Neuronal Cell Proliferation Research Articles

Neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: applicability to Parkinson's disease

Ethnopharmacology relevanceAyahuasca is a tea produced through decoction of Amazonian plants. It has been used for centuries by indigenous people of South America. The beverage is considered to be an ethnomedicine, and it is traditionally used for the treatment of a wide range of diseases, including neurological illness. Besides, some scientific evidence suggests it may be applicable to Parkinson's disease (PD) treatment. Thus, Ayahuasca deserves in depth studies to clarify its potential role in this disease. Aim of the studyThis study aimed to use an untargeted metabolomics approach to evaluate the neuroprotective potential of the Ayahuasca beverage, the extracts from its matrix plants (Banisteriopsis caapi and Psychotria viridis), its fractions and its main alkaloids on the viability of SH-SY5Y neuroblastoma cells in an in vitro PD model. Material and methodsThe cytotoxicity of Ayahuasca, crude extracts, and fractions of B. caapi and P. viridis, as well as neuroprotection promoted by these samples in a 6-hydroxydopamine (6-OHDA)-induced neurodegeneration model, were evaluated by the MTT assay at two time-points: 48 h (T1) and 72 h (T2). The main alkaloids from Ayahuasca matrix plants, harmine (HRE) and N,N-dimethyltryptamine (DMT), were also isolated and evaluated. An untargeted metabolomics approach was developed to explore the chemical composition of samples with neuroprotective activity. Ultra-Performance Liquid Chromatography coupled to Electrospray Ionisation and Time-of-Flight (UPLC-ESI-TOF) metabolome data was treated and further analysed using multivariate statistical analyses (MSA): principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The metabolites were dereplicated using the Dictionary of Natural Products and an in house database. The main alkaloids were also quantified by UPLC-MS/MS. ResultsThe samples did not cause cytotoxicity in vitro and three of samples intensely increased cell viability at T1. The crude extracts, alkaloid fractions and HRE demonstrated remarkable neuroprotective effect at T2 while the hydroalcoholic fractions demonstrated this neuroprotective effect at T1 and T2. Several compounds from different classes, such as β-carbolines and monoterpene indole alkaloids (MIAs) were revealed correlated with this property by MSA. Additionally, a total of 2419 compounds were detected in both ionisation modes. HRE showed potent neuroprotective action at 72 h, but it was not among the metabolites positively correlated with the most efficacious neuroprotective profile at either time (T1 and T2). Furthermore, DMT was statistically important to differentiate the dataset (VIP value > 1), although it did not exhibit sufficient neuroprotective activity by in vitro assay, neither a positive correlation with T1 and T2 neuroprotective profile, which corroborated the MSA results. ConclusionThe lower doses of the active samples stimulated neuronal cell proliferation and/or displayed the most efficacious neuroprotection profile, namely by preventing neuronal damage and improving cell viability against 6-OHDA-induced toxicity. Intriguingly, the hydroalcoholic fractions exhibited enhanced neuroprotective effects when compared to other samples and isolated alkaloids. This finding corroborates the significance of a holistic approach. The results demonstrate that Ayahuasca and its base plants have potential applicability for PD treatment and to prevent its progression differently from current drugs to treat PD.

The Requirement of Sox2 for the Spinal Cord Motor Neuron Development of Zebrafish.

Sex-determining region Y box 2 (Sox2), expressed in neural tissues, plays an important role as a transcription factor not only in the pluripotency and proliferation of neuronal cells but also in the opposite function of cell differentiation. Nevertheless, how Sox2 is linked to motor neuron development remains unknown. Here, we showed that Sox2 was localized in the motor neurons of spinal cord by in situ hybridization and cell separation, which acted as a positive regulator of motor neuron development. The deficiency of Sox2 in zebrafish larvae resulted in abnormal PMN development, including truncated but excessively branched CaP axons, loss of MiP, and increase of undifferentiated neuron cells. Importantly, transcriptome analysis showed that Sox2-depleted embryos caused many neurogenesis, axonogenesis, axon guidance, and differentiation-related gene expression changes, which further support the vital function of Sox2 in motor neuron development. Taken together, these data indicate that Sox2 plays a crucial role in the motor neuron development by regulating neuron differentiation and morphology of neuron axons.

Mature silkworm powders ameliorated scopolamine-induced amnesia by enhancing mitochondrial functions in the brains of mice

Abstract The main goal of this study was to elucidate the neuron proliferation and cognition improvement effects of steamed and freeze-dried mature silkworm powders (SMSP). Concentrates of 80% methanol extracts from golden silk-SMSP (GS-SMSP) contained 3.6–4.9 times more phytochemicals and 1.8–3.1 times more antioxidant activities and showed significantly higher mouse hippocampal HT22 neuronal cell proliferation effects than those of white jade (WJ)-SMSP. In addition, GS-SMSP was more effective in suppressing scopolamine (SCO)-induced amnesia in the mice than WJ-SMSP. Furthermore, the suppression of SCO-induced amnesia by GS-SMSP in the mice was dose-dependent. The significantly reduced mitochondrial respiratory complex (MitoCom) activities and ATP amounts in the brains of SCO-injected mice were recovered in the mice supplemented with GS-SMSP. Taken together, the results of this study indicate that enhanced mitochondrial function in the brains of mice supplemented with GS-SMSP was the molecular basis of suppression of SCO-induced amnesia in a rodent model.

Controlling Neuronal Cell Growth through Composite Laminin Supramolecular Hydrogels

Designing an extracellular matrix mimic by biofunctionalization of polymeric scaffolds is a popular strategy and extremely crucial for facilitating the interactions between cells and the matrix. To this direction, supramolecular gels are gaining exponential attention over the last few years, owing to their potential biocompatibility and biodegradability. In spite of diverse biological roles of native laminin, the bioactivities of self-assembling laminin-derived short peptides were less explored. In this work, we have explored the minimalist design to develop hydrogel scaffolds based on IKVAV and YIGSR peptides individually and their composite matrix, which can provide structurally and functionally relevant materials for tissue engineering. Till date, composite supramolecular gels solely made up of self-assembling IKVAV and YIGSR peptides have never been reported. Such composite gels can be a closer mimic of natural laminin protein, which could mimic the essential functions of the short peptide fragments present on different chains of the extracellular matrix protein, laminin. Interestingly, we used a unique strategy of simple mixing of the two laminin mimetic peptides, which tend to induce coassembly with a self-sorted nanofibrous network with relatively enhanced mechanical strength. The physicochemical properties of the biofunctional hydrogels were studied using different microscopic, spectroscopic, and rheology techniques. To assess the bioactivity of laminin-derived scaffolds in controlling neuronal cell growth, its biocompatibility, cellular growth, and proliferation were quantified using C6 glial cells and SHSY5Y neuroblastoma cells. The live/dead staining further confirmed the adhesion and proliferation of the cells. A significant increase in neurite length provides clear evidence on mimicking the neurite extension function of native laminin protein by its short derivatives. Interestingly, similar β-III tubulin expression and cell cycle phases were observed, in comparison to control, which indicated normal cellular functioning of the cells cultured over short laminin hydrogel scaffolds. All bioassays suggested that Fmoc YIGSR promotes growth of neural cells to a greater extent and maintains healthier morphology, in comparison to hydrophobic Fmoc IKVAV, owing to the entangled longer fibrous network formed by YIGSR peptide. It is expected that thinner long fibers provide a more uniform surface and are more supportive for cell adhesion in comparison to hydrophobic, shorter fibers IKVAV peptide. However, in composite gels, the detrimental effect of hydrophobic IKVAV peptide could be reduced and better adhesion and proliferation could be achieved along with enhanced cell survival. These observations demonstrate the high potential of the laminin-derived hydrogels in tissue engineering and neuronal stem cell differentiation in future.

Penetrative needling of scalp-points improves neurological function by promoting stem cell proli-feration and activating Shh/Gil1 signaling in intracerebral hemorrhage rats

To observe the effect of penetrative needling from "Baihui" (GV20) to "Qubin" (GB7) on neural stem cell proliferation and sonic hedgehog (Shh) signaling in subventricular zone (SVZ) in intracerebral hemorrhage (ICH) rats so as to explore its mechanisms underlying improvement of ischemic injury of brain. Male SD rats were randomly divided into blank control, model, acupuncture and agonist (Purmorphamine, an activator of Shh signaling pathway) groups (n＝18 in each group, 6 for H．E. stain, 6 for examining neuronal cell proliferation, and 6 for immunohistochemistry). The ICH model was established by injecting autogenous blood (50 µL) into the right caudate nucleus. The neurological defect was scored with refe-rence to Bederson's method. Penetrative needling from GV20 to GB7 was performed by manipulating the needle for 6 min (repeated 3 times in 30 min), once daily for 7 days. Intraperitoneal injection of Purmorphamine (1 mg/mL, 1 mg/kg) was performed, once daily for 7 days. Histopathological changes of the hemorrhagic penumbra region were observed under microscope after H．E. stain, the newborn neural stem cell proliferation (BrdU＋/Nestin＋ double labeled cells) in the SVZ was observed by immunofluorescence after intraperitoneal injection of BrdU (50 mg/kg), and the expression of Shh and glioma-associated hemolog-1 (Gli1) detected by immunohistochemistry. After modeling, the neurological score and expression levels of Shh and Gil1 proteins were significantly increased in the model group relevant to the blank control group (P<0.001). Following the interventions, the neurological score was evidently decreased (P<0.05), while the number of BrdU＋/Nestin＋ double labeled cells and the expression levels of Shh and Gil1 proteins were significantly increased in both acupuncture and agonist groups in comparison with the model group (P<0.001). No significant differences were found between the acupuncture and agonist groups in down-regulating the neurological score and in up-regulating the number of BrdU＋/Nestin＋ double labeled cells and the expression of Shh and Gil1 proteins (P>0.05). Outcomes of H．E. stain showed obvious edema, disordered arrangement of cells, infiltration of inflammatory cells and red blood cells with glial cell hyperplasia around the hematoma area in the model group, which was relatively milder in both acupuncture and agonist groups such as in basic disappearance of edema and inflammatory reaction. Penetrative needling from GV20 to GB7 can obviously improve neurological function in ICH rats, which is related to its effects in activating Shh/Gil1 signaling and in further promoting neural stem cell proliferation in the SVZ region.

A cell type-specific expression map of NCoR1 and SMRT transcriptional co-repressors in the mouse brain.

The ability to rapidly change gene expression patterns is essential for differentiation, development, and functioning of the brain. Throughout development, or in response to environmental stimuli, gene expression patterns are tightly regulated by the dynamic interplay between transcription activators and repressors. Nuclear receptor corepressor 1 (NCoR1) and silencing mediator for retinoid or thyroid-hormone receptors (SMRT) are the best characterized transcriptional co-repressors from a molecular point of view. They mediate epigenetic silencing of gene expression in a wide range of developmental and homeostatic processes in many tissues, including the brain. For instance, NCoR1 and SMRT regulate neuronal stem cell proliferation and differentiation during brain development and they have been implicated in learning and memory. However, we still have a limited understanding of their regional and cell type-specific expression in the brain. In this study, we used fluorescent immunohistochemistry to map their expression patterns throughout the adult mouse brain. Our findings reveal that NCoR1 and SMRT share an overall neuroanatomical distribution, and are detected in both excitatory and inhibitory neurons. However, we observed striking differences in their cell type-specific expression in glial cells. Specifically, all oligodendrocytes express NCoR1, but only a subset express SMRT. In addition, NCoR1, but not SMRT, was detected in a subset of astrocytes and in the microglia. These novel observations are corroborated by single cell transcriptomics and emphasize how NCoR1 and SMRT may contribute to distinct biological functions, suggesting an exclusive role of NCoR1 in innate immune responses in the brain.

Fzr/Cdh1 Promotes the Differentiation of Neural Stem Cell Lineages in Drosophila.

How stem cells and progenitors balance between self-renewal and differentiation is a central issue of stem cell biology. Here, we describe a novel and essential function of Drosophila Fzr/Cdh1, an evolutionary conserved protein, during the differentiation of neural stem cell (NSC) lineages in the central nervous system. We show that Fzr, a known co-activator of Anaphase Promoting Complex/Cyclosome (APC/C) ubiquitin ligase, promotes the production of neurons from neural progenitors called ganglion mother cells (GMCs). However, knockdown of APC/C subunit Ida or another APC/C co-activator CDC20 does not similarly impair GMC-neuron transition. We also observe a concomitant loss of differentiation factor Prospero expression and ectopic accumulation of mitotic kinase Polo in fzr mutant clones, strongly supporting the impairment of GMC to neuron differentiation. Besides functioning in GMCs, Fzr is also present in NSCs to facilitate the production of intermediate neural progenitors from NSCs. Taken together, Fzr plays a novel function in promoting differentiation programs during Drosophila NSC lineage development. Given that human Fzr is inactivated in multiple types of human cancers including brain tumors and that Fzr regulates neurotoxicity in various models of neurodegenerative diseases, our study on the role of Fzr in turning off proliferation in neuronal cells may provide insights into how Fzr deficits may contribute to human neurodegenerative diseases and tumors.

Expression of genes involved in neurogenesis, and neuronal precursor cell proliferation and development: Novel pathways of human ovarian granulosa cell differentiation and transdifferentiation capability invitro.

The process of neural tissue formation is associated primarily with the course of neurogenesis during embryonic life. The source of neural-like cells is stem cells, which, under the influence of appropriate differentiating factors, may differentiate/transdifferentiate towards a neural-like lineage. The present study suggested that, under long-term in vitro culture conditions, human ovarian granulosa cells (GCs), obtained from granulosa-rich follicular fluid, acquired new properties and expressed genes characteristic of the ontological groups ‘neurogenesis’ (GO:0022008), ‘neuronal precursor cell proliferation’ (GO:0061351) and ‘nervous system development’ (GO:0007399), which are closely related to the formation of neurons. The present study collected GCs from 20 women referred for the procedure of in vitro fertilization. Cells were maintained in long-term in vitro culture for 30 days, and RNA was isolated after 1, 7, 15 and 30 days of culture. The expression profile of individual genes was determined using the Affymetrix microarray method. The 131 genes with the highest expression change in relation to day 1 of culture were then selected; the 10 most affected genes found to be primarily involved in nerve cell formation processes were chosen for consideration in this study: CLDN11, OXTR, DFNA5, ATP8B1, ITGA3, CD9, FRY, NANOS1, CRIM1 and NTN4. The results of the present study revealed that these genes may be considered potential markers of the uninduced differentiation potential of GCs. In addition, it was suggested that GCs may be used to develop a cell line showing neuronal characteristics after 30 days of cultivation. In addition, due to their potential, these cells could possibly be used in the treatment of neurodegenerative diseases, not only in the form of ‘cultured neurons’ but also as producers of factors involved in the regeneration of the nervous system.

L-histidine and L-carnosine exert anti-brain aging effects in D-galactose-induced aged neuronal cells.

BACKGROUND/OBJECTIVESBrain aging is a major risk factor for severe neurodegenerative diseases. Conversely, L-histidine and L-carnosine are known to exhibit neuroprotective effects. The aim of this study was to examine the potential for L-histidine, L-carnosine, and their combination to mediate anti-brain aging effects in neuronal cells subjected to D-galactose-induced aging.MATERIALS/METHODSThe neuroprotective potential of L-histidine, L-carnosine, and their combination was examined in a retinoic acid-induced neuronal differentiated SH-SY5Y cell line exposed to D-galactose (200 mM) for 48 h. Neuronal cell proliferation, differentiation, and expression of anti-oxidant enzymes and apoptosis markers were subsequently evaluated.RESULTSTreatment with L-histidine (1 mM), L-carnosine (10 mM), or both for 48 h efficiently improved the proliferation, neurogenesis, and senescence of D-galactose-treated SH-SY5Y cells. In addition, protein expression levels of both neuronal markers (β tubulin-III and neurofilament heavy protein) and anti-oxidant enzymes, glutathione peroxidase-1 and superoxide dismutase-1 were up-regulated. Conversely, protein expression levels of amyloid β (1-42) and cleaved caspase-3 were down-regulated. Levels of mRNA for the pro-inflammatory cytokines, interleukin (IL)-8, IL-1β, and tumor necrosis factor-α were also down-regulated.CONCLUSIONSTo the best of our knowledge, we provide the first evidence that L-histidine, L-carnosine, and their combination mediate anti-aging effects in a neuronal cell line subjected to D-galactose-induced aging. These results suggest the potential benefits of L-histidine and L-carnosine as anti-brain aging agents and they support further research of these amino acid molecules.

Laminin-modified gellan gum hydrogels loaded with the nerve growth factor to enhance the proliferation and differentiation of neuronal stem cells.

The reconstruction of peripheral nerves has lately received great attention as many patients suffer from peripheral nerve injury every year around the world. However, the damage to human nerve cells has different degrees of irreversibility due to a slow growth speed and low adhesion with the surrounding tissues. In an effort to overcome this challenge, we applied novel laminin (LN)-modified thiolated gellan gum (TGG) and loaded the nerve growth factor (NGF) as a tissue engineering scaffold for facilitating neuronal stem cell proliferation via a synergy effect for the ERK–MAPK pathway. TGG was characterized by 1H NMR spectroscopy and scanning electron microscopy, and its rheological behavior was also studied. The NGF release curve fitted the Korsmeyer–Peppas model and belonged to a Fickian diffusion-controlled release mechanism. The neuronal stem cells from newborn SD rats could adhere tightly and proliferate at a relatively rapid speed, showing excellent biocompatibility and the ability to promote growth in the modified TGG. LN and NGF could decrease the apoptosis effects of neuronal stem cells, as shown via the flow cytometry results. In a three-dimensional culture environment, LN and NGF could facilitate neuronal stem cells to differentiate into neurons, as proved by immunofluorescence, q-PCR, and western blot analyses. Therefore, the rational design of the TGG gel loaded with NGF has promising applications in the reconstruction of peripheral nerves.

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases.

Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.

Emerging roles of Golgi/endosome-localizing monomeric clathrin adaptors GGAs.

GGAs (Golgi-localized, γ-adaptin ear-containing, ADP ribosylation factor [Arf]-binding proteins) are a family of ubiquitously expressed, Arf-dependent monomeric clathrin adaptor proteins, and are conserved from yeast to humans. Mammals have three GGAs (GGA1-3) that work not only at the trans-Golgi network, but also in endosomes to sort transmembrane cargo proteins such as mannose 6-phosphate receptors, sortilin, β-site amyloid precursor protein cleaving enzyme 1, and epidermal growth factor receptor. The cytoplasmic regions of these cargoes possess motifs of acidic amino acid cluster-dileucine and/or ubiquitination sites, which can be recognized by GGAs. Despite seminal investigations of the three molecules, their in vivo roles and functional redundancies, as well as relationships with a heterotetrameric adaptor protein, AP-1, which is functionally similar to GGAs were still poorly understood. Studies over the past two decades, however, discovered several new GGA cargoes, their interaction modes, and accessory proteins. These findings collectively suggest distinct and more fundamental roles of each GGA in regulating neuronal survival, lipid metabolism, and cell proliferation. This review aims to provide an update to the GGA research focusing on how GGAs became considered not only as players in the context of the TGN-endosome transport, but also as key regulators for physiologically and pathologically important phenomena.

Metabolomic evidence for the therapeutic effect of gentiopicroside in a corticosterone-induced model of depression

BackgroundDepression is a disease that seriously threatens the quality of human life. To explore the effect of gentiopicroside on depression, this study investigated the therapeutic effect of gentiopicroside on corticosterone-induced depressionin vivo and in vitro by using metabolomic methods. MethodsA total of 36 rats were randomly assigned to three groups: a normal group, model group (depression), and treatment group (depression + gentiopicroside). Corticosterone was administrated to induce depression-like model rats. Morris water maze test was used to validated the behavior performance. The hippocampus of rats was obtained for metabolomic detection. Metabolites that were differentially expressed between the groups were extracted for Heatmap, Go, and pathway enrichment analyses. Finally, neuronal cells were cultured and examined to validated the effect of gentiopicroside. ResultsCorticosterone injured rats learning capacity, and decreased the levels of 5-HT, and reversed by gentiopicroside delivery. Metabolites obtained from the hippocampus of rats in the three groups were subjected to a principal component analysis (PCA). Go and pathway enrichment analyses revealed the involvement of sphingolipid metabolism et al. Gentiopicroside could inhibit apoptosis caused by corticosterone, and also decrease neuronal cell proliferation and BDNF levels in vitro. Arachidonic acid (ARA) reversed the protective effect of gentiopicroside on neuronal cells. ConclusionThese findings suggest that gentiopicroside reduces apoptosis and increases the proliferation of hippocampus cells in depressed animals by regulating metabolites. Moreover, our study provides a new basis for the clinical treatment of depression and demonstrates the potential efficacy of gentiopicroside in this area of pathology.

Suppression of miR-10a-5p in bone marrow mesenchymal stem cells enhances the therapeutic effect on spinal cord injury via BDNF

Backgrounds/AimsBrain-derived neurotrophic factor (BDNF) plays a primary role in the maturation, proliferation, and differentiation of neuronal cells, can induce bone-marrow-derived mesenchymal stem cells (MSCs) to differentiate into nerve cells. This study aims to explore whether regulation of BDNF through microRNAs (miRNAs) in MSCs may further enhance the therapeutic effect on spinal cord injury (SCI). MethodsBioinformatics analyses were done to predict miRNAs that target BDNF in MSCs. Dual-luciferase reporter gene assays were performed to verify the target relationship between microRNA and BDNF. We examined the mRNA and protein levels of BDNF in MSCs by RT-qPCR and Western blot, respectively. CCK 8 assay was chosen to assess cell viability. MSCs were transduced with miR-10a-5p-ASO, which were transplanted into rats that underwent SCI. The tissue integrity percentage, cavity volume, and Basso-Beattie-Bresnahan (BBB) scale were assessed. Neurofilament (NF) was detected using immunohistochemistry. Histological features of spinal cord tissues examined following HE staining. ResultsMiR-10a-5p inhibited protein translation of BDNF, through binding to the 3’-UTR of the BDNF. MSCs transduced with MiR-10a-5p-ASO further increased the tissue integrity percentage, decreased cavity volume, and enhanced the recovery of BBB score in SCI model rats, compared to control MSCs. ConclusionUpregulation of BDNF by miR-10a-5p suppression in MSCs further improve the therapeutic potential of MSCs in treating SCI in rats.

Pattern of triptans use: a retrospective prescription study in Calabria, Italy

A large number of chemokines, cytokines, other trophic factors and the extracellular matrix molecules form a favorable microenvironment for peripheral nerve regeneration. This microenvironment is one of the major factors for regenerative success. Therefore, it is important to investigate the key molecules and regulators affecting nerve regeneration after peripheral nerve injury. However, the identities of specific cytokines at various time points after sciatic nerve injury have not been determined. The study was performed by transecting the sciatic nerve to establish a model of peripheral nerve injury and to analyze, by protein microarray, the expression of different cytokines in the distal nerve after injury. Results showed a large number of cytokines were up-regulated at different time points post injury and several cytokines, e.g., ciliary neurotrophic factor, were downregulated. The construction of a protein-protein interaction network was used to screen how the proteins interacted with differentially expressed cytokines. Kyoto Encyclopedia of Genes and Genomes pathway and Gene ontology analyses indicated that the differentially expressed cytokines were significantly associated with chemokine signaling pathways, Janus kinase/signal transducers and activators of transcription, phosphoinositide 3-kinase/protein kinase B, and notch signaling pathway. The cytokines involved in inflammation, immune response and cell chemotaxis were up-regulated initially and the cytokines involved in neuronal apoptotic processes, cell-cell adhesion, and cell proliferation were up-regulated at 28 days after injury. Western blot analysis showed that the expression and changes of hepatocyte growth factor, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were consistent with the results of protein microarray analysis. The results provide a comprehensive understanding of changes in cytokine expression and changes in these cytokines and classical signaling pathways and biological functions during Wallerian degeneration, as well as a basis for potential treatments of peripheral nerve injury. The study was approved by the Institutional Animal Care and Use Committee of the Chinese PLA General Hospital, China (approval number: 2016-x9-07) in September 2016.

Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor.

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of our study was to investigate the molecular mechanism of ketamine at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). Notably, ketamine increased the proliferation of NPCs independent of the NMDA receptor, while transcriptome analysis revealed significant upregulation of insulin-like growth factor 2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 h after ketamine treatment. Ketamine (1 µM) was able to increase cyclic adenosine monophosphate (cAMP) signaling in NPCs within 15 min and cell proliferation, while ketamine-induced IGF2 expression was reduced after PKA inhibition with cAMPS-Rp. Furthermore, 24 h post-administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes the proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

Characterization of astrocytes and microglial cells in the hippocampal CA1 region after transient focal cerebral ischemia in rats treated with Ilexonin A.

Ilexonin A is a compound isolated from the root of Ilex pubescens, a traditional Chinese medicine. Ilexonin A has been shown to play a neuroprotective role by regulating the activation of astrocytes and microglia in the peri-infarct area after ischemia. However, the effects of ilexonin A on astrocytes and microglia in the infarct-free region of the hippocampal CA1 region remain unclear. Focal cerebral ischemia models were established by 2-hour occlusion of the middle cerebral artery in rats. Ilexonin A (20, 40 or 80 mg/kg) was administered immediately after ischemia/reperfusion. The astrocyte marker glial fibrillary acidic protein, microglia marker Iba-1, neural stem cell marker nestin and inflammation markers were detected by immunohistochemistry and western blot assay. Expression levels of tumor necrosis factor-α and interleukin 1β were determined by enzyme linked immunosorbent assay in the hippocampal CA1 tissue. Astrocytes were activated immediately in progressively increasing numbers from 1, 3, to 7 days post-ischemia/reperfusion. The number of activated astrocytes further increased in the hippocampal CA1 region after treatment with ilexonin A. Microglial cells remained quiescent after ischemia/reperfusion, but became activated after treatment with ilexonin A. Ilexonin A enhanced nestin expression and reduced the expression of tumor necrosis factor-α and interleukin 1β in the hippocampus post-ischemia/reperfusion. The results of the present study suggest that ilexonin A has a neuroprotective effect in the hippocampus after ischemia/reperfusion, probably through regulating astrocytes and microglia activation, promoting neuronal stem cell proliferation and reducing the levels of pro-inflammatory factors. This study was approved by the Animal Ethics Committee of the Fujian Medical University Union Hospital, China.

Adequate expression of Globin1 is required for development and maintenance of nervous system in Drosophila

Neurogenesis is driven by spatially and temporally regulated proliferation of neuronal progenitor cells that generates enormous number of assorted neurons to drive the complex behavior of an organism. Drosophila nervous system provides an advantageous model for identification and elucidation of the functional significance of the novel gene(s) involved in neurogenesis. The present study attempts to investigate the role(s) of globin1 (glob1) in the development and maintenance of the nervous system in Drosophila. It is increasingly clear now that globin genes play important role(s) in the various biological phenomena. The vertebrate neuroglobin has been reported to profoundly express in neuronal tissues and provides neuroprotection. We noted ubiquitous presence of Glob1 in the developing neuronal tissues with enhanced concentration throughout the VNC which comprises of midline cell clusters, which subsequently forms numerous types of progenitor cells and finally differentiate into specific neurons of the nervous system. Ubiquitous or pan-neuronal downregulation of glob1 causes partial lethality and mis-positioning of various neural-progenitor cells present in the embryonic midline cell clusters. Subsequently, profound expression of Glob1 was noted in the outer proliferation center of larval brain and photoreceptor axons of optic stalk. The overall arrangement of photoreceptor axons and stereotype positioning of neuroblast cells present in the central region of the brain were severally affected due to reduced expression of glob1. In addition, such larvae and surviving adults develop significant neuro-muscular disabilities. For the first time, our study suggests a novel role of glob1 in development and maintenance of the nervous system adding a new dimension to the functional significance of the multi-tasking glob1 gene in Drosophila.

Neuroprotective Properties of Linagliptin: Focus on Biochemical Mechanisms in Cerebral Ischemia, Vascular Dysfunction and Certain Neurodegenerative Diseases.

Linagliptin is a representative of dipeptidyl peptidase 4 (DPP-4) inhibitors which are registered and used effectively in a treatment of diabetes mellitus type 2. They increase the levels of active forms of endogenous incretins such as GLP-1 and GIP by inhibiting their enzymatic decomposition. Scientific reports suggest beneficial effects of linagliptin administration via immunological and biochemical pathways involved in neuroprotective processes of CNS. Linagliptin’s administration leads to a decrease in the concentration of proinflammatory factors such as: TNF-α, IL-6 and increases the number of anti-inflammatory patrolling monocytes CX3CR1bright. Significant reduction in Aβ42 level has been associated with the use of linagliptin implying potential application in Alzheimer’s disease. Linagliptin improved vascular functions by increasing production of nitric oxide (NO) and limiting concentration of apolipoprotein B. Linagliptin-induced decrease in macrophages infiltration may provide improvement in atheromatous plaque stabilization. Premedication with linagliptin increases neuron’s survival after stroke and augments neuronal stem cells proliferation. It seems to be connected with SDF-1α/CXCR4 signaling pathway. Linagliptin prevented abnormal proliferation and migration of rat brain microvascular endothelial cells in a state of hypoperfusion via SIRT1/HIF-1α/VEGF pathway. The article presents a summary of the studies assessing neuroprotective properties of linagliptin with special emphasis on cerebral ischemia, vascular dysfunction and neurodegenerative diseases.

Oncostatin M, a muscle-secreted myokine, recovers high-glucose-induced impairment of Akt phosphorylation by Fos induction in hippocampal neuron cells.

Oncostatin M is a muscle-secreted myokine that has various effects on neuronal function, however, the underlying molecular mechanism has been poorly defined. In this study, we showed that Oncostatin M increased the phosphorylation of Akt and ERK, proteins crucial for neuron cell survival and proliferation. Furthermore, Oncostatin M increased the expression of c-Fos, a protein with significant involvement in neuronal cell proliferation and survival, through both Akt and ERK. Oncostatin M also increased intracellular calcium concentrations that act upstream of Akt and ERK. Treatment with Oncostatin M led to the recovery of high-glucose-induced impairment of Akt phosphorylation. Thus, Oncostatin M can protect neuronal cell damage related to high-glucose conditions, showing potential as a therapeutic agent.