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Novel Defense by Metallothionein Induction Against Cognitive Decline: From Amyloid β 1–42 -Induced Excess Zn 2+ to Functional Zn 2+ Deficiency
AbstractThe role of metallothioneins (MTs) in cognitive decline associated with intracellular Zn2+ dysregulation remains unclear. Here, we report that hippocampal MT induction defends cognitive decline, which was induced by amyloid β1 –42 (A β1 –42)-mediated excess Zn2+ and functional Zn2+ deficiency. Excess increase in intracellular Zn2+, which was induced by local injection of A β1 –42 into the dentate granule cell layer, attenuated in vivo perforant pathway LTP, while the attenuation was rescued by preinjection of MT inducers into the same region. Intraperitoneal injection of dexamethaso...
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

miRNA Editing: New Insights into the Fast Control of Gene Expression in Health and Disease
AbstractPost-transcriptional modifications are essential mechanisms for mRNA biogenesis and function in eukaryotic cells. Beyond well-characterized events such as splicing, capping, and polyadenylation, there are several others, as RNA editing mechanisms and regulation of transcription mediated by miRNAs that are taking increasing attention in the last years. RNA editing through A-to-I deamination increases transcriptomic complexity, generating different proteins with amino acid substitution from the same transcript. On the other hand, miRNAs can regulate gene expression modulating target mRNA decay and translation. Intere...
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

Hypoxia-Preconditioned Human Umbilical Vein Endothelial Cells Protect Against Neurovascular Damage After Hypoxic Ischemia in Neonatal Brain
AbstractTherapy targeting the neurovascular unit may provide effective neuroprotection against neonatal hypoxia –ischemia (HI). We hypothesized that the peripheral injection of hypoxia-preconditioned human umbilical vein endothelial cells (HUVECs) following HI protects against neurovascular damage and provides long-term neuroprotection in a postpartum (P) day-7 rat pup model. Compared with normoxic HUVECs, hypoxic HUVECs showed enhanced migration and angiogenesis in vitro and had augmented migration effects into the brain when administered intraperitoneally in vivo after HI. Moreover, 24 and 72 h post-HI, the hy...
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

Towards a TDP-43-Based Biomarker for ALS and FTLD
AbstractTDP-43 accumulates in nerve cells of nearly all cases of amyotrophic lateral sclerosis (ALS; the commonest form of motor neuron disease) and in the majority of Tau-negative frontotemporal lobar degeneration (FTLD). There is currently no biochemical test or marker of disease activity for ALS or FTLD, and the clinical diagnosis depends on the opinion of an experienced neurologist. TDP-43 has a key role in the pathogenesis of ALS/FTLD. Measuring TDP-43 in easily accessible biofluids, such as blood or cerebrospinal fluid, might reduce diagnostic delay and offer a readout for use in future drug trials. However, attempts...
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

Interaction of Peptide Aptamers with Prion Protein Central Domain Promotes α-Cleavage of PrP C
AbstractPrion diseases are infectious and fatal neurodegenerative diseases affecting humans and animals. Transmission is possible within and between species with zoonotic potential. Currently, no prophylaxis or treatment exists. Prions are composed of the misfolded isoform PrPSc of the cellular prion protein PrPC. Expression of PrPC is a prerequisite for prion infection, and conformational conversion of PrPC is induced upon its direct interaction with PrPSc. Inhibition of this interaction can abrogate prion propagation, and we have previously established peptide aptamers (PAs) binding to PrPC as new anti-prion compounds. H...
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

Increased Levels of Rictor Prevent Mutant Huntingtin-Induced Neuronal Degeneration
In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin. (Source: Molecular Neurobiology)
Source: Molecular Neurobiology - February 19, 2018 Category: Neurology Source Type: research

BIG2-ARF1-RhoA-mDia1 Signaling Regulates Dendritic Golgi Polarization in Hippocampal Neurons
AbstractProper dendrite development is essential for establishing neural circuitry, and Rho GTPases play key regulatory roles in this process. From mouse brain lysates, we identified Brefeldin A-inhibited guanine exchange factor 2 (BIG2) as a novel Rho GTPase regulatory protein involved in dendrite growth and maintenance. BIG2 was highly expressed during early development, and knockdown of theARFGEF2 gene encoding BIG2 significantly reduced total dendrite length and the number of branches. Expression of the constitutively active ADP-ribosylation factor 1 ARF1  Q71L rescued the defective dendrite morphogenesis ofARFGEF...
Source: Molecular Neurobiology - February 17, 2018 Category: Neurology Source Type: research

PLP1 Gene Variation Modulates Leftward and Rightward Functional Hemispheric Asymmetries
AbstractMolecular neurobiological factors determining corpus callosum physiology and anatomy have been suggested to be one of the major factors determining functional hemispheric asymmetries. Recently, it was shown that allelic variations in two myelin-related genes, the proteolipid protein 1 genePLP1 and the contactin 1 geneCNTN1, are associated with differences in interhemispheric integration. Here, we investigated whether three single nucleotide polymorphisms that were associated with interhemispheric integration via the corpus callosum in a previous study also are relevant for functional hemispheric asymmetries. To thi...
Source: Molecular Neurobiology - February 13, 2018 Category: Neurology Source Type: research

Acupuncture Prevents the Impairment of Hippocampal LTP Through β1-AR in Vascular Dementia Rats
AbstractIt is widely accepted that the synaptic dysfunction and synapse loss contribute to the cognitive deficits of vascular dementia (VD) patients. We have previously reported that acupuncture improved cognitive function in rats with VD. However, the mechanisms involved in acupuncture improving cognitive ability remain to be elucidated. The present study aims to investigate the pathways and molecules involved in the neuroprotective effect of acupuncture. We assessed the effects of acupuncture on hippocampal long-term potentiation (LTP), the most prominent cellular model of memory formation. Acupuncture enhanced LTP and n...
Source: Molecular Neurobiology - February 13, 2018 Category: Neurology Source Type: research

The Metabolic Disturbances of Motoneurons Exposed to Glutamate
AbstractGlutamate-induced excitotoxicity is considered as one of the major pathophysiological factors of motoneuron death in amyotrophic lateral sclerosis and other motoneuron diseases. In order to expand our knowledge on mechanisms of glutamate-induced excitotoxicity, the present study proposes to determine the metabolic consequences of glutamate and astrocytes in primary enriched motoneuron culture. Using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS), we showed that the presence of astrocytes and glutamate profoundly modified the metabolic profile of motoneurons. Our study highlights for th...
Source: Molecular Neurobiology - February 12, 2018 Category: Neurology Source Type: research

Herp Promotes Degradation of Mutant Huntingtin: Involvement of the Proteasome and Molecular Chaperones
AbstractIn neurodegenerative diseases, pathogenic proteins tend to misfold and form aggregates that are difficult to remove and able to induce excessive endoplasmic reticulum (ER) stress, leading to neuronal injury and apoptosis. Homocysteine-induced endoplasmic reticulum protein (Herp), an E3 ubiquitin ligase, is an important early marker of ER stress and is involved in the ubiquitination and degradation of many neurodegenerative proteins. However, in Huntington ’s disease (HD), a typical polyglutamine disease, whether Herp is also involved in the metabolism and degradation of the pathogenic protein, mutant huntingt...
Source: Molecular Neurobiology - February 12, 2018 Category: Neurology Source Type: research

Design, Synthesis, and In Vitro Evaluation of a Novel Probucol Derivative: Protective Activity in Neuronal Cells Through GPx Upregulation
In this study, we present a novel organoselenium PB derivative (RC513) and investigate its potential protective activity in an in vitro experimental model of oxidative toxicit y induced bytert-butyl hydroperoxide (tBuOOH) in HT22 neuronal cells, as well as exploit potential protective mechanisms. tBuOOH exposure caused a significant decrease in the cell viability, which was preceded by (i) increased reactive species generation and (ii) decreased mitochondrial maximum oxygen consumption rate. RC513 pretreatment (48  h) significantly prevented the tBuOOH-induced decrease of cell viability, RS generation, and mitochondri...
Source: Molecular Neurobiology - February 12, 2018 Category: Neurology Source Type: research

Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice
In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ER β) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in...
Source: Molecular Neurobiology - February 12, 2018 Category: Neurology Source Type: research

A Regulatory Circuitry Between Gria2, miR-409, and miR-495 Is Affected by ALS FUS Mutation in ESC-Derived Motor Neurons
AbstractMutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). FUS is a multifunctional protein involved in the biogenesis and activity of several types of RNAs, and its role in the pathogenesis of ALS may involve both direct effects of disease-associated mutations through gain- and loss-of-function mechanisms and indirect effects due to the cross talk between different classes of FUS-dependent RNAs. To explore how FUS mutations impinge on motor neuron-specific RNA-based circuitries, we performed transcriptome profiling of small and long RNAs of motor neurons (MNs) derived from mouse embryonic stem ...
Source: Molecular Neurobiology - February 12, 2018 Category: Neurology Source Type: research

Peptide YY Causes Apathy-Like Behavior via the Dopamine D2 Receptor in Repeated Water-Immersed Mice
AbstractApathy is observed across several neurological and psychiatric conditions; however, its pathogenesis remains unclear. We clarified the involvement of brain –gut signaling in the disruption of goal-directed behavior. Male C57BL/6J mice were exposed to water immersion (WI) stress for 3 days. Food intake and nesting behavior were measured as indexes of motivation. Repeated WI caused decrease in food intake and nesting behavior. Plasma levels of peptide YY (PYY), IL-6, and ratio of dopamine metabolites in the striatum were significantly elevated after WI. PYY and IL-6 administration significantly decreased n...
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

Molecular and Clinical Aspects of Protein Aggregation Assays in Neurodegenerative Diseases
AbstractThe presence of protein deposits is a common pathological hallmark in patients suffering from neurodegenerative conditions and other proteinopathies. Deciphering the molecular basis of protein misfolding and aggregation is a crucial step towards the full comprehension of the factors that trigger the onset of these diseases and for the development of efficient therapeutical strategies. In this regard, in vitro aggregation assays for misfolded proteins offer an excellent tool to study pathological processes of protein deposition under controlled conditions, where confounders can be easily discriminated. These methods...
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

Cilostazol Mediated Nurr1 and Autophagy Enhancement: Neuroprotective Activity in Rat Rotenone PD Model
In conclusion, cilostazol could be a promising candidate for PD treatment through modulating Nurr1 expression, as well as SIRT-1/autophagy, and GSK-3β/apoptosis cross-regulation.Graphical AbstractIn the rat rotenone model of Parkinson ’s disease (PD), Nurr1 expression was downregulated, GSK-3β was activated, and autophagic flux was inhibited. Those deleterious effects were associated with deteriorated motor functions, striatal TH content, enhanced inflammatory state, and apoptotic cascade. Cilostazol, a phosphodiesterase-3 inh ibitor, exerted a potential protective effect against PD through Nurr1 enhancemen...
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

Implication of Genes for the N -Methyl- d -Aspartate (NMDA) Receptor in Substance Addictions
AbstractDrug dependence is a chronic brain disease with harmful consequences for both individual users and society. Glutamate is a primary excitatory neurotransmitter in the brain, and both in vivo and in vitro experiments have implicatedN-methyl-d-aspartate (NMDA) receptor, a glutamate receptor, as an element in various types of addiction. Recent findings from genetics-based approaches such as genome-wide linkage, candidate gene association, genome-wide association (GWA), and next-generation sequencing have demonstrated the significant association of NMDA receptor subunit genes such asGluN3A,GluN2B, andGluN2A with various...
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity
AbstractParkinson ’s disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in theSubstantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson ’s disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson’s disease, we first usedC elegans to demonstrate the role of the small GTPaseRAC1 (ce...
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

Correction to: Roles of Retinoic Acid Signaling in Shaping the Neuronal Architecture of the Developing Amphioxus Nervous System
AbstractThe original version of this article unfortunately contained a mistake. The Fig. 7 sub-panel “f” was missing in the figure of the online first proofs of this article. The corrected Fig. 7 is hereby given below. (Source: Molecular Neurobiology)
Source: Molecular Neurobiology - February 10, 2018 Category: Neurology Source Type: research

Effect of Resveratrol on Oxidative Stress and Mitochondrial Dysfunction in Immature Brain during Epileptogenesis
AbstractThe presence of oxidative stress in immature brain has been demonstrated during the acute phase of status epilepticus (SE). The knowledge regarding the long periods of survival after SE is not unequivocal, lacking direct evidence. To examine the presence and time profile of oxidative stress, its functional effect on mitochondria and the influence of an antioxidant treatment in immature rats during epileptogenesis, status epilepticus (SE) was induced in immature 12-day-old rats by Li-pilocarpine and at selected periods of the epileptogenesis; rat pups were subjected to examinations. Hydroethidine method was employed...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells
This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases. (Source: Molecular Neurobiology)
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Fluoxetine Inhibits Natural Decay of Long-Term Memory via Akt/GSK-3 β Signaling
AbstractUnderstanding the mechanisms underlying the natural decay of long-term memory can help us find means of extending the duration of long-term memory. However, the neurobiological processes involved in the decay of long-term memory are poorly understood. In the present study, we examined the effect of acute and chronic treatment of fluoxetine on natural decay of long-term memory and the possible mechanism. Late administration of fluoxetine prolonged the persistence of long-term memory in mice, as demonstrated by object location recognition and Barnes maze tests. Fluoxetine altered Akt/glycogen synthase kinase-3 β...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

XBP1 and PERK Have Distinct Roles in A β-Induced Pathology
AbstractEndoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer ’s disease (AD). However, the role of ER stress in β-amyloid (Aβ)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematicall y examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring en...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Rosmarinic Acid Mitigates Mitochondrial Dysfunction and Spinal Glial Activation in Oxaliplatin-induced Peripheral Neuropathy
AbstractChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting complication which develops as a consequence of treatment with chemotherapeutic agents like oxaliplatin and is a mainstay of therapy for colorectal cancer. Ever since CIPN was identified, understanding its exact pathomechanisms remains a clinical challenge. The role of mitochondrial dysfunction and glial cell activation has surfaced in the etiology of CIPN. Rosmarinic acid (RA), a known mitoprotectant exerts neuroprotection against the oxidative stress and neuroinflammation in various disease conditions. Hence, in the present study, we investigate...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Brain Metabolic DNA in Rat Cytoplasm
AbstractBrain metabolic DNA (BMD) is not involved in cell division or DNA repair but is modulated by memory acquisition, sleep processing, and circadian oscillations. Using routine methods of subcellular fractionation, newly synthesized BMD from male rats is shown to be localized in crude nuclear, mitochondrial, and microsomal fractions and in two fractions of purified nuclei. Sub-fractionation of the mitochondrial fraction indicates the prevalent localization of BMD in free mitochondria and to a lesser degree in synaptosomes and myelin. Cesium density profiles of homogenate, subcellular fractions, and purified nuclei obta...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Neuroinflammation Alters Integrative Properties of Rat Hippocampal Pyramidal Cells
AbstractNeuroinflammation is consistently found in many neurological disorders, but whether or not the inflammatory response independently affects neuronal network properties is poorly understood. Here, we report that intracerebroventricular injection of the prototypical inflammatory molecule lipopolysaccharide (LPS) in rats triggered a strong and long-lasting inflammatory response in hippocampal microglia associated with a concomitant upregulation of Toll-like receptor (TLR4) in pyramidal and hilar neurons. This, in turn, was associated with a significant reduction of the dendritic hyperpolarization-activated cyclic AMP-g...
Source: Molecular Neurobiology - February 9, 2018 Category: Neurology Source Type: research

Characterization of Behavioral, Signaling and Cytokine Alterations in a Rat Neurodevelopmental Model for Schizophrenia, and Their Reversal by the 5-HT 6 Receptor Antagonist SB-399885
This study examined the ability of the 5-HT6 receptor antagonist SB-399885 to reverse isolation-induced cognitive deficits, then investigated alterations in hippocampal cell proliferation and hippocampal and frontal cortical expression of selected intracellular signaling molecules and cytokines. Male Lister hooded rats (weaned on post-natal days 21 –24 and housed individually or in groups of 3–4) received six i.p. injections of vehicle (1% Tween 80, 1 mL/kg) or SB-399885 (5 or 10 mg/kg) over a 2-week period starting 40 days post-weaning, on the days that locomotor activity, novel object discrimin...
Source: Molecular Neurobiology - February 8, 2018 Category: Neurology Source Type: research

Inhibiting Effect of Zinc Oxide Nanoparticles on Advanced Glycation Products and Oxidative Modifications: a Potential Tool to Counteract Oxidative Stress in Neurodegenerative Diseases
AbstractAdvanced glycation end products (AGEs) are implicated in several central nervous system (CNS) pathologies including Alzheimer and Parkinson ’s diseases. In the face-off of AGE menace, we have attempted to investigate the zinc oxide nanoparticle (ZnONP) role in inhibition of AGE formation. Synthesized ZnONPs were used to investigate the inhibitory effects on AGE formation. The inhibitory effects of ZnONPs on AGE formation were determin ed by biophysical immunological and biochemical techniques. The results showed that ZnONP is a potential anti-glycating agent inhibiting AGE formation as well as protecting the ...
Source: Molecular Neurobiology - February 8, 2018 Category: Neurology Source Type: research

Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function
We report the 1.6 Å resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology o f aging are discussed. (Source: Molecular Neurobiology)
Source: Molecular Neurobiology - February 8, 2018 Category: Neurology Source Type: research

Qi Fu Yin –a Ming Dynasty Prescription for the Treatment of Dementia
AbstractThe Traditional Chinese Medicine (TCM) theory that “kidneys give rise to marrow, and the brain is the sea of marrow” has been a guide for the clinical application of kidney, qi and blood tonics for prevention and treatment of dementia and improvement in memory. As low resistance end-organs, both the brain and the kidneys are subjected to blood f low of high volumes throughout the cardiac cycle. Alzheimer’s disease and vascular dementia are two common causes of dementia, and it is increasingly recognized that many older adults with dementia have both AD and vascular pathologies. The underlying mole...
Source: Molecular Neurobiology - February 7, 2018 Category: Neurology Source Type: research

MicroRNA-34 Contributes to the Stress-related Behavior and Affects 5-HT Prefrontal/GABA Amygdalar System through Regulation of Corticotropin-releasing Factor Receptor 1
AbstractRecent studies show that microRNA-34 (miR-34) family is critical in the regulation of stress response also suggesting that it may contribute to the individual responsiveness to stress. We have recently demonstrated that mice carrying a genetic deletion of all miR-34 isoforms (triple knockout, TKO) lack the stress-induced serotonin (5-HT) and GABA release in the medial prefrontal cortex (mpFC) and basolateral amygdala (BLA), respectively. Here, we evaluated if the absence of miR-34 was also able to modify the stress-coping strategy in the forced swimming test. We found that the blunted neurochemical response to stre...
Source: Molecular Neurobiology - February 7, 2018 Category: Neurology Source Type: research

Understanding Miro GTPases: Implications in the Treatment of Neurodegenerative Disorders
AbstractThe Miro GTPases represent an unusual subgroup of the Ras superfamily and have recently emerged as important mediators of mitochondrial dynamics and for maintaining neuronal health. It is now well-established that these enzymes act as essential components of a Ca2+-sensitive motor complex, facilitating the transport of mitochondria along microtubules in several cell types, including dopaminergic neurons. The Miros appear to be critical for both anterograde and retrograde mitochondrial transport in axons and dendrites, both of which are considered essential for neuronal health. Furthermore, the Miros may be signific...
Source: Molecular Neurobiology - February 6, 2018 Category: Neurology Source Type: research

A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications
AbstractCurrently, a psychologically based model is widely held to be the basis for the aetiology and treatment of chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME)/systemic exertion intolerance disease (SEID). However, an alternative, molecular neurobiological approach is possible and in this paper evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood –brain barrier and intestinal permeability, cytokines...
Source: Molecular Neurobiology - February 6, 2018 Category: Neurology Source Type: research

Rare Risk Variants Identification by Identity-by-Descent Mapping and Whole-Exome Sequencing Implicates Neuronal Development Pathways in Schizophrenia and Bipolar Disorder
This study investigated a familial cohort of SCZ and BPD patients from a closed population sample, where the high recurrence of the disorders and the homogenous genetic background indicate a possible enrichment in rare risk alleles. A total of 230 subjects (161 cases, 22 unaffected relatives, and 47 controls) were genetically investigated through an innovative strategy that integrates identity-by-descent (IBD) mapping and whole-exome sequencing (WES). IBD analysis allowed to track high-risk haplotypes (IBDrisk) shared exclusively by multiple patients from different families and possibly carrying the most penetrant alleles....
Source: Molecular Neurobiology - February 6, 2018 Category: Neurology Source Type: research

Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson ’s Disease Models
AbstractThe exact mechanism of gut dysfunction in Parkinson ’s disease and, conversely, the role of gut pathology in brain dopaminergic degeneration are controversial. We investigated the effects of nigral lesions on the colonic neurotransmission, the effect of gut inflammation on the nigrostriatal dopaminergic function, and the possible involvement of the vagus nerve and the local renin-angiotensin system (RAS). Nigrostriatal dopamine depletion was performed by bilateral injection 6-hydroxydopamine, and gut inflammation was induced by dextran sulfate sodium salt treatment in rats and mice, respectively, with or with...
Source: Molecular Neurobiology - February 5, 2018 Category: Neurology Source Type: research

Conserved Upstream Regulatory Regions in Mammalian Tyrosine Hydroxylase
In this study, we examined the 11  kb upstream nucleotide sequence ofTh from nine mammalian species and identified five highly conserved regions. Using cultured human cells and mouse olfactory bulb tissue, chromatin immunoprecipitation (ChIP) assays show that these conserved regions recruit transcription factors that are established regulators ofTh transcription (such as NURR1, PITX3, FOXA2, MEIS2, and PAX6). This analysis also identified a conserved binding site for CTCF, and functional studies in cultured human cells and ChIP assays with mouse tissue show that CTCF is a novel regulator ofTh transcription in the fore...
Source: Molecular Neurobiology - February 5, 2018 Category: Neurology Source Type: research

Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer ’s Disease
AbstractThere is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer ’s disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), aN-methyl-d-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present resea...
Source: Molecular Neurobiology - February 5, 2018 Category: Neurology Source Type: research

Neurofascin Knock Down in the Basolateral Amygdala Mediates Resilience of Memory and Plasticity in the Dorsal Dentate Gyrus Under Stress
AbstractActivation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo-hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of...
Source: Molecular Neurobiology - February 5, 2018 Category: Neurology Source Type: research

Buttermilk and Krill Oil Phospholipids Improve Hippocampal Insulin Resistance and Synaptic Signaling in Aged Rats
AbstractImpaired glucose metabolism and mitochondrial decay greatly increase with age, when cognitive decline becomes rampant. No pharmacological or dietary intervention has proven effective, but proper diet and lifestyle do postpone the onset of neurodegeneration and some nutrients are being investigated. We studied insulin signaling, mitochondrial activity and biogenesis, and synaptic signaling in the hippocampus and cortex following dietary supplementation with bioactive phospholipid concentrates of krill oil (KOC), buttermilk fat globule membranes (BMFC), and a combination of both in aged rats. After 3  months of ...
Source: Molecular Neurobiology - February 3, 2018 Category: Neurology Source Type: research

Anti-Oxidative Effects of Melatonin Receptor Agonist and Omega-3 Polyunsaturated Fatty Acids in Neuronal SH-SY5Y Cells: Deciphering Synergic Effects on Anti-Depressant Mechanisms
In this study, we aimed to decipher the individual and synergistic actions of n-3 PUFAs and RMT, as compared with the conventional antidepressant fluoxetine (FLX), in a cellular model of oxidative stress, which might play an important role in the pathophysiology of depression and associated disorders. We investigated the rescue and prevention effects of FLX, RMT, and n-3 PUFAs, e.g., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), by using cell viability in SH-SY5Y cells under oxidative stress along with measurements of key cellular markers of oxidative stress, inflammatory, and neuroprotection. The results rev...
Source: Molecular Neurobiology - February 3, 2018 Category: Neurology Source Type: research

Whole-Transcriptome Analysis of Mouse Models with MPTP-Induced Early Stages of Parkinson ’s Disease Reveals Stage-Specific Response of Transcriptome and a Possible Role of Myelin-Linked Genes in Neurodegeneration
AbstractParkinson ’s disease (PD) is characterized by degeneration of dopaminergic neurons. A whole-transcriptome analysis of the substantia nigra and striatum of an MPTP-induced mouse models of the earliest stages of PD was performed. Functional clustering of differentially represented transcripts revealed process es associated with the functioning of synapses, dendrites, axons, and myelination of neuronal projections. All of these processes occur in both the substantia nigra and striatum, but they are aimed at the functioning of neuron terminals in the striatum. One cluster was identified at the earliest sta ge mod...
Source: Molecular Neurobiology - February 3, 2018 Category: Neurology Source Type: research

Glutamate Excitotoxicity Linked to Spermine Oxidase Overexpression
AbstractExcitotoxic stress has been associated with several different neurological disorders, and it is one of the main causes of neuronal degeneration and death. To identify new potential proteins that could represent key factors in excitotoxic stress and to study the relationship between polyamine catabolism and excitotoxic damage, a novel transgenic mouse line overexpressing spermine oxidase enzyme in the neocortex (Dach-SMOX) has been engineered. These transgenic mice are more susceptible to excitotoxic injury and display a higher oxidative stress, highlighted by 8-Oxo-2 ′-deoxyguanosine increase and activation o...
Source: Molecular Neurobiology - February 3, 2018 Category: Neurology Source Type: research

Targeting Histone Deacetylase Activity to Arrest Cell Growth and Promote Neural Differentiation in Ewing Sarcoma
AbstractThere is an urgent need for advances in the treatment of Ewing sarcoma (EWS), an aggressive childhood tumor with possible neuroectodermal origin. Inhibition of histone deacetylases (HDAC) can revert aberrant epigenetic states and reduce growth in different experimental cancer types. Here, we investigated whether the potent HDAC inhibitor, sodium butyrate (NaB), has the ability to reprogram EWS cells towards a more differentiated state and affect their growth and survival. Exposure of two EWS cell lines to NaB resulted in rapid and potent inhibition of HDAC activity (1  h, IC50 1.5  mM) and a significant a...
Source: Molecular Neurobiology - February 3, 2018 Category: Neurology Source Type: research

Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex
AbstractLipid metabolism, specifically fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase (CPT) 1A, has been described to be an important actor of ghrelin action in hypothalamus. However, it is not known whether CPT1A and FAO mediate the effect of ghrelin on the cortex. Here, we show that ghrelin produces a differential effect on CPT1 activity and γ-aminobutyric acid (GABA) metabolism in the hypothalamus and cortex of mice. In the hypothalamus, ghrelin enhances CPT1A activity while GABA transaminase (GABAT) activity, a key enzyme in GABA shunt metabolism, is unaltered. However, in cortex CPT1A acti...
Source: Molecular Neurobiology - February 2, 2018 Category: Neurology Source Type: research

Brain-Derived Neurotrophic Factor Prevents Depressive-Like Behaviors in Early-Symptomatic YAC128 Huntington ’s Disease Mice
In conclusion, our results suggest that non-invasive administration of BDNF via the intranasal route may have important therapeutic potential for treating mood disturbances in early-symptomatic HD patients. (Source: Molecular Neurobiology)
Source: Molecular Neurobiology - January 31, 2018 Category: Neurology Source Type: research

Loss of Angelman Syndrome Protein E6AP Disrupts a Novel Antagonistic Estrogen-Retinoic Acid Transcriptional Crosstalk in Neurons
AbstractAngelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2 –15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the geneUBE3A, which is located in this region, and it has been shown that ...
Source: Molecular Neurobiology - January 31, 2018 Category: Neurology Source Type: research

Elastase-2 Knockout Mice Display Anxiogenic- and Antidepressant-Like Phenotype: Putative Role for BDNF Metabolism in Prefrontal Cortex
In this study, we addressed this question, submitting ELA2KO and wild-type (WT) mice to several models sensitive to anxiety- and depression-like, memory, and repetitive behaviors. Our data indicates a higher incidence of barbering behavior in ELA2KO compared to WT, as well as an anxiogenic phenotype, evaluated in the elevated plus maze (EPM). While a decrease in locomotor activity was observed in ELA2KO in EPM, this feature was not the main source of variation in the other parameters analyzed. The marble-burying test (MBT) indicated increase in repetitive behavior, observed by a higher number of buried marbles. The actimet...
Source: Molecular Neurobiology - January 30, 2018 Category: Neurology Source Type: research

Glia Maturation Factor Dependent Inhibition of Mitochondrial PGC-1 α Triggers Oxidative Stress-Mediated Apoptosis in N27 Rat Dopaminergic Neuronal Cells
In this study, we found that incubation of immortalized rat dopaminergic (N27) neurons with GMF influences the expression of peroxisome PGC-1α and increases oxidative stress, mitochondrial dysfunction, a nd apoptotic cell death. We show that incubation with GMF reduces the expression of PGC-1α with concomitant decreases in the mitochondrial complexes. Besides, there is increased oxidative stress and depolarization of mitochondrial membrane potential (MMP) in these cells. Further, GMF reduces tyrosi ne hydroxylase (TH) expression and shifts Bax/Bcl-2 expression resulting in release of cytochrome-c and increased ...
Source: Molecular Neurobiology - January 30, 2018 Category: Neurology Source Type: research

Disruption of De Novo Serine Synthesis in M üller Cells Induced Mitochondrial Dysfunction and Aggravated Oxidative Damage
In this study, we inhibited de novo serine synthesis using CBR-5884, a specific inhibitor of phosphoglycerate dehydrogenase (PHGDH, a rate limiting enzyme in de novo serine metabolism) in MIO-M1 cells (immortalized human Müller cells) and huPMCs (human primary Müller c ells) under mild oxidative stress. Alamar blue and LDH (lactate dehydrogenase) assays showed significantly reduced metabolic activities and increased cellular damage of Müller cells, when exposed to CBR-5884 accompanied by mild oxidative stress; however, CBR-5884 alone had little effect. The increa sed cellular damage was partially reversed by...
Source: Molecular Neurobiology - January 30, 2018 Category: Neurology Source Type: research