Journal of Neurochemistry最新文献

Adult central nervous system (CNS) neurons exhibit limited intrinsic regenerative capacity, contributing to poor recovery after injury. MicroRNAs (miRNAs) have emerged as key regulators of many biological processes, yet their therapeutic potential in CNS repair remains incompletely understood. Here, we investigated whether adeno-associated virus (AAV) vector-mediated overexpression of miR-146a enhances neurite and axon regeneration in primary cortical neurons from Wistar rats. We found that AAV.miR-146a significantly increased neurite outgrowth, branching, and long-distance neurite regeneration following scratch injury. Using a microfluidic platform that allows us to selectively lesion axons, we further demonstrated that AAV.miR-146a robustly promotes axonal regrowth. Bioinformatic analyses revealed enrichment of miR-146a target genes involved in transcriptional regulation and synaptic function, with the inflammatory adaptor TRAF6 emerging as a key predicted target. Consistent with these predictions, AAV.miR-146a markedly reduced TRAF6 expression. Together, our results identify miR-146a as a promising therapeutic candidate for enhancing CNS axonal repair and highlight TRAF6 signaling as a potential mechanistic link to its regenerative effects.

Glutathione is a major component of the cellular antioxidant system, providing a means of controlling redox homeostasis and affording protection against oxidative damage. Proton magnetic resonance spectroscopy (MRS) offers insights into brain metabolism by enabling the noninvasive quantification of metabolites. Previous studies have demonstrated that the neurotransmitters glutamate and GABA detected by MRS show activity-dependent concentration changes and correlate with cognitive performance. Yet how MRS detected antioxidant capacity, particularly glutathione levels, relates to cognition remains unclear. In this issue, Lee et al. report that higher cortical glutathione levels are associated with better cognitive outcomes in older adults. These findings might contribute to understanding whether glutathione levels index resilience or degeneration. However, observations reported across the literature remain inconsistent, and the observed discrepancies underscore the need for further research using harmonized MRS acquisitions, deeper metabolic and cognitive phenotyping, and longitudinal study designs to clarify the role of cortical glutathione in cognitive trajectories.

CTBP1 (C-terminal-binding protein 1) is a multifunctional protein that acts as a transcriptional co-repressor in the nucleus and a regulator of membrane fission in the cytoplasm. Variants in CTBP1 have been associated with neurodevelopmental disorder termed HADDTS (Hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome; OMIM#617915). However, the pathophysiological mechanism of this genetic disorder remains unclear. Whole exome sequencing was performed on a 20-year-old male patient with severe mental retardation, atrial septal defect, ataxia, and dysmorphic features. The patient was found to have a de novo missense variant, c.107G>C,p.(R36P), within the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft of CTBP1. However, the patient did not fulfill the diagnostic criteria for HADDTS. Therefore, the pathophysiological significance of this variant was investigated in vitro and in vivo, comparing it with p.R342W, a recurrent pathogenic variant in HADDTS. Transient expression of the p.R36P and p.R342W variants reduced the number and total length of dendrites in primary cultured hippocampal neurons. In vivo acute expression of them caused a migration delay of excitatory neurons and disrupted both dendritic arborization and spine formation during corticogenesis. Subsequent electrophysiological analyses suggested that these variants reduced excitatory synaptic transmission. Additionally, the p.R36P variant, but not p.R342W, reduced the excitability of layer II/III pyramidal neurons. We also report two new cases with the p.R342W variant that meet the diagnostic criteria for HADDTS. Our results show that CTBP1 plays an essential role in brain development and that the novel variant may cause a new developmental disorder distinct from HADDTS.

Microglia are the primary innate immune cells of the central nervous system and act as dynamic regulators of neural development, homeostasis, and response to injury. This review summarizes key discussions from the Glial Club South Cone Meeting 2025, focusing on (i) mechanisms and regulation of microglial phagocytosis and its dual role in tissue repair and neurodegeneration, (ii) the emerging immunometabolic and neuroprotective functions of the lipid-sensing receptor CD300f in aging and Alzheimer's disease models, and (iii) the context-dependent roles of autophagy in microglial activation, inflammation control and proteostasis. We highlight how phagocytic signaling (IFN, IL-6, "eat-me," "don't-eat-me" cues), immune receptors and epigenetic regulation shape microglial states and function. Translational implications are discussed, including strategies to preserve beneficial microglial functions while limiting detrimental phagoptotic and pro-inflammatory responses. Identifying receptor-specific ligands, clarifying causal roles of phagocytosis in neurodegeneration, and dissecting autophagy-dependent quality-control pathways emerge as priority areas for future research.

Multiple sclerosis is a chronic inflammatory and demyelinating disease that primarily affects young adults. Active demyelination and neurodegeneration have been associated with early microglial and astroglial activation. While reactive microglia (MG) can contribute to tissue damage and exacerbate neurodegeneration, they also play a neuroprotective role by clearing debris through phagocytosis and secreting growth factors that support repair. The aim of this study was to evaluate the effects of MG depletion and repopulation on the response to lysophosphatidylcholine-induced oligodendroglial damage using an in vitro model previously characterized by our laboratory. Since microglial development and survival critically depend on colony-stimulating factor-1 receptor (CSF-1R) signaling, we employed CSF-1R inhibition with BLZ945 to effectively deplete MG. Results show that repopulation occurs even in demyelinating conditions and, at early time points, results in MG exhibiting a morphology indicative of a less activated phenotype. Despite having higher phagocytic activity, early repopulating MG are few and thus unable to efficiently clear myelin debris. However, these repopulating MG still demonstrated to induce oligodendroglial differentiation. Studies using conditioned media revealed that early repopulating MG release factors into the environment which promote oligodendroglial progenitor cell viability and facilitate oligodendroglial differentiation in a demyelinating context, an effect not observed in neurons. Interestingly, our in vitro results show a close correlation with in vivo findings previously reported and demonstrate the relevance of our model in developing therapies for demyelinating diseases. These findings underscore both the potential and limitations of microglial modulation aimed at eliminating pro-inflammatory profiles and promoting repopulation with pro-regenerative characteristics.

The spinal cord stands as a crucial nexus in the central nervous system (CNS), integrating and modulating signals that ultimately shape our everyday interactions with the world. Its gray matter is arranged into discrete laminae spanning the dorsal–ventral axis that encompass circuit-specific modalities. Concurrently, extensive interconnected interneuron networks within and between these laminae confer remarkable flexibility in the behavioral outputs for a given input. The flexibility of spinal cord information processing in light of its organized architecture makes it a particularly intriguing region to explore the neuronal computations underlying behaviors, particularly as they relate to neurological dysfunction. At the same time, astrocytes engage in highly dynamic interactions with underlying neuronal circuitries, suggesting they may add another dimension to spinal cord information processing. Technical limitations specific to the spinal cord have long limited our ability to interrogate the relationship between astrocyte–neuron interactions and ongoing spinal cord function. In this review, we highlight emerging insights—particularly those from recent in vivo studies—that illustrate astrocytes actively shape spinal cord behavioral outputs in both health and disease. We briefly review the spinal cord's neuronal organization to provide a structural foundation for assessing the relative spatial relationship between astrocyte and neuron activity as it relates to different spinal cord outputs. Within this architectural framework, we review growing evidence that spinal cord astrocytes respond to activity associated with spinal cord function and, in turn, modulate underlying neuronal circuits to alter future behavioral outputs. Moreover, we propose an overall conceptual framework for understanding circuit-specific spinal cord modulations through the lens of astrocyte-neuron interactions and underscore how it can be leveraged to uncover novel ways of targeting spinal cord disease states. Finally, we put forth key outstanding questions related to this conceptual framework and emphasize the technological advances that will facilitate future studies addressing them.

Currently, no effective treatment exists for injuries at the interface between the CNS/PNS, largely due to their complex pathophysiology and the limited efficacy of single-target therapies. To address this challenge, we investigated a novel combinatorial therapeutic strategy integrating surgical VRR with fibrin sealant biopolymer (FSB) and DMT in a rat model of ventral root avulsion VRA. DMT was extracted from Mimosa tenuiflora roots and structurally characterized using standard analytical methods. Adult female Lewis rats underwent unilateral L4-L6 VRA and received daily DMT treatment (1, 2.5, or 5 mg/kg; i.p) for 2 weeks to determine the optimal therapeutic dose. Subsequently, the identified optimal DMT dose was combined with VRR, and animals were evaluated 2 weeks post-injury. Outcome measures encompassed quantitative assessments of neuronal survival, glial reactivity, synaptic preservation, and differential gene expression of neurotrophic factors (GDNF, FGF-2, VGF-A) and anti-apoptotic genes (Bcl-2, Bcl-XL). Extracted DMT met all structural and analytical criteria for experimental use. Proximal axotomy led to substantial MN loss (78%), accompanied by pronounced glial reactivity and synaptic detachment. DMT at 1 mg/kg yielded the strongest neuroprotective profile, significantly enhancing MN survival, reducing glial reactivity, and preserving pre-synaptic boutons. Notably, these effects were further potentiated when DMT treatment was combined with VRR. Moreover, the combined VRR + DMT therapy significantly upregulated GDNF expression, indicating a synergistic effect on neurotrophic support. Overall, our findings suggest that DMT is a promising neuroprotective agent for treating MN degeneration following CNS/PNS interface injuries, particularly when integrated into a combinatorial therapeutic strategy.

Ex vivo acute brain slice is a popular technique in neuroscience research with many variations. While many variations are currently used by labs around the world, no study has comprehensively examined the impact of these variations on the quality of the acute brain slice preparation. In this study, we compared different animal sacrifice methods (decapitation or transcardial perfusion) and cutting solution (normal or sucrose artificial cerebrospinal fluid). Brain slices were prepared from 10 to 12 weeks old male Wistar rats (Rattus norvegicus). Neuronal population was quantified by immunohistochemistry against various neuronal markers. Neuronal dynamics was evaluated by in vitro electrophysiology using two acute epilepsy models—zero-magnesium and 4-aminopyridine. We found that the method of brain slice preparation significantly affected the quality of the brain slice preparation. In general, the combination of transcardial perfusion and sucrose artificial cerebrospinal fluid produces the optimal brain slice preparation. The slices prepared with transcardial perfusion and sucrose aCSF had higher preservation of inhibitory interneurons and subsequently less successful induction of acute epileptiform activity. We also found that loss of inhibitory GABAergic neurons during brain slice preparation is primarily due to oxidative damage. Limiting oxidative stress is an effective neuroprotection strategy to prevent loss of inhibition in brain slice preparation. In conclusion, consideration of brain slice preparation method is crucial in preserving inhibitory GABAergic neurons and the degree of inhibition in the slice. Loss of inhibitory interneuron due to oxidative stress significantly affects quality of brain slice preparation and subsequent ex vivo epileptiform activity induction and dynamics.

We describe the development of neurochemistry in Brazil, Argentina, Uruguay, and Chile in the XX century through Latin American scientists who pioneered the discipline in their countries. In addition, we analyze the research groups that succeeded the pioneers and the fields explored in greater depth in different countries. We examine the history of glial cell research and the efforts made despite financial constraints. We also highlight the role of the International Society of Neurochemistry (ISN) in the history of neurochemistry in Latin America. A special section is dedicated to neurochemistry in Venezuela, given its significant role in the past.