Neural Regeneration Research最新文献

Noninvasive brain stimulation techniques offer promising therapeutic and regenerative prospects in neurological diseases by modulating brain activity and improving cognitive and motor functions. Given the paucity of knowledge about the underlying modes of action and optimal treatment modalities, a thorough translational investigation of noninvasive brain stimulation in preclinical animal models is urgently needed. Thus, we reviewed the current literature on the mechanistic underpinnings of noninvasive brain stimulation in models of central nervous system impairment, with a particular emphasis on traumatic brain injury and stroke. Due to the lack of translational models in most noninvasive brain stimulation techniques proposed, we found this review to the most relevant techniques used in humans, i.e., transcranial magnetic stimulation and transcranial direct current stimulation. We searched the literature in PubMed, encompassing the MEDLINE and PMC databases, for studies published between January 1, 2020 and September 30, 2024. Thirty-five studies were eligible. Transcranial magnetic stimulation and transcranial direct current stimulation demonstrated distinct strengths in augmenting rehabilitation post-stroke and traumatic brain injury, with emerging mechanistic evidence. Overall, we identified neuronal, inflammatory, microvascular, and apoptotic pathways highlighted in the literature. This review also highlights a lack of translational surrogate parameters to bridge the gap between preclinical findings and their clinical translation.

Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism. Previous studies have shown that PPARα plays a key role in the onset and progression of neurodegenerative diseases. Consequently, peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders. This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases. Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues. Although it is conventionally believed to be primarily localized in the nucleus, its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling. Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects. Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases. For instance, peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway. Additionally, peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra, and it can mitigate motor dysfunction in Parkinson's disease mouse models. Furthermore, peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases. In summary, peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases, and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases, providing new options for patient care.

JOURNAL/nrgr/04.03/01300535-202604000-00043/figure1/v/2025-06-30T060627Z/r/image-tiff Downregulation of the inwardly rectifying potassium channel Kir4.1 is a key step for inducing retinal Müller cell activation and interaction with other glial cells, which is involved in retinal ganglion cell apoptosis in glaucoma. Modulation of Kir4.1 expression in Müller cells may therefore be a potential strategy for attenuating retinal ganglion cell damage in glaucoma. In this study, we identified seven predicted phosphorylation sites in Kir4.1 and constructed lentiviral expression systems expressing Kir4.1 mutated at each site to prevent phosphorylation. Following this, we treated Müller glial cells in vitro and in vivo with the mGluR I agonist DHPG to induce Kir4.1 or Kir4.1 Tyr 9 Asp overexpression. We found that both Kir4.1 and Kir4.1 Tyr 9 Asp overexpression inhibited activation of Müller glial cells. Subsequently, we established a rat model of chronic ocular hypertension by injecting microbeads into the anterior chamber and overexpressed Kir4.1 or Kir4.1 Tyr 9 Asp in the eye, and observed similar results in Müller cells in vivo as those seen in vitro . Both Kir4.1 and Kir4.1 Tyr 9 Asp overexpression inhibited Müller cell activation, regulated the balance of Bax/Bcl-2, and reduced the mRNA and protein levels of pro-inflammatory factors, including interleukin-1β and tumor necrosis factor-α. Furthermore, we investigated the regulatory effects of Kir4.1 and Kir4.1 Tyr 9 Asp overexpression on the release of pro-inflammatory factors in a co-culture system of Müller glial cells and microglia. In this co-culture system, we observed elevated adenosine triphosphate concentrations in activated Müller cells, increased levels of translocator protein (a marker of microglial activation), and elevated interleukin-1β mRNA and protein levels in microglia induced by activated Müller cells. These changes could be reversed by Kir4.1 and Kir4.1 Tyr 9 Asp overexpression in Müller cells. Kir4.1 overexpression, but not Kir4.1 Tyr 9 Asp overexpression, reduced the number of proliferative and migratory microglia induced by activated Müller cells. Collectively, these results suggest that the tyrosine residue at position nine in Kir4.1 may serve as a functional modulation site in the retina in an experimental model of glaucoma. Kir4.1 and Kir4.1 Tyr 9 Asp overexpression attenuated Müller cell activation, reduced ATP/P2X receptor-mediated interactions between glial cells, inhibited microglial activation, and decreased the synthesis and release of pro-inflammatory factors, consequently ameliorating retinal ganglion cell apoptosis in glaucoma.

JOURNAL/nrgr/04.03/01300535-202604000-00045/figure1/v/2025-06-30T060627Z/r/image-tiff Ischemia-reperfusion injury is a common pathophysiological mechanism in retinal degeneration. PANoptosis is a newly defined integral form of regulated cell death that combines the key features of pyroptosis, apoptosis, and necroptosis. Oligomerization of mitochondrial voltage-dependent anion channel 1 is an important pathological event in regulating cell death in retinal ischemia-reperfusion injury. However, its role in PANoptosis remains largely unknown. In this study, we demonstrated that voltage-dependent anion channel 1 oligomerization-mediated mitochondrial dysfunction was associated with PANoptosis in retinal ischemia-reperfusion injury. Inhibition of voltage-dependent anion channel 1 oligomerization suppressed mitochondrial dysfunction and PANoptosis in retinal cells subjected to ischemia-reperfusion injury. Mechanistically, mitochondria-derived reactive oxygen species played a central role in the voltage-dependent anion channel 1-mediated regulation of PANoptosis by promoting PANoptosome assembly. Moreover, inhibiting voltage-dependent anion channel 1 oligomerization protected against PANoptosis in the retinas of rats subjected to ischemia-reperfusion injury. Overall, our findings reveal the critical role of voltage-dependent anion channel 1 oligomerization in regulating PANoptosis in retinal ischemia-reperfusion injury, highlighting voltage-dependent anion channel 1 as a promising therapeutic target.

Spinal cord injuries have overwhelming physical and occupational implications for patients. Moreover, the extensive and long-term medical care required for spinal cord injury significantly increases healthcare costs and resources, adding a substantial burden to the healthcare system and patients' families. In this context, chondroitinase ABC, a bacterial enzyme isolated from Proteus vulgaris that is modified to facilitate expression and secretion in mammals, has emerged as a promising therapeutic agent. It works by degrading chondroitin sulfate proteoglycans, cleaving the glycosaminoglycanchains of chondroitin sulfate proteoglycans into soluble disaccharides or tetrasaccharides. Chondroitin sulfate proteoglycans are potent axon growth inhibitors and principal constituents of the extracellular matrix surrounding glial and neuronal cells attached to glycosaminoglycan chains. Chondroitinase ABC has been shown to play an effective role in promoting recovery from acute and chronic spinal cord injury by improving axonal regeneration and sprouting, enhancing the plasticity of perineuronal nets, inhibiting neuronal apoptosis, and modulating immune responses in various animal models. In this review, we introduce the classification and pathological mechanisms of spinal cord injury and discuss the pathophysiological role of chondroitin sulfate proteoglycans in spinal cord injury. We also highlight research advancements in spinal cord injury treatment strategies, with a focus on chondroitinase ABC, and illustrate how improvements in chondroitinase ABC stability, enzymatic activity, and delivery methods have enhanced injured spinal cord repair. Furthermore, we emphasize that combination treatment with chondroitinase ABC further enhances therapeutic efficacy. This review aimed to provide a comprehensive understanding of the current trends and future directions of chondroitinase ABC -based spinal cord injury therapies, with an emphasis on how modern technologies are accelerating the optimization of chondroitinase ABC development.

Traumatic spinal cord injury often leads to the disintegration of nerve cells and axons, resulting in a substantial accumulation of myelin debris that can persist for years. The abnormal buildup of myelin debris at sites of injury greatly impedes nerve regeneration, making the clearance of debris within these microenvironments crucial for effective post-spinal cord injury repair. In this review, we comprehensively outline the mechanisms that promote the clearance of myelin debris and myelin metabolism and summarize their roles in spinal cord injury. First, we describe the composition and characteristics of myelin debris and explain its effects on the injury site. Next, we introduce the phagocytic cells involved in myelin debris clearance, including professional phagocytes (macrophages and microglia) and non-professional phagocytes (astrocytes and microvascular endothelial cells), as well as other cells that are also proposed to participate in phagocytosis. Finally, we focus on the pathways and associated targets that enhance myelin debris clearance by phagocytes and promote lipid metabolism following spinal cord injury. Our analysis indicates that myelin debris phagocytosis is not limited to monocyte-derived macrophages, but also involves microglia, astrocytes, and microvascular endothelial cells. By modulating the expression of genes related to phagocytosis and lipid metabolism, it is possible to modulate lipid metabolism disorders and influence inflammatory phenotypes, ultimately affecting the recovery of motor function following spinal cord injury. Additionally, therapies such as targeted mitochondrial transplantation in phagocytic cells, exosome therapy, and repeated trans-spinal magnetic stimulation can effectively enhance the removal of myelin debris, presenting promising potential for future applications.

Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood-brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood-brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.