Single-Cell Mapping of Brain Myeloid Cell Subsets Reveals Key Transcriptomic Changes Favoring Neuroplasticity after Ischemic Stroke / 神经科学通报·英文版

Interactions between brain-resident and peripheral infiltrated immune cells are thought to contribute to neuroplasticity after cerebral ischemia. However, conventional bulk sequencing makes it challenging to depict this complex immune network. Using single-cell RNA sequencing, we mapped compositional and transcriptional features of peri-infarct immune cells. Microglia were the predominant cell type in the peri-infarct region, displaying a more diverse activation pattern than the typical pro- and anti-inflammatory state, with axon tract-associated microglia (ATMs) being associated with neuronal regeneration. Trajectory inference suggested that infiltrated monocyte-derived macrophages (MDMs) exhibited a gradual fate trajectory transition to activated MDMs. Inter-cellular crosstalk between MDMs and microglia orchestrated anti-inflammatory and repair-promoting microglia phenotypes and promoted post-stroke neurogenesis, with SOX2 and related Akt/CREB signaling as the underlying mechanisms. This description of the brain's immune landscape and its relationship with neurogenesis provides new insight into promoting neural repair by regulating neuroinflammatory responses.

Establishment and characterization of bone marrow mesenchymal stem cell lines stably synthesizing high-level dopamine / 生物工程学报

A triple-transgenic (tyrosine hydroxylase/dopamine decarboxylase/GTP cyclohydrolase 1, TH/DDC/GCH1) bone marrow mesenchymal stem cell line (BMSCs) capable of stably synthesizing dopamine (DA) transmitters were established to provide experimental evidence for the clinical treatment of Parkinson's disease (PD) by using this cell line. The DA-BMSCs cell line that could stably synthesize and secrete DA transmitters was established by using the triple transgenic recombinant lentivirus. The triple transgenes (TH/DDC/GCH1) expression in DA-BMSCs was detected using reverse transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. Moreover, the secretion of DA was tested by enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography (HPLC). Chromosome G-banding analysis was used to detect the genetic stability of DA-BMSCs. Subsequently, the DA-BMSCs were stereotactically transplanted into the right medial forebrain bundle (MFB) of Parkinson's rat models to detect their survival and differentiation in the intracerebral microenvironment of PD rats. Apomorphine (APO)-induced rotation test was used to detect the improvement of motor dysfunction in PD rat models with cell transplantation. The TH, DDC and GCH1 were expressed stably and efficiently in the DA-BMSCs cell line, but not expressed in the normal rat BMSCs. The concentration of DA in the cell culture supernatant of the triple transgenic group (DA-BMSCs) and the LV-TH group was extremely significantly higher than that of the standard BMSCs control group (P < 0.000 1). After passage, DA-BMSCs stably produced DA. Karyotype G-banding analysis showed that the vast majority of DA-BMSCs maintained normal diploid karyotypes (94.5%). Moreover, after 4 weeks of transplantation into the brain of PD rats, DA-BMSCs significantly improved the movement disorder of PD rat models, survived in a large amount in the brain microenvironment, differentiated into TH-positive and GFAP-positive cells, and upregulated the DA level in the injured area of the brain. The triple-transgenic DA-BMSCs cell line that stably produced DA, survived in large numbers, and differentiated in the rat brain was successfully established, laying a foundation for the treatment of PD using engineered culture and transplantation of DA-BMSCs.

Tu-Xian Decoction ameliorates diabetic cognitive impairment by inhibiting DAPK-1 / 中国天然药物

Tu-Xian decoction (TXD), a traditional Chinese medicine (TCM) formula, has been frequently administered to manage diabetic cognitive impairment (DCI). Despite its widespread use, the mechanisms underlying TXD's protective effects on DCI have yet to be fully elucidated. As a significant regulator in neurodegenerative conditions, death-associated protein kinase-1 (DAPK-1) serves as a focus for understanding the action of TXD. This study was designed to whether TXD mediates its beneficial outcomes by inhibiting DAPK-1. To this end, a diabetic model was established using Sprague-Dawley (SD) rats through a high-fat, high-sugar (HFHS) diet regimen, followed by streptozotocin (STZ) injection. The experimental cohort was stratified into six groups: Control, Diabetic, TC-DAPK6, high-dose TXD, medium-dose TXD, and low-dose TXD groups. Following a 12-week treatment period, various assessments-including blood glucose levels, body weight measurements, Morris water maze (MWM) testing for cognitive function, brain magnetic resonance imaging (MRI), and histological analyses using hematoxylin-eosin (H&E), and Nissl staining-were conducted. Protein expression in the hippocampus was quantified through Western blotting analysis. The results revealed that TXD significantly improved spatial learning and memory abilities, and preserved hippocampal structure in diabetic rats. Importantly, TXD administration led to a down-regulation of proteins indicative of neurological damage and suppressed DAPK-1 activity within the hippocampal region. These results underscore TXD's potential in mitigating DCIvia DAPK-1 inhibition, positioning it as a viable therapeutic candidate for addressing this condition. Further investigation into TXD's molecular mechanisms may elucidate new pathways for the treatment of DCI.

The microbiota-gut-brain axis and neurodevelopmental disorders

The gut microbiota has been found to interact with the brain through the microbiota-gut-brain axis, regulating various physiological processes. In recent years, the impacts of the gut microbiota on neurodevelopment through this axis have been increasingly appreciated. The gut microbiota is commonly considered to regulate neurodevelopment through three pathways, the immune pathway, the neuronal pathway, and the endocrine/systemic pathway, with overlaps and crosstalks in between. Accumulating studies have identified the role of the microbiota-gut-brain axis in neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, and Rett Syndrome. Numerous researchers have examined the physiological and pathophysiological mechanisms influenced by the gut microbiota in neurodevelopmental disorders (NDDs). This review aims to provide a comprehensive overview of advancements in research pertaining to the microbiota-gut-brain axis in NDDs. Furthermore, we analyzed both the current state of research progress and discuss future perspectives in this field.

nNOS and Neurological, Neuropsychiatric Disorders: A 20-Year Story / 神经科学通报·英文版

In the central nervous system, nitric oxide (NO), a free gas with multitudinous bioactivities, is mainly produced from the oxidation of L-arginine by neuronal nitric oxide synthase (nNOS). In the past 20 years, the studies in our group and other laboratories have suggested a significant involvement of nNOS in a variety of neurological and neuropsychiatric disorders. In particular, the interactions between the PDZ domain of nNOS and its adaptor proteins, including post-synaptic density 95, the carboxy-terminal PDZ ligand of nNOS, and the serotonin transporter, significantly influence the subcellular localization and functions of nNOS in the brain. The nNOS-mediated protein-protein interactions provide new attractive targets and guide the discovery of therapeutic drugs for neurological and neuropsychiatric disorders. Here, we summarize the work on the roles of nNOS and its association with multiple adaptor proteins on neurological and neuropsychiatric disorders.

A Systematic Investigation of Complement and Coagulation-Related Protein in Autism Spectrum Disorder Using Multiple Reaction Monitoring Technology / 神经科学通报·英文版

Autism spectrum disorder (ASD) is one of the common neurodevelopmental disorders in children. Its etiology and pathogenesis are poorly understood. Previous studies have suggested potential changes in the complement and coagulation pathways in individuals with ASD. In this study, using multiple reactions monitoring proteomic technology, 16 of the 33 proteins involved in this pathway were identified as differentially-expressed proteins in plasma between children with ASD and controls. Among them, CFHR3, C4BPB, C4BPA, CFH, C9, SERPIND1, C8A, F9, and F11 were found to be altered in the plasma of children with ASD for the first time. SERPIND1 expression was positively correlated with the CARS score. Using the machine learning method, we obtained a panel composed of 12 differentially-expressed proteins with diagnostic potential for ASD. We also reviewed the proteins changed in this pathway in the brain and blood of patients with ASD. The complement and coagulation pathways may be activated in the peripheral blood of children with ASD and play a key role in the pathogenesis of ASD.

Neuroglobin Facilitates Neuronal Oxygenation through Tropic Migration under Hypoxia or Anemia in Rat: How Does the Brain Breathe? / 神经科学通报·英文版

The discovery of neuroglobin (Ngb), a brain- or neuron-specific member of the hemoglobin family, has revolutionized our understanding of brain oxygen metabolism. Currently, how Ngb plays such a role remains far from clear. Here, we report a novel mechanism by which Ngb might facilitate neuronal oxygenation upon hypoxia or anemia. We found that Ngb was present in, co-localized to, and co-migrated with mitochondria in the cell body and neurites of neurons. Hypoxia induced a sudden and prominent migration of Ngb towards the cytoplasmic membrane (CM) or cell surface in living neurons, and this was accompanied by the mitochondria. In vivo, hypotonic and anemic hypoxia induced a reversible Ngb migration toward the CM in cerebral cortical neurons in rat brains but did not alter the expression level of Ngb or its cytoplasm/mitochondria ratio. Knock-down of Ngb by RNA interference significantly diminished respiratory succinate dehydrogenase (SDH) and ATPase activity in neuronal N2a cells. Over-expression of Ngb enhanced SDH activity in N2a cells upon hypoxia. Mutation of Ngb at its oxygen-binding site (His64) significantly increased SDH activity and reduced ATPase activity in N2a cells. Taken together, Ngb was physically and functionally linked to mitochondria. In response to an insufficient oxygen supply, Ngb migrated towards the source of oxygen to facilitate neuronal oxygenation. This novel mechanism of neuronal respiration provides new insights into the understanding and treatment of neurological diseases such as stroke and Alzheimer's disease and diseases that cause hypoxia in the brain such as anemia.

Identification of de novo Mutations in the Chinese Autism Spectrum Disorder Cohort via Whole-Exome Sequencing Unveils Brain Regions Implicated in Autism / 神经科学通报·英文版

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.

WDR62-deficiency Causes Autism-like Behaviors Independent of Microcephaly in Mice / 神经科学通报·英文版

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.

Role of the Voltage-Gated Proton Channel Hv1 in Nervous Systems / 神经科学通报·英文版

Hv1 is the only voltage-gated proton-selective channel in mammalian cells. It contains a conserved voltage-sensor domain, shared by a large class of voltage-gated ion channels, but lacks a pore domain. Its primary role is to extrude protons from the cytoplasm upon pH reduction and membrane depolarization. The best-known function of Hv1 is the regulation of cytosolic pH and the nicotinamide adenine dinucleotide phosphate oxidase-dependent production of reactive oxygen species. Accumulating evidence indicates that Hv1 is expressed in nervous systems, in addition to immune cells and others. Here, we summarize the molecular properties, distribution, and physiological functions of Hv1 in the peripheral and central nervous systems. We describe the recently discovered functions of Hv1 in various neurological diseases, including brain or spinal cord injury, ischemic stroke, demyelinating diseases, and pain. We also summarize the current advances in the discovery and application of Hv1-targeted small molecules in neurological diseases. Finally, we discuss the current limitations of our understanding of Hv1 and suggest future research directions.

Artesunate alleviates hypoxic-ischemic brain damage in neonatal rats by inhibiting NLRP3 inflammasome activation and inflammatory cytokine secretion / 细胞与分子免疫学杂志

Objective To investigate the protective effect of artesunate on hypoxic-ischemic brain damage (HIBD) and its mechanism in neonatal rats. Methods 7-day-old neonatal SD rats were randomly divided into sham operation group, model group, artesunate 5 mg/kg group, artesunate 10 mg/kg group, artesunate 20 mg/kg group and dexamethasone 6 mg/kg group, with 18 rats in each group. HIBD models were established in groups except for the sham operation group. The sham operation group only needed to separate the left common carotid artery without ligation and nitrogen-oxygen mixed gas ventilation. Each group was injected with drug intraperitoneally right after surgery and the rats in the sham operation group and the model group were injected with an equal volume of normal saline (once a day for a total of 5 times). One hour after the last injection, the rats in each group were scored for neurological defects. After the rats were sacrificed, the brain water content was measured and the pathological changes of the brain tissues of rats were observed. Terminal-deoxynucleotidyl transferase mediated nick end labeling (TUNEL) was used to detect the neuronal cell apoptosis, and ELISA was applied to detect the levels of IL-1β, IL-6 and TNF-α in brain tissues and peripheral blood of each group of rats. Western blot analysis was adopted to detect the protein expression levels of NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 in the rats brain tissues of each group. Results Compared with the model group, the neurological deficit score was decreased; the pathological damage of brain tissues was relieved; the brain water content was significantly reduced; the apoptosis number of hippocampal neurons was decreased significantly; the levels of IL-1β, IL-6 and TNF-α in brain tissues and peripheral blood were significantly reduced; the protein expression levels of NLRP3, ASC and caspase-1 were significantly lowered in the middle-dose and high-dose artesunate groups and the dexamethasone group. Conclusion Artesunate can improve the neurological function, relieve the brain damage, and alleviate the brain edema in neonatal rats with HIBD. It can protect the HIBD, which may be related to the inhibition of NLRP3 inflammasome activation and reduction of inflammatory cytokine secretion.

Resolving the lineage relationship between malignant cells and vascular cells in glioblastomas

Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.

Discovery and confirmation of protein action site AK1 of ginsenosides in brain based on DARTS technology / 中国中药杂志

This study aims to explore the targets of ginsenosides in brain based on drug affinity responsive target stability(DARTS) technology. Specifically, DARTS technology was combined with label-free liquid chromatography tandem mass spectrometry(LC-MS) to screen out the proteins in the brain that might interact with ginsenosides. Based on the screening results, adenylate kinase 1(AK1) was selected for further confirmation. First, the His-AK1 fusion protein was yielded successively through the construction of recombinant prokaryotic expression vector, expression of target protein, and purification of the fusion protein. Biolayer interferometry(BLI) was employed to detect the direct interaction of Rg_1, Re, Rb_1, Rd, Rh_2, F1, Rh_1, compound K(CK), 25-OH-PPD, protopanaxa-diol(PPD), and protopanaxatriol(PPT) with AK1, thereby screening the ginsenoside monomer or sapogenin that had strong direct interaction with the suspected target protein AK1. Then, the BLI was used to further determine the kinetic parameters for the binding of PPD(strongest interaction with AK1) to His-AK1 fusion protein. Finally, molecular docking technology was applied to analyze the binding properties between the two. With DARTS and LC-MS, multiple differential proteins were screened out, and AK1 was selected based on previous research for target verification. Fusion protein His-AK1 was obtained by prokaryotic expression, and the response(nm) of Re, Rg_1, Rd, Rb_1, Rh_1, Rh_2, F1, PPT, PPD, 25-OH-PPD, and CK with His-AK1 was respectively 0.003 1, 0.001 9, 0.042 8, 0.022 2, 0.013 4, 0.037 3, 0.013 9, 0.030 7, 0.140 2, 0.016 0, and 0.040 8. The K_(on), K_(off), and K_D values of PPD and His-AK1 were determined by the BLI as 1.22×10~2 mol~(-1)·L·s~(-1), 1.04×10~(-2) s~(-1), 8.52×10~(-5) mol·L~(-1). According to the molecular docking result, PPD bound to AK1 with the absolute value of the docking score of 3.438, and hydrogen bonds mainly formed between the two. Thus, AK1 is one of the protein action sites of ginsenosides in the brain. The direct interaction between ginsenoside metabolite PPD and AK1 is the strongest.

Expert Consensus on the Treatment of Antiangiogenic Agents for Radiation Brain Necrosis / 中国肺癌杂志

Vascular damage is followed by vascular endothelial growth factor (VEGF) expression at high levels, which is an important mechanism for cerebral radiation necrosis (CRN) development. Antiangiogenic agents (Bevacizumab) alleviates brain edema symptoms caused by CRN through inhibiting VEGF and acting on vascular tissue around the brain necrosis area. Many studies have confirmed that Bevacizumab effectively relieves symptoms caused by brain necrosis, improves patients' performance status and brain necrosis imaging. Considering that the efficacy of antiangiogenic therapy is mainly related to the duration of drug action, low-dose antiangiogenic agents can achieve favorable efficacy. Prevention is the best treatment. The occurrence of CRN is associated with tumor-related factors and treatment-related factors. By controlling these factors, CRN can be effectively prevented.
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The hypothalamus for whole-body physiology: from metabolism to aging

Obesity and aging are two important epidemic factors for metabolic syndrome and many other health issues, which contribute to devastating diseases such as cardiovascular diseases, stroke and cancers. The brain plays a central role in controlling metabolic physiology in that it integrates information from other metabolic organs, sends regulatory projections and orchestrates the whole-body function. Emerging studies suggest that brain dysfunction in sensing various internal cues or processing external cues may have profound effects on metabolic and other physiological functions. This review highlights brain dysfunction linked to genetic mutations, sex, brain inflammation, microbiota, stress as causes for whole-body pathophysiology, arguing brain dysfunction as a root cause for the epidemic of aging and obesity-related disorders. We also speculate key issues that need to be addressed on how to reveal relevant brain dysfunction that underlines the development of these disorders and diseases in order to develop new treatment strategies against these health problems.

Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebral β-amyloid deposition and brain atrophy / 中华医学杂志(英文版)

BACKGROUND@#Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease (AD). However, there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology. We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.@*METHODS@#We enrolled a group of cognitively normal patients (median age: 64 years) with unilateral chronic cerebral hypoperfusion. Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion. 11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.@*RESULTS@#The median age of the 10 participants, consisting of 4 males and 6 females, was 64 years (47-76 years). We found that there were no differences in standard uptake ratios of the cortex (volume of interest [VOI]: P = 0.721, region of interest [ROI]: P = 0.241) and grey/white ratio (VOI: P = 0.333, ROI: P = 0.445) and brain atrophy indices (Bicaudate, Bifrontal, Evans, Cella, Cella media, and Ventricular index, P > 0.05) between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.@*CONCLUSION@#Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebral β-amyloid deposition and neurodegeneration in humans.

Different expressions of AQP1 and AQP4 in hyponatremic rat brain / Diferentes expresiones de AQP1 y AQP4 en cerebro de rata hiponatrémico

SUMMARY: The expression of aquaporin-1 (AQP1) in choroid plexus and aquaporin-4 (AQP4) in astrocyte of the hippocampal formation (HF) was studied in the rat to determine the role of AQP1 and AQP4 in the pathophysiology of systemic hyponatremia (SH). SH was induced by coadministration of dextrose solution intraperitoneally and through subcutaneous implantation of an osmotic minipump containing 8-deamino-arginin vasopressin (50ng/µl/h) for 24 and 48 h. Twenty- four and 48 h after the drug administration, there were significant reductions in Na+ concentration (111 ± 5 and 104 ± 2 mmol) and serum osmolarity (240 ± 13 and 221 ± 14 mOsm/L) as compared with control values (140 ± 4.7 mmol and 296 ± 5.2 mOsm/L), (p<0.01). The expression of AQP1 in the choroid plexus was increased three to five times from 24 h to 48 h after SH (329.86 ± 10.2 % and 531.5 ± 4.4 %, n=4, p<0.01). In contrast, AQP4 expression was significantly decreased up to 48 h after SH (36 ± 9 %, n=4, p<0.01). Quantitative immunoblotting revealed significant decreases of neuronal proteins in the HF after 24 to 48 h of SH. Therefore, we suggest that altered expression of AQP1 and AQP4 plays important role in the pathogenesis of systemic hyponatremia.

RESUMEN: En este análisis se estudió la expresión de acuaporina-1 (AQP1) en plexo coroideo y acuaporina-4 (AQP4) en astrocitos de la formación hipocampal (FH) en ratas para determinar el papel de AQP1 y AQP4 en la fisiopatología de la hiponatremia sistémica (HS). La HS fue inducida mediante la coadministración de solución de dextrosa por vía intraperitoneal y mediante la implantación subcutánea de una minibomba osmótica que contenía vasopresina 8-desaminoarginina (50 ng /µ l / h) durante 24 y 48 h. Veinticuatro y 48 h después de la administración del fármaco, hubo reducciones significativas en la concentración de Na + (111 ± 5 y 104 ± 2 mmol) y la osmolaridad sérica (240 ± 13 y 221 ± 14 mOsm /µL) en comparación con los valores de control (140 ± 4,7 mmol y 296 ± 5,2 mOsm / L), (p <0,01). La expresión de AQP1 en el plexo coroideo se incrementó de tres a cinco veces de 24 a 48 h después de HS (329,86 ± 10,2 % y 531,5 ± 4,4 %, n = 4, p <0,01). Por el contrario, la expresión de AQP4 se redujo significativamente hasta 48 h después de HS (36 ± 9 %, n = 4, p <0,01). La inmunotransferencia cuantitativa reveló disminuciones significativas de proteínas neuronales en el FH después de 24 a 48 h de SH. Por lo tanto, sugerimos que la expresión alterada de AQP1 y AQP4 juega un papel importante en la patogénesis de la hiponatremia sistémica.

Blood-cerebrospinal fluid (CSF) barrier dysfunction means reduced CSF flow not barrier leakage - conclusions from CSF protein data / Disfunção da barreira hemato-liquórica significa redução do fluxo de líquido cefalorraquidiano, e não quebra de barreira - conclusões a partir de estudos sobre as proteínas do LCR

ABSTRACT Background: Increased concentrations of serum proteins in cerebrospinal fluid (CSF) are interpreted as blood-CSF barrier dysfunction. Frequently used interpretations such as barrier leakage, disruption or breakdown contradict CSF protein data, which suggest a reduced CSF flow rate as the cause. Results: Even the severest barrier dysfunctions do not change the molecular size-dependent selectivity or the interindividual variation of the protein transfer across barriers. Serum protein concentrations in lumbar CSF increase with hyperbolic functions, but the levels of proteins that do not pass the barrier remain constant (brain proteins) or increase linearly (leptomeningal proteins). All CSF protein dynamics above and below a lumbar blockade can also be explained, independent of their barrier passage, by a reduced caudally directed flow. Local accumulation of gadolinium in multiple sclerosis (MS) is now understood as due to reduced bulk flow elimination by interstitial fluid (ISF). Nonlinear change of the steady state in barrier dysfunction and along normal rostro-caudal gradients supports the diffusion/flow model and contradicts obstructions of diffusion pathways. Regardless of the cause of the disease, pathophysiological flow blockages are found in bacterial meningitis, leukemia, meningeal carcinomatosis, Guillain-Barré syndrome, MS and experimental allergic encephalomyelitis. In humans, the fortyfold higher albumin concentrations in early fetal development decrease later with maturation of the arachnoid villi, i.e., with beginning CSF outflow, which contradicts a relevant outflow to the lymphatic system. Respiration- and heartbeat-dependent oscillations do not disturb net direction of CSF flow. Conclusion: Blood-CSF and blood-brain barrier dysfunctions are an expression of reduced CSF or ISF flow rate.

RESUMO Introdução: Concentrações aumentadas de proteínas séricas no líquido cefalorraquidiano são interpretadas como disfunção da barreira (hemato-liquórica) sanguínea do LCR. Interpretações frequentemente usadas, como vazamento de barreira (quebra ou rompimento de barreira), rompimento ou quebra, contradiz os dados de proteína do LCR, que sugerem uma taxa de fluxo reduzida do LCR como a causa. Resultados: Mesmo as disfunções de barreira mais graves não alteram a seletividade dependente do tamanho molecular nem a variação interindividual da transferência de proteína através de barreiras. As concentrações de proteínas séricas no LCR lombar aumentam com as funções hiperbólicas, mas as proteínas que não passam a barreira permanecem constantes (proteínas do cérebro) ou aumentam linearmente (proteínas leptomeningeais). Toda a dinâmica das proteínas do LCR acima e abaixo de um bloqueio lombar também pode ser explicada, independente de sua passagem pela barreira, por um fluxo caudal reduzido. O acúmulo local de gadolínio na esclerose múltipla (EM) é agora entendido como decorrente da redução da eliminação do bulk flow pelo fluido intersticial (FIS). A mudança não linear do estado estacionário na disfunção da barreira e ao longo dos gradientes rostro-caudais normais apoia o modelo de difusão/fluxo e contradiz as obstruções das vias de difusão. Independentemente da causa da doença, os bloqueios fisiopatológicos do fluxo são encontrados na meningite bacteriana, leucemia, carcinomatose meníngea, síndrome de Guillain-Barré, EM e encefalomielite alérgica experimental. Em humanos, as concentrações de albumina quarenta vezes mais altas no desenvolvimento fetal inicial diminuem tarde com a maturação das vilosidades aracnoides, isto é, com o início do fluxo de LCR, o que contradiz um fluxo relevante para o sistema linfático. As oscilações dependentes da respiração e do batimento cardíaco não perturbam a direção do fluxo do LCR. Conclusão: As disfunções das barreiras hemato-liquórica e hemato-encefálica são uma expressão da redução da taxa de fluxo do LCR ou FIS.

Protective effects of active compounds from on heart and brain of mice at simulated high altitude / 浙江大学学报·医学版

To investigate the active compounds from on the heart and brain of mice at simulated high altitude.Fifty healthy male adult BALB/c mice were randomly divided into normal control group, hypoxic model group, acetazolamide group, petroleum ether extract of (PESI) group and octacosan group with 10 mice in each group. Acetazolamide group, PESI group and octacosan group were treated with acetazolamide PESI (200 mg/kg) or octacosan by single tail vein injection, respectively. Except normal control group, the mice were exposed to a simulated high altitude of for in an animal decompression chamber. After the mice were sacrificed by cervical dislocation, the heart and brain were histologically observed by HE staining; superoxide dismutase (SOD) activity, total anti-oxidant capacity (T-AOC) and the content of malondialdehyde (MDA) in plasma, heart and brain tissues were detected by WST-1 method, ABTS method and TBA method, respectively; lactic acid and lactate dehydrogenase (LDH) activity in plasma, heart and brain tissues were detected by colorimetric method and microwell plate method, respectively; ATP content and ATPase activity in heart and brain tissues were detected by colorimetric method. PESI and octacosane significantly attenuated the pathological damages of heart and brain tissue at simulated high altitude; increased SOD activity, T-AOC and LDH activity, and decreased the contents of MDA and lactic acid in plasma, heart and brain tissues; increased the content of ATP in heart and brain tissues; increased the activities of Na-K ATPase, Mg ATPase, Ca ATPase and Ca-Mg ATPase in myocardial tissue; and increased the activities of Mg ATPase, Ca-Mg ATPase in brain tissue. PESI and octacosan exert anti-hypoxic activity by improving the antioxidant capacity, reducing the free radical levels, promoting the anaerobic fermentation, and alleviating the energy deficiency and metabolic disorders caused by hypoxia in mice.