Neural Regeneration Research最新文献

JOURNAL/nrgr/04.03/01300535-202606000-00062/figure1/v/2026-02-11T151048Z/r/image-tiff The blood-spinal cord barrier is crucial for preserving homeostasis of the central nervous system. After spinal cord injury, autophagic flux within endothelial cells is disrupted, compromising the integrity of the blood-spinal cord barrier. This disruption facilitates extensive infiltration of inflammatory cells, resulting in exacerbated neuroinflammatory responses, neuronal death, and impaired neuronal regeneration. Previous research has demonstrated that photobiomodulation promotes the regeneration of damaged nerves following spinal cord injury by inhibiting the recruitment of inflammatory cells to the injured site and restoring neuronal mitochondrial function. However, the precise mechanisms by which photobiomodulation regulates neuroinflammation remain incompletely elucidated. In this study, we established a mouse model of spinal cord injury and assessed the effects of photobiomodulation treatment. Photobiomodulation effectively cleared damaged mitochondria from endothelial cells in mice, promoting recovery of hindlimb motor function. Using microvascular endothelial bEnd.3 cells subjected to oxygen-glucose deprivation, we found that the effects of photobiomodulation were mediated through activation of the PINK1/Parkin pathway. Additionally, photobiomodulation reduced mitochondrial oxidative stress levels and increased the expression of tight junction proteins within the blood-spinal cord barrier. Our findings suggest that photobiomodulation activates mitochondrial autophagy in endothelial cells through the PINK1/Parkin pathway, thereby promoting repair of the blood-spinal cord barrier following spinal cord injury.

Emerging evidence suggests that the gut microbiota is closely associated with the pathological manifestations of multiple neurodegenerative diseases via the gut-brain axis, which refers to the crosstalk between the gut and the central nervous system. More importantly, mitochondria have been considered prominent mediators of the interplay between the gut microbiota and the brain. Intestinal microbes may modulate mitochondrial function in the central nervous system to affect the progression of neurodegenerative diseases. Mitochondria are essential for meeting the host's substantial neuronal metabolic demands, maintaining excitability, and facilitating synaptic transmission. Dysfunctional mitochondria are considered critical hallmarks of various neurodegenerative diseases. Therefore, this review provides novel insights into the intricate roles of gut microbiota-mitochondrial crosstalk in the underlying mechanisms during the progression of neurodegeneration, as well as the existing potential therapeutic strategies for neurodegenerative disorders. These suggest intestinal microbiota-mitochondrial interaction play a crucial role in the occurrence and development of neurodegenerative diseases, and targeting this interaction may be a promising therapeutic approach to neurodegenerative diseases. However, this review found that there was relatively little research on the effect of this crosstalk on other neurodegenerative diseases, such as Huntington's disease and Multiple sclerosis, and the potential therapeutic strategies were translated into clinical trials, which face many challenges in developing personalized treatment plans based on the unique gut microbiota of different individuals.

JOURNAL/nrgr/04.03/01300535-202606000-00069/figure1/v/2026-02-11T151048Z/r/image-tiff Alzheimer's disease is the most common cause of dementia. Although increasing evidence suggests that disruptions in lipid metabolism are closely associated with the disease, the overall profile of lipid and sterol changes that occur in the brain during Alzheimer's disease remains unclear. In this study, we compared brain tissues extracted from 32-week-old male wild-type mice and 5×FAD transgenic Alzheimer's disease model mice, which carry mutations in the amyloid precursor protein ( APP ) and presenilin 1 ( PS1 ) genes. Using untargeted lipidomics and sterolomics techniques, we investigated the metabolic profiles of lipids, with a focus on sterols specifically, in three brain regions: cerebellum, hippocampus, and olfactory bulb. Our results revealed significant alterations in various lipids, particularly in the hippocampus and olfactory bulb, suggesting changes in energy levels in these regions. Further pathway analysis indicated notable disruptions in key metabolic processes, particularly those related to fatty acids and cell membrane components. Additionally, we observed decreased expression of 15 genes involved in lipid and sterol regulation. Collectively, these findings provide new insights into how imbalances in lipid and sterol metabolism may contribute to the progression of Alzheimer's disease, highlighting potential metabolic pathways involved in the development of this debilitating disease.

Spinal cord injury is a severe neurological condition with limited neuronal regeneration and functional recovery. Currently, no effective treatments exist to improve spinal cord injury prognosis. Neuronal guidance proteins are a diverse group of molecules that play crucial roles in axon and dendrite growth during nervous system development. Increasing evidence highlights their regulatory functions in spinal cord injury. This review provides a brief overview of the modulation patterns of key neuronal guidance proteins in neuronal axon growth during nervous system formation and subsequently focuses on their roles in neuronal regeneration and functional recovery following spinal cord injury. Neuronal guidance proteins include, but are not limited to, semaphorins and their receptors, plexins; netrins and their receptors, deleted in colorectal cancer and UNC5; Eph receptors and their ligands, ephrins; Slit and its receptor, Robo; repulsive guidance molecules and their receptor, neogenin; Wnt proteins and their receptor, Frizzled; and protocadherins. Localized Netrin-1 at the injury site inhibits motor axon regeneration after adult spinal cord injury while promoting oligodendrocyte growth. Slit2 enhances synapse formation in the injured spinal cord of rats. EphA7 regulates acute apoptosis in the early pathophysiological stages of spinal cord injury, while ephrinA1 plays a role in the nervous system's injury response, with its reduced expression leading to impaired motor function in rats. EphA3 is upregulated following spinal cord injury, promoting an inhibitory environment for axonal regeneration. After spinal cord injury, bidirectional activation of ephrinB2 and EphB2 in astrocytes and fibroblasts results in the formation of a dense astrocyte-meningeal fibroblast scar. EphB1/ephrinB1 signaling mediates pain processing in spinal cord injury by regulating calpain-1 and caspase-3 in neurons. EphB3 expression increases in white matter after spinal cord injury, further inhibiting axon regeneration. Sema3A, expressed by neurons and fibroblasts in the scar surrounding the injury, inhibits motor neuron and sensory nerve growth after spinal cord injury. Sema4D suppresses neuronal axon myelination and axon regeneration, while its inhibition significantly enhances axon regeneration and motor recovery. Sema7A is involved in glial scar formation and may influence serotonin channel remodeling, thereby affecting motor coordination. Given these findings, the local or systemic application of neuronal guidance proteins represents a promising avenue for spinal cord injury treatment.

JOURNAL/nrgr/04.03/01300535-202606000-00050/figure1/v/2026-02-11T151048Z/r/image-tiff Mesenchymal stem cell-derived extracellular vesicles have emerged as a promising form of regenerative and immunomodulatory therapy; indeed, micro (mi)RNAs contained within mesenchymal stem cell-derived extracellular vesicles modulate target gene expression and impact disease-associated pathways. Chronic alcohol consumption leads to neuroinflammation, brain damage, and impaired cognition. Evidence indicates that females are more vulnerable to alcohol-induced damage than males. While mesenchymal stem cell-derived extracellular vesicles have been studied in various neuroinflammatory conditions, their potential to counteract alcohol-induced brain damage remains unclear. In this study, we investigated whether repeated intravenous administration of mesenchymal stem cell-derived extracellular vesicles could ameliorate neuroinflammation and behavioral impairment induced by chronic alcohol consumption in female mice. Mesenchymal stem cell-derived extracellular vesicles diminished the increased binding of a micro-positron emission tomography tracer ( 18 F-FDG) when analyzing whole-brain 3D images and brain coronal sections of ethanol-treated mice. Mesenchymal stem cell-derived extracellular vesicle administration protected against ethanol-induced proinflammatory gene upregulation, cognitive dysfunction, and the conditioned rewarding effects of cocaine. MiRNA sequencing data from mesenchymal stem cell-derived extracellular vesicles revealed the elevated expression of extracellular vesicle-derived miR-483-5p and miR-140-3p in the brains of ethanol-treated female mice following mesenchymal stem cell-derived extracellular vesicle administration. In addition, mesenchymal stem cell-derived extracellular vesicles modulated the expression of pro-inflammatory-related miRNA target genes (e.g., Socs3 , Tnf , Mtor , and Atf6 ) in the brains of ethanol-treated female mice. These results suggest that mesenchymal stem cell-derived extracellular vesicles could function as a neuroprotective therapy to ameliorate the neuroinflammation, cognitive dysfunction, and conditioned rewarding effects of cocaine associated with chronic alcohol consumption.

The mechanisms leading to neurological and neurodegenerative diseases are not completely known, and new, more effective, therapeutic treatments are necessary for most neurological pathologies. The treatment of neurological and neurodegenerative diseases is complicated due to the blood-brain barrier, which makes it difficult for drugs to access the brain areas in which they must act to improve the pathology. A tool that can help to overcome this difficulty is the use of extracellular vesicles, which can easily cross the blood-brain barrier. The extracellular vesicles are considered a main way of communication between the brain and the rest of the body, with important implications for the physiopathology and therapy of neurological diseases. In recent years, the involvement of microbiota in many neurological pathologies, as well as its possible therapeutic role, has also become evident. A key mediator in the pathologic and beneficial effects of microbiota seems to be the bacterial extracellular vesicles. There is an important communication between the brain and the intestinal microbiota (the gut-brain axis), by which the microbiota influences brain function, impacts on mental health, and plays a role in different neurological and neurodegenerative diseases. The identification of the mechanisms involved in this gut-brain axis is essential to understanding the mechanisms of neurological pathologies and to developing more effective treatments for these diseases. Bacterial extracellular vesicles would play a relevant role in these processes. This review compiles the recent information and evidence on the role of bacterial extracellular vesicles in brain pathologies and on the therapeutic utility of bacterial extracellular vesicles in neurological and neurodegenerative diseases. One advantage of bacterial extracellular vesicles compared to extracellular vesicles derived from other cell types, such as stem cells, is that bacterial extracellular vesicles are generally easier to produce and modify. Bacterial extracellular vesicles may be easily modified to target a specific pathology and/or to enhance its therapeutic efficacy. Although the studies are still scarce, they open a wide field of possibilities for future studies, which will lead to a deeper understanding of the role of microbiota and bacterial extracellular vesicles in neurological pathologies and the underlying mechanisms, as well as to the development of new treatments based on the use of bacterial extracellular vesicles in neurological diseases.

JOURNAL/nrgr/04.03/01300535-202606000-00073/figure1/v/2026-02-11T151048Z/r/image-tiff Our recent study demonstrated that knockout of microRNA-301a attenuates migration and phagocytosis in macrophages. Considering that macrophages and Schwann cells synergistically clear the debris of degraded axons and myelin during Wallerian degeneration, which is a prerequisite for nerve regeneration, we hypothesized that microRNA-301a regulates Wallerian degeneration and nerve regeneration via impacts on Schwann cell migration and phagocytosis. Herein, we found low expression of microRNA-301a in intact sciatic nerves, with no impact of the microRNA-301a knockout on nerve structure and function. By contrast, we found significant upregulation of microRNA-301a in injured sciatic nerves. We established a sciatic nerve crush model in microRNA-301a knockout mice, which exhibited attenua9ted morphological and functional regeneration following sciatic nerve crush injury. The microRNA-301a knockout also led to significantly inhibited Wallerian degeneration in an in vivo sciatic nerve-transection model and in an in vitro nerve explant block model. Schwann cells with the microRNA-301a knockout showed inhibition of phagocytosis and migration, which was reversible under transfection with microRNA-301a mimics. Rescue experiments involving transfection of microRNA-301a-knockout Schwann cells with microRNA-301a mimics or treatment with the C-X-C motif receptor 4 inhibitor WZ811 indicated the mechanistic involvement of the Yin Yang 1/C-X-C motif receptor 4 pathway in the role of microRNA-301a. Combined with our previous findings in macrophages, we conclude that microRNA-301a plays a key role in peripheral nerve injury and repair by regulating the migratory and phagocytic capabilities of Schwann cells and macrophages via the Yin Yang 1/C-X-C motif receptor 4 pathway.