Neural Regeneration Research最新文献

Voltage-gated sodium channels are essential ionic-conductance pathways in the nervous system, which play an irreplaceable role in modulating neuronal excitability and signal transduction. This review comprehensively analyzes the molecular mechanisms and pathophysiological significance of voltage-gated sodium channels, with particular emphasis on elucidating the molecular-action mechanisms of the distinct subtypes of these channels, including Nav1.1, Nav1.2, and Nav1.6, across various neurological disorders such as familial hemiplegic migraine, epilepsy, autism spectrum disorder, and retinal dysfunction. This review also provides a comprehensive overview of the pathogenic mechanisms associated with voltage-gated sodium channels, and systematically clarifies the evolutionary pathway of treatment strategies from conventional to innovative approaches. It analyzes two major categories of conventional sodium channel blockers and their applications: antiepileptic drugs (such as carbamazepine, lamotrigine, and phenytoin) and antiarrhythmic drugs (such as lidocaine, flecainide, and quinidine). However, these conventional blockers show limitations because of the lack of selectivity, driving research toward more precise therapeutic directions. Additionally, this review evaluates gabapentin, cannabidiol, and calcium channel blockers with different mechanisms of action. These drugs modulate neuronal excitability from multiple perspectives, providing diverse options for symptom relief. This review also highlights advances in gene therapy for specific diseases, such as STK-001, which promotes effective splicing of the sodium channel voltage-gated type 1 alpha subunit ( SCN1A ) gene, and ETX101, which utilizes adeno-associated virus 9 vectors to deliver engineered transcription factors. These two agents provide targeted therapeutic solutions for Dravet syndrome. Furthermore, this review summarizes some innovative therapeutic agents in clinical trials, including PRAX-222 (for SCN2A gain-of-function mutation-related epilepsy), which has received Food and Drug Administration orphan drug designation, and the selective Nav1.6 inhibitor NBI-921352 (for SCN8A -related epilepsy). Collectively, this review comprehensively compares the advantages and disadvantages of conventional drugs and gene therapy and envisions future treatment strategies that integrate the strengths of both approaches, facilitating personalized precision medicine to provide more accurate and effective treatment options for patients with ion channel diseases.

JOURNAL/nrgr/04.03/01300535-202606000-00068/figure1/v/2026-02-11T151048Z/r/image-tiff Alzheimer's disease is initially thought to be caused by age-associated accumulation of plaques, in recent years, research has increasingly associated Alzheimer's disease with lysosomal storage and metabolic disorders, and the explanation of its pathogenesis has shifted from amyloid and tau accumulation to oxidative stress and impaired lipid and glucose metabolism aggravated by hypoxic conditions. However, the underlying mechanisms linking those cellular processes and conditions to disease progression have yet to be defined. Here, we applied a disease similarity approach to identify unknown molecular targets of Alzheimer's disease by using transcriptomic data from congenital diseases known to increase Alzheimer's disease risk, namely Down syndrome, Niemann-Pick type C disease, and mucopolysaccharidoses I. We uncovered common pathways, hub genes, and miRNAs across in vitro and in vivo models of these diseases as potential molecular targets for neuroprotection and amelioration of Alzheimer's disease pathology, many of which have never been associated with Alzheimer's disease. We then investigated common molecular alterations in brain samples from a Niemann-Pick type C disease mouse model by juxtaposing them with brain samples of both human and mouse models of Alzheimer's disease. Detailed phenotypic, molecular, chronological, and biological aging analyses revealed that the Npc1tm(I1061T)Dso mouse model can serve as a potential short-lived in vivo model for brain aging and Alzheimer's disease research. This research represents the first comprehensive approach to congenital disease association with neurodegeneration and a new perspective on Alzheimer's disease research while highlighting shortcomings and lack of correlation in diverse in vitro models. Considering the lack of an Alzheimer's disease mouse model that recapitulates the physiological hallmarks of brain aging, the short-lived Npc1tm(I1061T)Dso mouse model can further accelerate the research in these fields and offer a unique model for understanding the molecular mechanisms of Alzheimer's disease from a perspective of accelerated brain aging.

Globally, glaucoma stands as a primary cause of irreversible blindness, marked by intricate pathophysiological processes in which neuroinflammation plays a pivotal role. As the principal immune cells within the central nervous system, microglia play a dual function in the progression of glaucoma. Under standard physiological states, microglia safeguard the retina by offering neurotrophic support and removing cellular debris. In the pathological progression of glaucoma, microglia become activated and release significant levels of inflammatory factors, resulting in retinal ganglion cell injury, cell death, and impaired neuroregeneration. This review focuses on examining the dual functions of microglia in glaucoma, evaluating their influence on retinal neurodegeneration and repair, and suggesting that modulating microglial activity could serve as a promising therapeutic strategy. Understanding the mechanisms of microglial action in glaucoma is crucial for unveiling the complex pathophysiological processes of the disease and developing new therapeutic strategies.

JOURNAL/nrgr/04.03/01300535-202606000-00051/figure1/v/2026-02-11T151048Z/r/image-tiff Inflammation plays a key role in driving the secondary brain injury that follows ischemic stroke. Melatonin is an endogenous neuroendocrine hormone that regulates mitochondrial homeostasis. However, the role and mechanisms by which melatonin regulates microglial pyroptosis and the inflammatory cascade through double-stranded DNA (dsDNA)-sensing cyclic GMP-AMP synthase (cGAS) signaling warrant further study. Using middle cerebral artery occlusion mice, we investigated the effects of melatonin on cGAS-mediated pyroptosis and neuroinflammation. Middle cerebral artery occlusion model mice exhibited significantly increased DNA damage and cytoplasmic dsDNA release, as reflected by γH2AX staining, as well as heightened activation of the cytosolic dsDNA-sensing cGAS-STING pathway, both of which were notably suppressed by melatonin treatment. Melatonin also mitigated NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome activation and nuclear factor (NF)-κB/gasdermin D-mediated pyroptosis in microglia following ischemic stroke, while exhibiting the capacity to attenuate the immune response to ischemia in mice. This led to reduced infiltration of peripheral neutrophils and monocytes/macrophages in the ischemic brain. Specifically, melatonin administration resulted in reductions in the numbers of ionized calcium-binding adapter molecule 1-positive cells and production of interleukin-6 and tumor necrosis factor-α by microglia. Regarding neurological outcomes, melatonin significantly reduced cerebral infarct volume and ameliorated neurological deficits in mice. Notably, the neuroprotective effect of melatonin was correlated with the inhibition of cGAS activity. We also developed and tested melatonin co-loaded macrophage membrane-biomimetic reactive oxygen species-responsive nanoparticles (Mф-MLT@FNGs), which exhibited therapeutic properties in middle cerebral artery occlusion mice. Our findings suggest that melatonin acts on microglial pyroptosis to inhibit neuroinflammation and reshape the immune microenvironment through regulation of the cGAS-STING-NF-κB signaling pathway. By doing so, melatonin rescues damaged brain tissue and protects neurological function, highlighting its potential as a neuroprotective treatment for ischemic stroke.