of treatment-induced spinal cord tissue regeneration on brain functional reorganization remains unclear. This study was designed to investigate the large-scale functional interactions in the brains of adult female Rhesus monkeys with injured and regenerated thoracic spinal cord.Materials and methods Resting-state functional magnetic resonance imaging (fMRI) combined with Granger Causality analysis (GCA) and motor behaviour analysis were used to assess the causal interaction between sensorimotor cortices, and calculate the relationship between causal interaction and hindlimb stepping in nine Rhesus monkeys undergoing lesion-induced spontaneous recovery (injured, n = 4) and neurotrophin-3/chitosan transplantation-induced regeneration (NT3-chitosan, n = 5) after SCI.Results The results showed that the injured and NT3-chitosan-treated animals had distinct spatiotemporal features of brain functional reorganization. The spontaneous recovery followed the model of “early intra-hemispheric reorganization dominant, late inter-hemispheric reorganization dominant”, whereas regenerative therapy animals showed the opposite trend. Although the variation degree of information flow intensity was consistent, the tendency and the relationship between local neuronal activity properties and coupling strength were different between the two groups. In addition, the injured and NT3-chitosan-treated animals had similar motor adjustments but various relationship modes between motor performance and information flow intensity.Conclusions Our findings show that brain functional reorganization induced by regeneration therapy differed from spontaneous recovery after SCI. The influence of unique changes in brain plasticity on the therapeutic effects of future regeneration therapy strategies should be considered. Key messagesNeural regeneration elicited a unique spatiotemporal mode of brain functional reorganization in the spinal cord injured monkeys, and that regeneration does not simply reverse the process of brain plasticity induced by spinal cord injury (SCI).Independent “properties of local activity – intensity of information flow” relationships between the injured and treated animals indicating that spontaneous recovery and regenerative therapy exerted different effects on the reorganization of the motor network after SCI.A specific information flow from the left thalamus to the right insular can serve as an indicator to reflect a heterogeneous “information flow – motor performance” relationship between injured and treated animals at similar motor adjustments.

The age-dependent loss of neuronal plasticity is a well-known phenomenon that is poorly understood. The loss of this capacity for axonal regeneration is emphasized following traumatic brain injury, which is a major cause of disability and death among adults in the US. We have previously shown the intrinsic capacity of magnocellular neurons within the supraoptic nucleus to undergo axonal regeneration following unilateral axotomization in an age-dependent manner. The aim of this research was to determine the age-dependent molecular mechanisms that may underlie this phenomenon. As such, we characterized the transcriptome and DNA methylome of the supraoptic nucleus in uninjured 35-day old rats and 125-day old rats. Our data indicates the downregulation of a large number of axonogenesis related transcripts in 125-day old rats compared to 35-day old rats. Specifically, several semaphorin and ephrin genes were downregulated, as well as growth factors including FGF’s, insulin-like growth factors (IGFs), and brain-derived neurotrophic factor (BDNF). Differential methylation analysis indicates enrichment of biological processes involved in axonogenesis and axon guidance. Conversely, we observed a robust and specific upregulation of MHCI related transcripts. This may involve the activator protein 1 (AP-1) transcription factor complex as motif analysis of differentially methylated regions indicate enrichment of AP-1 binding sites in hypomethylated regions. Together, our data suggests a loss of pro-regenerative capabilities with age which would prevent axonal growth and appropriate innervation following injury.

The neonatal brain is substantially more resistant to various forms of injury than the mature brain. For instance, the prognosis following ischemic stroke is generally poor in the elderly but favorable in neonates. Identifying the cellular and molecular mechanisms underlying reparative activities in the neonatal brain after ischemic injury may provide feasible targets for therapeutic interventions in adults. To this end, we compared the reparative activities in postnatal day 13 and adult (8–12-week-old) mouse brain following middle cerebral artery occlusion. Immunohistochemistry revealed considerably greater generation of ischemia-induced neural stem/progenitor cells (iNSPCs) expressing nestin or Sox2 in ischemic areas of the neonatal brain. The iNSPCs isolated from the neonatal brain also demonstrated greater proliferative activity than those isolated from adult mice. In addition, genes associated with neuronal differentiation were enriched in iNSPCs isolated from the neonatal brain according to microarray and gene ontogeny analyses. Immunohistochemistry further revealed considerably greater production of newborn doublecortin+ neurons at the sites of ischemic injury in the neonatal brain compared to the adult brain. These findings suggest that greater iNSPC generation and neurogenic differentiation capacities contribute to the superior regeneration of the neonatal brain following ischemia. Together, our findings may help identify therapeutic targets for enhancing the reparative potential of the adult brain following stroke.

Natural electric fields exist throughout the body during development and following injury, and, as such, EFs have the potential to be utilized to guide cell growth and regeneration. Electrical stimulation (ES) can also affect gene expression and other cellular behaviors, including cell migration and proliferation. To investigate the effects of electric fields on cells in vitro, a sterile chamber that delivers electrical stimuli is required. Here, we describe the construction of an ES chamber through the modification of an existing lid of a 6-well cell culture plate. Using human SH-SY5Y neuroblastoma cells, we tested the biocompatibility of materials, such as Araldite®, Tefgel™ and superglue, that were used to secure and maintain platinum electrodes to the cell culture plate lid, and we validated the electrical properties of the constructed ES chamber by calculating the comparable electrical conductivities of phosphate-buffered saline (PBS) and cell culture media from voltage and current measurements obtained from the ES chamber. Various electrical signals and durations of stimulation were tested on SH-SY5Y cells. Although none of the signals caused significant cell death, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that shorter stimulation times and lower currents minimized negative effects. This design can be easily replicated and can be used to further investigate the therapeutic effects of electrical stimulation on neural cells.

Peripheral nerve regeneration remains a significant clinical challenge due to the unsatisfactory functional recovery and public health burden. Exosomes, especially those derived from mesenchymal stem cells (MSCs), are promising as potential cell-free therapeutics and gene therapy vehicles for promoting neural regeneration. In this study, we reported the differentiation of human adipose derived MSCs (hADMSCs) towards the Schwann cell (SC) phenotype (hADMSC-SCs) and then isolated exosomes from hADMSCs with and without differentiation (i.e., dExo vs uExo). We assessed and compared the effects of uExo and dExo on antioxidative, angiogenic, anti-inflammatory, and axon growth promoting properties by using various peripheral nerve-related cells. Our results demonstrated that hADMSC-SCs secreted more neurotrophic factors and other growth factors, compared to hADMSCs without differentiation. The dExo isolated from hADMSC-SCs protected rat SCs from oxidative stress and enhanced HUVEC migration and angiogenesis. Compared to uExo, dExo also had improved performances in downregulating pro-inflammatory gene expressions and cytokine secretions and promoting axonal growth of sensory neurons differentiated from human induced pluripotent stem cells. Furthermore, microRNA (miRNA) sequencing analysis revealed that exosomes and their parent cells shared some similarities in their miRNA profiles and exosomes displayed a distinct miRNA signature. Many more miRNAs were identified in dExo than in uExo. Several upregulated miRNAs, like miRNA-132-3p and miRNA-199b-5p, were highly related to neuroprotection, anti-inflammation, and angiogenesis. The dExo can effectively modulate various peripheral nerve-related cellular functions and is promising for cell-free biological therapeutics to enhance neural regeneration.

Neural tissue engineering (NTE) has made remarkable strides in recent years and holds great promise for treating several devastating neurological disorders. Selecting optimal scaffolding material is crucial for NET design strategies that enable neural and non-neural cell differentiation and axonal growth. Collagen is extensively employed in NTE applications due to the inherent resistance of the nervous system against regeneration, functionalized with neurotrophic factors, antagonists of neural growth inhibitors, and other neural growth-promoting agents. Recent advancements in integrating collagen with manufacturing strategies, such as scaffolding, electrospinning, and 3D bioprinting, provide localized trophic support, guide cell alignment, and protect neural cells from immune activity. This review categorises and analyses collagen-based processing techniques investigated for neural-specific applications, highlighting their strengths and weaknesses in repair, regeneration, and recovery. We also evaluate the potential prospects and challenges of using collagen-based biomaterials in NTE. Overall, this review offers a comprehensive and systematic framework for the rational evaluation and applications of collagen in NTE.

Organic erectile dysfunction (ED) is a type of sexual disorder in men that is usually associated with illness, surgical injury, normal aging and has a high incidence across the globe. And the essence of penile erection is a neurovascular event regulated by a combination of factors. Nerve and vascular injury are the main causes of erectile dysfunction. Currently, the main treatment options for ED include phosphodiesterase type 5 inhibitors (PDE5Is), intracorporeal injections and vacuum erection devices (VEDs), which are ineffective. Therefore, it is essential to find an emerging, non-invasive and effective treatment for ED. The histopathological damage causing ED can be improved or even reversed with hydrogels, in contrast to current therapies. Hydrogels have many advantages, they can be synthesized from various raw materials with different properties, possess a definite composition, and have good biocompatibility and biodegradability. These advantages make hydrogels an effective drug carrier. In this review, we began with an overview of the underlying mechanisms of organic erectile dysfunction, discussed the dilemmas of existing treatments for ED, and described the unique advantages of hydrogel over other approaches. Then emphasizing the progress of research on hydrogels in the treatment of ED.

Spinal cord injury (SCI) is a complex tissue injury resulting in permanent and degenerating damage to the central nervous system (CNS). Detrimental cellular processes occur after SCI, including axonal degeneration, neuronal loss, neuroinflammation, reactive gliosis, and scar formation. The glial scar border forms to segregate the neural lesion and isolate spreading inflammation, reactive oxygen species, and excitotoxicity at the injury epicenter to preserve surrounding healthy tissue. The scar border is a physicochemical barrier composed of elongated astrocytes, fibroblasts, and microglia secreting chondroitin sulfate proteoglycans, collogen, and the dense extra-cellular matrix. While this physiological response preserves viable neural tissue, it is also detrimental to regeneration. To overcome negative outcomes associated with scar formation, therapeutic strategies have been developed: the prevention of scar formation, the resolution of the developed scar, cell transplantation into the lesion, and endogenous cell reprogramming. This review focuses on cellular/molecular aspects of glial scar formation, and discusses advantages and disadvantages of strategies to promote regeneration after SCI. [ABSTRACT FROM AUTHOR]

Background: Hyperbaric oxygen (HBO) plays positive roles in the therapy of traumatic brain injury (TBI); however, the mechanism underlying its effects on TBI is largely unknown. The study aims to elucidate the molecular mechanism implicated with the interaction between platelet-derived growth factor-BB (PDGF-BB) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, which may play critical roles during HBO treatment both in the astrocyte scratching model in vitro and rat TBI model in vivo. Methods: Changes in neurological function and wound healing were evaluated using the neurological severity scores (NSS) scale, immunohistochemistry, western blotting, and qRT-PCR, respectively. Results: The results showed that PDGF-BBi (PDGB interfered with small RNA) dramatically improves neuronal viability in vitro when transfected into the scratched astrocytes derived from the cerebral cortex of neonatal rats. Moreover, in vivo experiments revealed that HBO therapy substantially elevated the NSS scores and simultaneously reduced the mortality in TBI rats, as indicated by the NSS scales. Notably, HBO therapy was found to possess the ability to inhibit glial cell proliferation, promote the regeneration of neurons and synapses, and ultimately facilitate the wound healing, as revealed by immunohistochemistry and glial scar formation found in TBI rats. Importantly, HBO markedly decreased the expression levels of PDGF-BB and ERK1/2. It can clearly be seen that downregulated PDGF-BB and ERK1/2 levels were corresponding with the status of significant amelioration of the therapeutic effect of HBO. Conversely, the upregulation of PDGF-BB and ERK1/2 levels was in line with the opposite effect. Conclusion: It has been concluded that HBO therapy may play its active role in TBI treatment dependent on astrogliosis inhibition, which may be achieved by downregulating the ERK1/2 signaling pathway mediated by PDGF-BB. [ABSTRACT FROM AUTHOR]

Previous research shows that scar tissue formed in the injured area after spinal cord injury blocks nerve regeneration and functional recovery. However, those researchers tried to prevent the formation of scar after spinal cord injury to promote nerve regeneration, but it ran counter to their desire, indicating that the formation of scar might play a role in functional recovery after spinal cord injury. To investigate roles of scar formation on functional repair after spinal cord injury, we selected several different key time points to resect the scar tissue formed after spinal cord injury based on the rat models of the T8-T9 transection injury of spinal cord. First, the recovery of motor function was evaluated by Basso Beattie Bresnahan score and electrophysiologic examination; second, the pathologic features of functional recovery were analyzed mainly by immunofluorescence βⅢ-tubulin staining; finally, the genes related to the recovery of motor function were predicted by high-throughput sequencing analysis. Immunofluorescence results showed that the resection of scar tissue promoted significantly the recovery of motor function and the expression of βⅢ-tubulin in the injured area in the second week after spinal cord injury. Furthermore, RNA-seq studies showed that Tubb3 and Tubb6 gene expression and other neural regeneration pathways were significantly different in the tissue before and after early resection. Excision of scar tissue in the second week promoted nerve regeneration after spinal cord injury. Tubb3 and Tubb6 genes might be the potential targets for spinal cord injury therapy in our study. [ABSTRACT FROM AUTHOR]

Wound repair, along with skin appendage regeneration, is challenged by insufficient angiogenesis and neural regeneration. Therefore, promoting both proangiogenic and neuro-regenerative therapeutic effects is essential for effective wound repair. However, most therapeutic systems apply these strategies separately or ineffectively. This study investigates the performance of an all-in-one smart dressing (ASD) that integrates angiogenic functional materials and multiple biological factors within a light crosslinked hydrogel, forming a multi-functional dressing capable of facilitating simultaneous micro-vascularization and neural regeneration. The ASD uses a zeolite-imidazolate framework 67 with anchored vanadium oxide (VO2@ZIF-67) that allows for the on-demand release of Co2+ with fluctuations in pH at the wound site to stimulate angiogenesis. It can simultaneously release CXCL12, ligustroflavone, and ginsenoside Rg1 in a sustained manner to enhance the recruitment of endogenous mesenchymal stem cells, inhibit senescence, and induce neural differentiation to achieve in situ nerve regeneration. The ASD can stimulate rapid angiogenesis and nerve regeneration within 17 days through multiple angiogenic and neuro-regenerative cues within one dressing. This study provides a proof-of-concept for integrating functional nanomaterials and multiple complementary drugs within a smart dressing for simultaneous angiogenesis and neural regeneration. [ABSTRACT FROM AUTHOR]

As brain stroke is one of the leading causes of death worldwide, in the current research neuroprotection and performance improvement have been investigated in the Middle cerebral artery occlusion/reperfusion (MCAO/R) animal model treated with exosomes combined with recombinant tissue plasminogen activator (rt-PA). MCAO/R was induced in 25 adult male Wistar rats. Rats received rt-PA (10 mg/kg, i.v.) or exosomes (100 µg/kg) derived from bone marrow mesenchymal stem cells (MSCs). Following the administration of rt-PA alone or in combination with exosomes, a significant increased score of the EBST test was recorded. Also, a decrease in error level of beam test was observed in the treated groups. Cresyl violet staining revealed that the population of dark cells was significantly reduced in all treated groups. The amount of catalase enzyme was significantly increased in all treated groups, especially in the combination therapy group (P<0.05). A considerable increase in superoxide dismutase (SOD) enzyme was observed in the combination therapy group compared to the MCAO/R group (P=0.001). Our conclusion was approved by the Nlrp1 and Nlrp3 downregulation during combination therapy in the MCAO/R model by a reduction in cell death rate. The density of GFAP-positive cells showed a significant decrease in the exosome with or without rt-PA-treated groups compared to the MCAO/R group (P<0.05). Our observation indicated that exosomes, in combination with rt-PA resulted in a noticeable functional recovery, neuronal regeneration, and reduction of neuronal cell death after a 7-day period of the MCAO/R induction. This novel therapeutic strategy probably can provide a promising treatment for patients who suffered from a stroke. [ABSTRACT FROM AUTHOR]

Abstract Background The damaged neuronal cells of adult mammalian lack the regenerative ability to replace the neuronal connections. Periodontal ligament stem cells (PDLSCs) are the promising source for neuroregenerative applications that can improve the injured microenvironment of the damaged neural system. They provide neuronal progenitors and neurotrophic, anti-apoptotic and anti-inflammatory factors. In this study, we aimed to comprehensively explore the various neuronal differentiation potentials of PDLSCs for application in neural regeneration therapy. Main text PDLSCs have superior potential to differentiate into various neural-like cells through a dedifferentiation stage followed by differentiation process without need for cell division. Diverse combination of nutritional factors can be used to induce the PDLSCs toward neural lineage. PDLSCs when coupled with biomaterials could have significant implications for neural tissue repair. PDLSCs can be a new clinical research target for Alzheimer's disease treatment, multiple sclerosis and cerebral ischemia. Moreover, PDLSCs have beneficial effects on retinal ganglion cell regeneration and photoreceptor survival. PDLSCs can be a great source for the repair of injured peripheral nerve through the expression of several neural growth factors and differentiation into Schwann cells. Conclusion In conclusion, these cells are an appealing source for utilizing in clinical treatment of the neuropathological disorders. Although significant in vitro and in vivo investigations were carried out in order for neural differentiation evaluation of these cells into diverse types of neurons, more preclinical and clinical studies are needed to elucidate their therapeutic potential for neural diseases.

This study was designed to compare the effects of various doses of botulinum neurotoxin A (BoNT/A) on nerve regeneration. Sixty-five six-week-old rats with sciatic nerve injury were randomly allocated to three experimental groups, a control group, and a sham group. The experimental groups received a single session of intraneural BoNT/A (3.5, 7.0, or 14 U/kg) injection immediately after nerve-crushing injury. The control group received normal intraneural saline injections after sciatic nerve injury. At three, six, and nine weeks after nerve damage, immunofluorescence staining, an ELISA, and toluidine blue staining was used to evaluate the regenerated nerves. Serial sciatic functional index analyses and electrophysiological tests were performed every week for nine weeks. A higher expression of GFAP, S100β, GAP43, NF200, BDNF, and NGF was seen in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The average area and myelin thickness were significantly greater in the 3.5 U/kg and 7.0 U/kg BoNT/A groups. The sciatic functional index and compound muscle action potential amplitudes exhibited similar trends. These findings indicate that the 3.5 U/kg and 7.0 U/kg BoNT/A groups exhibited better nerve regeneration than the 14 U/kg BoNT/A and control group. As the 3.5 U/kg and the 7.0 U/kg BoNT/A groups exhibited no statistical difference, we recommend using 3.5 U/kg BoNT/A for its cost-effectiveness.

[INLINE:1] No definite consensus has currently been reached regarding the safety and efficacy of low- or high-frequency repetitive transcranial magnetic stimulation in the treatment of post-stroke muscle spasticity. The latest research indicates that when combined with local injections of botulinum toxin type A, it is more effective on post-stroke muscle spasticity than local injections of botulinum toxin type A alone. We designed a prospective, single-center, non-randomized, controlled clinical trial to investigate the safety and efficacy of different frequencies of repetitive transcranial magnetic stimulation combined with local injections of botulinum toxin type A in treating post-stroke lower limb muscle spasticity to determine an optimal therapeutic regimen. This trial will enroll 150 patients with post-stroke muscle spasticity admitted to the Department of Rehabilitation Medicine at the First Affiliated Hospital of China Medical University. All enrolled patients will undergo routine rehabilitation training and will be divided into five groups (n = 30 per group) according to the particular area of cerebral infarction and treatment methods. Group A: Patients with massive cerebral infarction will be given local injections of botulinum toxin type A and low-frequency (1 Hz) repetitive transcranial magnetic stimulation on the contralateral side; Group B: Patients with non-massive cerebral infarction will be given local injections of botulinum toxin type A and high-frequency (10–20 Hz) repetitive transcranial magnetic stimulation on the affected side; Group C: Patients with massive/non-massive cerebral infarction will be given local injections of botulinum toxin type A; Group D: Patients with massive cerebral infarction will be given low-frequency (1 Hz) repetitive transcranial magnetic stimulation on the contralateral side; and Group E: Patients with non-massive cerebral infarction will be given high-frequency (10–20 Hz) repetitive transcranial magnetic stimulation on the affected side. The primary outcome measure of this trial is a modified Ashworth scale score from 1 day before treatment to 12 months after treatment. Secondary outcome measures include Fugl-Meyer Assessment of Lower Extremity, Visual Analogue Scale, modified Barthel index, and Berg Balance Scale scores for the same time as specified for primary outcome measures. The safety indicator is the incidence of adverse events at 3–12 months after treatment. We hope to draw a definite conclusion on whether there are differences in the safety and efficacy of low- or high-frequency repetitive transcranial magnetic stimulation combined with botulinum toxin type A injections in the treatment of patients with post-stroke lower limb spasticity under strict grouping and standardized operation, thereby screening out the optimal therapeutic regimen. The study protocol was approved by the Medical Ethics Committee of the First Affiliated Hospital of China Medical University (approval No. [2021] 2021-333-3) on August 19, 2021. The trial was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR2100052180) on October 21, 2021. The protocol version is 1.1.

At present, treatments for Alzheimer’s disease can temporarily relieve symptoms but cannot prevent the decline of cognitive ability and other neurodegenerative changes. Dendrobium nobile Lindl alkaloid is the main active component of Dendrobium nobile Lindl. Dendrobium nobile Lindl alkaloid has been shown to resist aging, prolong life span, and exhibit immunomodulatory effects in animals. This review summarizes the mechanisms behind the neuroprotective effects reported in Alzheimer’s disease animal models. The neuroprotective effects of Dendrobium nobile Lindl alkaloid have not been studied in patients. The mechanisms by which Dendrobium nobile Lindl alkaloid has been reported to improve cognitive dysfunction in Alzheimer’s disease animal models may be associated with extracellular amyloid plaque production, regulation of tau protein hyperphosphorylation, inhibition of neuroinflammation and neuronal apoptosis, activation of autophagy, and enhanced synaptic connections.

Autophagy has been shown to play an important role in Parkinson’s disease. We hypothesized that skin-derived precursor cells exhibit neuroprotective effects in Parkinson’s disease through affecting autophagy. In this study, 6-hydroxydopamine-damaged SH-SY5Y cells were pretreated with a culture medium containing skin-derived precursors differentiated into Schwann cells (SKP-SCs). The results showed that the SKP-SC culture medium remarkably enhanced the activity of SH-SY5Y cells damaged by 6-hydroxydopamine, reduced excessive autophagy, increased tyrosine hydroxylase expression, reduced α-synuclein expression, reduced the autophagosome number, and activated the PI3K/AKT/mTOR pathway. Autophagy activator rapamycin inhibited the effects of SKP-SCs, and autophagy inhibitor 3-methyladenine had the opposite effect. These findings confirm that SKP-SCs modulate the PI3K/AKT/mTOR pathway to inhibit autophagy, thereby exhibiting a neuroprotective effect in a cellular model of Parkinson’s disease. This study was approved by the Animal Ethics Committee of Laboratory Animal Center of Nantong University (approval No. S20181009-205) on October 9, 2018.

There is no effective treatment for hemiplegia after hypertensive intracerebral hemorrhage. Considering that the branches of L4 nerve roots in the lumbar plexus root control the movement of the lower extremity anterior and posterior muscles, we investigated a potential method of nerve repair using the L4 nerve roots. Rat models of hindlimb hemiplegia after a hypertensive intracerebral hemorrhage were established by injecting autogenous blood into the posterior limb of internal capsule. The L4 nerve root on the healthy side of model rats was transferred and then anastomosed with the L4 nerve root on the affected side to drive the extensor and flexor muscles of the hindlimbs. We investigated whether this method can restore the flexible movement of the hindlimbs of paralyzed rats after hypertensive intracerebral hemorrhage. In a beam-walking test and ladder rung walking task, model rats exhibited an initial high number of slips, but improved in accuracy on the paretic side over time. At 17 weeks after surgery, rats gained approximately 58.2% accuracy from baseline performance and performed ankle motions on the paretic side. At 9 weeks after surgery, a retrograde tracing test showed a large number of fluoro-gold-labeled motoneurons in the left anterior horn of the spinal cord that supports the L4-to-L4 nerve roots. In addition, histological and ultramicrostructural findings showed axon regeneration of motoneurons in the anterior horn of the spinal cord. Electromyography and paw print analysis showed that denervated hindlimb muscles regained reliable innervation and walking coordination improved. These findings suggest that the L4-to-L4 nerve root transfer method for the treatment of hindlimb hemiplegia after hypertensive intracerebral hemorrhage can improve the locomotion of hindlimb major joints, particularly of the distal ankle. Findings from study support that the L4-to-L4 nerve root transfer method can effectively repair the hindlimb hemiplegia after hypertensive intracerebral hemorrhage. All animal experiments were approved by the Animal Ethics Committee of the First Affiliated Hospital of Nanjing Medical University (No. IACUC-1906009) in June 2019.

Zebrafish are an effective vertebrate model to study the mechanisms underlying recovery after spinal cord injury. The subacute phase after spinal cord injury is critical to the recovery of neurological function, which involves tissue bridging and axon regeneration. In this study, we found that zebrafish spontaneously recovered 44% of their swimming ability within the subacute phase (2 weeks) after spinal cord injury. During this period, we identified 7762 differentially expressed genes in spinal cord tissue: 2950 were up-regulated and 4812 were down-regulated. These differentially expressed genes were primarily concentrated in the biological processes of the respiratory chain, axon regeneration, and cell-component morphogenesis. The genes were also mostly involved in the regulation of metabolic pathways, the cell cycle, and gene-regulation pathways. We verified the gene expression of two differentially expressed genes, clasp2 up-regulation and h1m down-regulation, in zebrafish spinal cord tissue in vitro. Pathway enrichment analysis revealed that up-regulated clasp2 functions similarly to microtubule-associated protein, which is responsible for axon extension regulated by microtubules. Down-regulated h1m controls endogenous stem cell differentiation after spinal cord injury. This study provides new candidate genes, clasp2 and h1m, as potential therapeutic intervention targets for spinal cord injury repair by neuroregeneration. All experimental procedures and protocols were approved by the Animal Ethics Committee of Tianjin Institute of Medical & Pharmaceutical Sciences (approval No. IMPS-EAEP-Q-2019-02) on September 24, 2019.

Oscillating field stimulation (OFS) is a potential method for treating spinal cord injury. Although it has been used in spinal cord injury (SCI) therapy in basic and clinical studies, its underlying mechanism and the correlation between its duration and nerve injury repair remain poorly understood. In this study, we established rat models of spinal cord contusion at T10 and then administered 12 weeks of OFS. The results revealed that effectively promotes the recovery of motor function required continuous OFS for more than 6 weeks. The underlying mechanism may be related to the effects of OFS on promoting axon regeneration, inhibiting astrocyte proliferation, and improving the linear arrangement of astrocytes. This study was approved by the Animal Experiments and Experimental Animal Welfare Committee of Capital Medical University (supplemental approval No. AEEI-2021-204) on July 26, 2021.

5-Bromo-2′-deoxyuridine (BrdU) is a halogenated pyrimidine that can be incorporated into newly synthesized DNA during the S phase of the cell cycle. BrdU is widely used in fate-mapping studies of embryonic and adult neurogenesis to identify newborn neurons, however side effects on neural stem cells and their progeny have been reported. In vivo astrocyte-to-neuron (AtN) conversion is a new approach for generating newborn neurons by directly converting endogenous astrocytes into neurons. The BrdU-labeling strategy has been used to trace astrocyte-converted neurons, but whether BrdU has any effect on the AtN conversion is unknown. Here, while conducting a NeuroD1-mediated AtN conversion study using BrdU to label dividing reactive astrocytes following ischemic injury, we accidentally discovered that BrdU inhibited AtN conversion. We initially found a gradual reduction in BrdU-labeled astrocytes during NeuroD1-mediated AtN conversion in the mouse cortex. Although most NeuroD1-infected astrocytes were converted into neurons, the number of BrdU-labeled neurons was surprisingly low. To exclude the possibility that this BrdU inhibition was caused by the ischemic injury, we conducted an in vitro AtN conversion study by overexpressing NeuroD1 in cultured cortical astrocytes in the presence or absence of BrdU. Surprisingly, we also found a significantly lower conversion rate and a smaller number of converted neurons in the BrdU-treated group compared with the untreated group. These results revealed an unexpected inhibitory effect of BrdU on AtN conversion, suggesting more caution is needed when using BrdU in AtN conversion studies and in data interpretation.

Transcutaneous auricular vagus nerve stimulation (ta-VNS) is a novel noninvasive treat-ment for stroke that directly stimulates the peripheral auricular branch of the vagus nerve. There have been recent reports that ta-VNS combined with conventional rehabilitation training promotes the recovery of neurological function of patients with acute stroke. However, these were small-sample-sized studies on the recovery of neurological function in patients after percutaneous vagus nerve stimulation in the subacute and chronic phases after stroke. This double-blinded randomized controlled trial involved 60 acute ischemic or hemorrhagic stroke patients aged 18–80 years who received treatment in the Second Affiliated Hospital of Chongqing Medical University. The subjects were randomly assigned to receive ta-VNS or sham ta-VNS combined with conventional rehabilitation training. The follow-up results over 1 year revealed that ta-VNS combined with conventional rehabilitation training greatly improved the recovery of motor and sensory functions and emotional responses compared with sham ta-VNS combined with conventional rehabilitation training. There were no obvious side effects. These findings suggest that ta-VNS combined with conventional rehabilitation training for the treatment of acute ischemic or hemorrhagic stroke patients is safe and effective.