Glucose-targeted niosomes deliver vasoactive intestinal peptide (VIP) to the brain

The aim of this study was to evaluate glucose-bearing niosomes as a brain targeted delivery system for the vasoactive intestinal peptide (VIP). To this end, VIP/125I-VIP-loaded glucose-bearing niosomes were intravenously injected to mice. Brain uptake was determined by measuring the radioactivity of 125I-labeled VIP using gamma-counting, after intravenous administration of VIP in solution or encapsulated in glucose-bearing niosomes or in control niosomes. VIP integrity was assessed by reversed-phase HPLC analysis of brain extracts. Distribution of 125I-VIP derived radioactivity was examined from serial brain slices. HPLC analysis confirmed the presence of intact VIP in brain after administration of VIP-loaded niosomes, but not after administration of VIP solution. Encapsulation within glucose-bearing niosomes mainly allowed a significantly higher VIP brain uptake compared to control niosomes (up to 86%, 5min after treatment). Brain distribution of intact VIP after injection of glucose-bearing niosomes, indicated that radioactivity was preferentially located in the posterior and the anterior parts of the brain, whereas it was homogeneously distributed in the whole brain after the administration of control vesicles. In conclusion, this novel vesicular formulation of VIP delivers intact VIP to particular brain regions in mice. Glucose-bearing vesicles might be therefore a novel tool to deliver drugs across the blood-brain barrier (BBB)

Global Transcriptional Programs in Peripheral Nerve Endoneurium and DRG Are Resistant to the Onset of Type 1 Diabetic Neuropathy in Ins2Akita/+ Mice

While the morphological and electrophysiological changes underlying diabetic peripheral neuropathy (DPN) are relatively well described, the involved molecular mechanisms remain poorly understood. In this study, we investigated whether phenotypic changes associated with early DPN are correlated with transcriptional alterations in the neuronal (dorsal root ganglia [DRG]) or the glial (endoneurium) compartments of the peripheral nerve. We used Ins2Akita/+ mice to study transcriptional changes underlying the onset of DPN in type 1 diabetes mellitus (DM). Weight, blood glucose and motor nerve conduction velocity (MNCV) were measured in Ins2Akita/+ and control mice during the first three months of life in order to determine the onset of DPN. Based on this phenotypic characterization, we performed gene expression profiling using sciatic nerve endoneurium and DRG isolated from pre-symptomatic and early symptomatic Ins2Akita/+ mice and sex-matched littermate controls. Our phenotypic analysis of Ins2Akita/+ mice revealed that DPN, as measured by reduced MNCV, is detectable in affected animals already one week after the onset of hyperglycemia. Surprisingly, the onset of DPN was not associated with any major persistent changes in gene expression profiles in either sciatic nerve endoneurium or DRG. Our data thus demonstrated that the transcriptional programs in both endoneurial and neuronal compartments of the peripheral nerve are relatively resistant to the onset of hyperglycemia and hypoinsulinemia suggesting that either minor transcriptional alterations or changes on the proteomic level are responsible for the functional deficits associated with the onset of DPN in type 1 DM

Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions

Hippocampal CA3 Transcriptome Signature Correlates with Initial Precipitating Injury in Refractory Mesial Temporal Lobe Epilepsy

Background: Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). in order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal Findings: DNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/Significance: CA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions

Current technical approaches to brain energy metabolism

Neuroscience is a technology‐driven discipline and brain energy metabolism is no exception. Once satisfied with mapping metabolic pathways at organ level, we are now looking to learn what it is exactly that metabolic enzymes and transporters do and when, where do they reside, how are they regulated, and how do they relate to the specific functions of neurons, glial cells, and their subcellular domains and organelles, in different areas of the brain. Moreover, we aim to quantify the fluxes of metabolites within and between cells. Energy metabolism is not just a necessity for proper cell function and viability but plays specific roles in higher brain functions such as memory processing and behavior, whose mechanisms need to be understood at all hierarchical levels, from isolated proteins to whole subjects, in both health and disease. To this aim, the field takes advantage of diverse disciplines including anatomy, histology, physiology, biochemistry, bioenergetics, cellular biology, molecular biology, developmental biology, neurology, and mathematical modeling. This article presents a well‐referenced synopsis of the technical side of brain energy metabolism research. Detail and jargon are avoided whenever possible and emphasis is given to comparative strengths, limitations, and weaknesses, information that is often not available in regular articles.Fondecyt, Grant Number: 1160317; MINECO, Grant Numbers: SAF2016‐78114‐R and RTC‐2015‐3237‐1; CIBERFES, Grant Numer: CB16/10/00282; SP3‐People‐MC‐ITN program, Grant Number: 608381; EU BATCure, Grant Number: 666918; FEDER (European regional development fund); Investissement d'Avenir, Grant Number: ANR‐11‐INBS‐0011; French State in the context of the “Investments for the future” Program IdEx and the LabEx TRAIL, Grant Numbers: ANR‐10‐IDEX and ANR‐10‐LABX‐57; French–Swiss ANR‐FNS, Grant Numer: ANR‐15‐ CE37‐0012. University of Nottingham; BBSRC, Grant Numers: BB/L019396/1 and BB/K009192/1; MRC, Grant Number: MR/L020661/1; Deutsche Forschungsgemeinschaft, Grant Numers: DFG SPP 1757, SFB 894, and FOR 2289; European Commission, Grant Number: H2020‐FETPROACT 732344; Neurofibres, Grant Number: H2020‐MSCA‐ITN‐722053 EU‐GliaPhD; US National Institutes of Health, Grant Number: R01NS087611; Teva Pharmaceuticals; Agilent Technologies. IdEx, Grant Number: ANR‐10‐IDEX‐03‐02; French–Swiss ANR‐FNS, Grant number: 310030E‐164271; National Institutes of Neurologic Disease and Stroke at the National Institutes of Health, Grant Numer: R01 NS077773; University of Zurich and the Swiss National Science Foundation; Comisión Nacional de Investigación Científica y Tecnológica, Grant Numer: PB 01; Fondo Nacional de Desarrollo Científico y Tecnológico, Grant Numer: 1160317; Ministerio de Economía y Competitividad, Grant Numer: RTC‐2015‐3237‐1,SAF2016‐78114‐R; Agence Nationale de la Recherche, Grant Numers: ANR‐10‐IDEX, ANR‐10‐IDEX‐03‐02, ANR‐10‐LABX‐57, ANR‐11‐INBS‐0011, and ANR‐15‐ CE37‐0012; Biotechnology and Biological Sciences Research Council, Grant Numers: BB/L019396/1 and BB/K009192/1; Medical Research Council, Grant Numer: MR/L020661/1.Peer reviewe

Glucose pathways adaptation supports acquisition of activated microglia phenotype

With its capacity to survey the environment and phagocyte debris, microglia assume a diversity of phenotypes to respond specifically through neurotrophic and toxic effects. Although these roles are well accepted, the underlying energetic mechanisms associated with microglial activation remain largely unclear. This study investigates microglia metabolic adaptation to ATP, NADPH, H(+) , and reactive oxygen species production. To this end, in vitro studies were performed with BV-2 cells before and after activation with lipopolysaccharide + interferon-γ. Nitric oxide (NO) was measured as a marker of cell activation. Our results show that microglial activation triggers a metabolic reprogramming based on an increased glucose uptake and a strengthening of anaerobic glycolysis, as well as of the pentose pathway oxidative branch, while retaining the mitochondrial activity. Based on this energy commitment, microglial defense capacity increases rapidly as well as ribose-5-phosphate and nucleic acid formation for gene transcription, essential to ensure the newly acquired functions demanded by central nervous system signaling. We also review the role of NO in this microglial energy commitment that positions cytotoxic microglia within the energetics of the astrocyte-neuron lactate shuttle