Translational Neuroscience最新文献

Our previous studies have shown that early exercise intervention after stroke increases neural activity and synaptic plasticity and promotes the recovery of nerve fiber bundle integrity in the brain. However, the effect of exercise on the repair of myelin in the brain and the related mechanism are still unclear. In this study, we randomly divided the rats into three groups. Before and after 28 days of intervention, body weight, nerve function, the infarct size, white matter fiber bundle integrity, and nerve myelin structure and function were observed by measuring body weight, analysis of modified neurological severity score, CatWalk gait analysis, MRI, luxol fast blue staining, immunofluorescence, and transmission electron microscopy. Changes in the expression of proteins in the MEK/ERK pathway were assessed. The results showed that early exercise intervention resulted in neurological recovery, decreased the infarct volume and increased nerve fiber integrity, the myelin coverage area, myelin basic protein (MBP) fluorescence intensity expression, and myelin thickness. Furthermore, the expression level of MBP was significantly increased after early exercise intervention, while the expression levels of p-MEK1/2 and p-ERK1/2 were significantly reduced. In the cell study, MBP expression levels were significantly higher in the oxygen and glucose deprivation and administration group.In summary, early exercise intervention after stroke can promote myelin repair by inhibiting the MEK/ERK signaling pathway.

Background: Silibinin has been found to inhibit glioblastoma (GBM) progression. However, the underlying molecular mechanism by which Silibinin regulates GBM process remains unclear.

Methods: GBM cell proliferation, apoptosis, invasion, and stemness are assessed by cell counting kit-8 assay, EdU assay, flow cytometry, transwell assay, and sphere formation assay. Western blot is used to measure the protein expression levels of apoptosis-related markers, solute carrier family 1 member 5 (SLC1A5), and Yin Yang-1 (YY1). Glutamine consumption, glutamate production, and α-ketoglutarate production are detected to evaluate glutamine metabolism in cells. Also, SLC1A5 and YY1 mRNA levels are examined using quantitative real-time PCR. Chromatin immunoprecipitation assay and dual-luciferase reporter assay are used to detect the interaction between YY1 and SLC1A5. Mice xenograft models are constructed to explore Silibinin roles in vivo.

Results: Silibinin inhibits GBM cell proliferation, invasion, stemness, and glutamine metabolism, while promotes apoptosis. SLC1A5 is upregulated in GBM and its expression is decreased by Silibinin. SLC1A5 overexpression abolishes the anti-tumor effect of Silibinin in GBM cells. Transcription factor YY1 binds to SLC1A5 promoter region to induce SLC1A5 expression, and the inhibition effect of YY1 knockdown on GBM cell growth, invasion, stemness, and glutamine metabolism can be reversed by SLC1A5 overexpression. In addition, Silibinin reduces GBM tumor growth by regulating YY1/SLC1A5 pathway.

Conclusion: Silibinin plays an anti-tumor role in GBM process, which may be achieved via inhibiting YY1/SLC1A5 pathway.

Objective: Heterozygous mutations within the voltage-gated sodium channel α subunit (SCN1A) are responsible for the majority of cases of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy. Development of novel therapeutic approaches is mandatory in order to directly target the molecular consequences of the genetic defect. The aim of the present study was to investigate whether cis-acting long non-coding RNAs (lncRNAs) of SCN1A are expressed in brain specimens of children and adolescent with epilepsy as these molecules comprise possible targets for precision-based therapy approaches.

Methods: We investigated SCN1A mRNA expression and expression of two SCN1A related antisense RNAs in brain tissues in different age groups of pediatric non-Dravet patients who underwent surgery for drug resistant epilepsy. The effect of different antisense oligonucleotides (ASOs) directed against SCN1A specific antisense RNAs on SCN1A expression was tested.

Results: The SCN1A related antisense RNAs SCN1A-dsAS (downstream antisense, RefSeq identifier: NR_110598) and SCN1A-usAS (upstream AS, SCN1A-AS, RefSeq identifier: NR_110260) were widely expressed in the brain of pediatric patients. Expression patterns revealed a negative correlation of SCN1A-dsAS and a positive correlation of lncRNA SCN1A-usAS with SCN1A mRNA expression. Transfection of SK-N-AS cells with an ASO targeted against SCN1A-dsAS was associated with a significant enhancement of SCN1A mRNA expression and reduction in SCN1A-dsAS transcripts.

Conclusion: These findings support the role of SCN1A-dsAS in the suppression of SCN1A mRNA generation. Considering the haploinsufficiency in genetic SCN1A related DS, SCN1A-dsAS is an interesting target candidate for the development of ASOs (AntagoNATs) based precision medicine therapeutic approaches aiming to enhance SCN1A expression in DS.

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders diagnosed in childhood. Two common features of ADHD are impaired behavioural inhibition and sustained attention. The Go/No-Go experimental paradigm with concurrent functional magnetic resonance imaging (fMRI) scanning has previously revealed important neurobiological correlates of ADHD such as the supplementary motor area and the prefrontal cortex. The coordinate-based meta-analysis combined with quantitative techniques, such as activation likelihood estimate (ALE) generation, provides an unbiased and objective method of summarising these data to understand the brain network architecture and connectivity in ADHD children. Go/No-Go task-based fMRI studies involving children and adolescent subjects were selected. Coordinates indicating foci of activation were collected to generate ALEs using threshold values (voxel-level: p < 0.001; cluster-level: p < 0.05). ALEs were matched to one of seven canonical brain networks based on the cortical parcellation scheme derived from the Human Connectome Project. Fourteen studies involving 457 children met the eligibility criteria. No significant convergence of Go/No-Go related brain activation was found for ADHD groups. Three significant ALE clusters were detected for brain activation relating to controls or ADHD < controls. Significant clusters were related to specific areas of the default mode network (DMN). Network-based analysis revealed less extensive DMN, dorsal attention network, and limbic network activation in ADHD children compared to controls. The presence of significant ALE clusters may be due to reduced homogeneity in the selected sample demographic and experimental paradigm. Further investigations regarding hemispheric asymmetry in ADHD subjects would be beneficial.

David M. Holtzman and his team at the University of Washington School of Medicine have made breakthroughs in their research on neurodegenerative diseases. They discovered that the infiltration of T cells into the brain, instigated by activated microglia, is a critical factor in the progression of tauopathy. The groundbreaking findings were published in Nature on March 8, 2023. This research delineates a pivotal immune hub linked to tauopathy and neurodegeneration; a complex interplay involving activated microglia and T cell responses. This discovery could potentially become a target for developing therapeutic interventions for Alzheimer's disease and primary neurodegeneration.

Brain vascular inflammation is characterized by endothelial activation and immune cell recruitment to the blood vessel wall, potentially causing a breach in the blood - brain barrier, brain parenchyma inflammation, and a decline of cognitive function. The clinical-stage small molecule, apabetalone, reduces circulating vascular endothelial inflammation markers and improves cognitive scores in elderly patients by targeting epigenetic regulators of gene transcription, bromodomain and extraterminal proteins. However, the effect of apabetalone on cytokine-activated brain vascular endothelial cells (BMVECs) is unknown. Here, we show that apabetalone treatment of BMVECs reduces hallmarks of in vitro endothelial activation, including monocyte chemoattractant protein-1 (MCP-1) and RANTES chemokine secretion, cell surface expression of endothelial cell adhesion molecule VCAM-1, as well as endothelial capture of THP-1 monocytes in static and shear stress conditions. Apabetalone pretreatment of THP-1 downregulates cell surface expression of chemokine receptors CCR1, CCR2, and CCR5, and of the VCAM-1 cognate receptor, integrin α4. Consequently, apabetalone reduces THP-1 chemoattraction towards soluble CCR ligands MCP-1 and RANTES, and THP-1 adhesion to activated BMVECs. In a mouse model of brain inflammation, apabetalone counters lipopolysaccharide-induced transcription of endothelial and myeloid cell markers, consistent with decreased neuroendothelial inflammation. In conclusion, apabetalone decreases proinflammatory activation of brain endothelial cells and monocytes in vitro and in the mouse brain during systemic inflammation.

Hypoxic-ischemic encephalopathy (HIE) is a common neurological disorder characterized by ischemia and hypoxia in the perinatal period, which seriously affects the growth and development of newborns. To date, there is no specific drug for the treatment of HIE. Previous studies have shown that ferroptosis plays an important role in the pathogenesis of HIE. Carthamin yellow (CY) is believed to have antioxidant and anti-inflammatory effects. However, no studies have reported the role of CY in ferroptosis in HIE in vivo until now. The aim of this study was to investigate the effect and mechanism of CY on HIE in vivo and to provide an experimental basis for the clinical treatment of HIE. The results demonstrated that CY increased the expression of NeuN in the neonatal rat hypoxic-ischemic brain damage (HIBD) model. Further exploration revealed that CY increased the expression of glutathione peroxidase 4 and ferritin heavy chain 1 while it decreased the expression of PTGS2 and ACSL2. Moreover, CY decreased malondialdehyde expression and increased superoxide dismutase and glutathione expression in vivo. The findings also indicated that CY downregulated the expression of Nrf2 and Keap-1. In conclusion, this study demonstrated that CY attenuated brain injury in an experimental HIBD model, potentially by alleviating hippocampal neuronal ferroptosis through inhibition of the Nrf2/Keap-1 signaling pathway. These findings provide a novel therapeutic strategy for the clinical treatment of HIE.

C. and O. Vogt had set up a research program with the aim of establishing a detailed cartography of the medullary fiber distribution of the human brain. As part of this program, around 200 cortical fields were differentiated based on their myeloarchitectural characteristics and mapped with regard to their exact location in the isocortex. The typical features were graphically documented and classified by a sophisticated linguistic coding. Their results have only recently received adequate attention and applications. The reasons for the revival of this spectrum of their research include interest in the myeloarchitecture of the cortex as a differentiating feature of the cortex architecture and function, as well as the importance for advanced imaging methodologies, particularly tractography and molecular imaging. Here, we describe our approach to exploit the original work of the Vogts and their co-workers to construct a myeloarchitectonic map that is referenced to the Atlas of the Human Brain (AHB) in standard space. We developed a semi-automatic pipeline for processing and integrating the various original maps into a single coherent map. To optimize the precision of the registration between the published maps and the AHB, we augmented the maps with topographic landmarks of the brains that were originally analyzed. Registration of all maps into the AHB opened several possibilities. First, for the majority of the fields, multiple maps from different authors are available, which allows for sophisticated statistical integration, for example, unification with a label-fusion technique. Second, each field in the myeloarchitectonic surface map can be visualized on the myelin-stained cross-section of the AHB at the best possible correspondence. The features of each field can be correlated with the fiber-stained cross-sections in the AHB and with the extensive published materials from the Vogt school and, if necessary, corrected. Third, mapping to the AHB allows the relationship between fiber characteristics of the cortex and the subcortex to be examined. Fourth, the cytoarchitectonic maps from Brodmann and von Economo and Koskinas, which are also registered to the AHB, can be compared. This option allows the study of the correspondence between cyto- and myeloarchitecture in each field. Finally, by using our "stripe" technology - where any other feature registered to the same space can be directly compared owing to the linear and parallel representation of the correlated cortex segments - this map becomes part of a multidimensional co-registration platform.

Background and purpose: Headache attributed to craniotomy is an underestimated and under-treated condition. Previous studies confirmed the efficacy of preemptive analgesia with non-steroidal anti-inflammatory agents. The aim of the present work was to test the hypothesis of whether a single preoperatively administered dose of dexketoprofen (DEX) has the potency to decrease postcraniotomy headache (PCH) as compared to placebo (PL).

Patients and methods: This is a single-centre, randomized, PL-controlled trial comparing the effect of a single oral dose of 25 mg DEX to PL on the intensity of PCH. Patients undergoing craniotomy were randomly allocated to DEX and PL groups. Patients rated their actual and worst daily pain using visual analogue scale (VAS) scores during intrahospital treatment (0-5 days) and 30 and 90 days postoperatively.

Results: Two hundred patients were included. DEX decreased the worst daily pain intensity in the first 24 h only; the 5-days cumulative score of actual pain was 9.7 ± 7.9 cm for the DEX group and 12.6 ± 10.5 cm for the PL group, respectively (p = 0.03). This difference disappeared in the late, 30-, and 90-day follow-up period. No differences in VAS scores could be detected in supra- and infratentorial cases among the DEX and PL groups.

Conclusions: A single preoperative dose of 25 mg of DEX slightly decreases the intensity of PCH in the first 5 days after craniotomy but it does not have an effect on chronic headaches and postoperative analgesic requirements.

Neuroinflammation, a complex process involving the activation of microglia, astrocytes, and other immune cells in the brain, plays a role in neurodegeneration and psychiatric disorders. Current therapeutic strategies for neuroinflammation are limited, necessitating the development of improved approaches. Nanopharmacology offers unprecedented opportunities to access and treat neuroinflammatory disorders at the brain level. Nanoscaffolds can target specific cells or tissues and protect drugs from degradation or elimination, making them ideal candidates for treating neurodegenerative and psychiatric diseases. Recent advancements in nanoparticle development have enabled the targeting of microglia, astrocytes, and other immune cells in the brain, reducing neuroinflammation and protecting neurons from injury. Nanoparticles targeting specific neurons have also been developed. Clinical trials are in progress to evaluate the safety and efficacy of nano drugs for treating neuroinflammatory, neurodegenerative, and psychiatric diseases. The successful development of these nanodrugs holds immense promise for treating these devastating and increasingly prevalent conditions. On the other hand, several limitations and unanswered questions remain. First, the long-term effects of nanoparticles on the brain need to be thoroughly investigated to ensure their safety. Second, optimizing the targeting and delivery of nanoparticles to specific brain regions remains a challenge. Understanding the complex interplay between nanoparticles and the brain's immune system is crucial for developing effective nanotherapies. Despite these limitations, nanopharmacology presents a transformative approach to treating neuroinflammatory disorders. Future research should address the aforementioned limitations and further elucidate the mechanisms of nanoparticle-mediated therapy. The successful development of safe and effective nanodrugs can revolutionize the treatment of neuroinflammatory disorders, alleviating the suffering of millions.