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https://www.readbyqxmd.com/read/29901635/rapamycin-treatment-for-amyotrophic-lateral-sclerosis-protocol-for-a-phase-ii-randomized-double-blind-placebo-controlled-multicenter-clinical-trial-rap-als-trial
#1
Jessica Mandrioli, Roberto D'Amico, Elisabetta Zucchi, Annalisa Gessani, Nicola Fini, Antonio Fasano, Claudia Caponnetto, Adriano Chiò, Eleonora Dalla Bella, Christian Lunetta, Letizia Mazzini, Kalliopi Marinou, Gianni Sorarù, Sara de Biasi, Domenico Lo Tartaro, Marcello Pinti, Andrea Cossarizza
INTRODUCTION: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions...
June 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29898390/psychedelics-promote-structural-and-functional-neural-plasticity
#2
Calvin Ly, Alexandra C Greb, Lindsay P Cameron, Jonathan M Wong, Eden V Barragan, Paige C Wilson, Kyle F Burbach, Sina Soltanzadeh Zarandi, Alexander Sood, Michael R Paddy, Whitney C Duim, Megan Y Dennis, A Kimberley McAllister, Kassandra M Ori-McKenney, John A Gray, David E Olson
Atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of depression and related disorders. The ability to promote both structural and functional plasticity in the PFC has been hypothesized to underlie the fast-acting antidepressant properties of the dissociative anesthetic ketamine. Here, we report that, like ketamine, serotonergic psychedelics are capable of robustly increasing neuritogenesis and/or spinogenesis both in vitro and in vivo. These changes in neuronal structure are accompanied by increased synapse number and function, as measured by fluorescence microscopy and electrophysiology...
June 12, 2018: Cell Reports
https://www.readbyqxmd.com/read/29883228/effectiveness-of-low-dose-of-rapamycin-in-preventing-seizure-induced-anxiety-like-behavior-cognitive-impairment-and-defects-in-neurogenesis-in-developing-rats
#3
Furong Liu, Meiling Wu, Jiejing Kai, Jingyin Dong, Binbin Zhang, Luna Liu, Feng Zhu, Ling-Hui Zeng
Previous studies have demonstrated that rapamycin prevents seizure-induced anxiety-like behaviors. However, rapamycin had been used at a higher dose of 3mg/kg and resulted in side effects in immature animals. The present work was designed to explore whether a lower dose of rapamycin has similar efficacy but has milder side effects. Acute seizures were induced by injection of pilocarpine at postnatal 10 day Sprague-Dawley rats. Western blot analysis was used to detect changes in mTOR pathway after seizure...
June 8, 2018: International Journal of Neuroscience
https://www.readbyqxmd.com/read/29861134/non-canonical-mtor-independent-role-of-depdc5-in-regulating-gabaergic-network-development
#4
Amrutha Swaminathan, Rahma Hassan-Abdi, Solène Renault, Aleksandra Siekierska, Raphaëlle Riché, Meijiang Liao, Peter A M de Witte, Constantin Yanicostas, Nadia Soussi-Yanicostas, Pierre Drapeau, Éric Samarut
Mutations in DEPDC5 are causal factors for a broad spectrum of focal epilepsies, but the underlying pathogenic mechanisms are still largely unknown. To address this question, a zebrafish depdc5 knockout model showing spontaneous epileptiform events in the brain, increased drug-induced seizure susceptibility, general hypoactivity, premature death at 2-3 weeks post-fertilization, as well as the expected hyperactivation of mTOR signaling was developed. Using this model, the role of DEPDC5 in brain development was investigated using an unbiased whole-transcriptomic approach...
May 22, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29846820/whole-exome-sequencing-in-dandy-walker-variant-with-intellectual-disability-reveals-an-activating-cip2a-mutation-as-novel-genetic-cause
#5
Chin-An Yang, I-Ching Chou, Der-Yang Cho, Chien-Yu Lin, Hsi-Yuan Huang, Yu-Chen Ho, Ting-Yuan Liu, Ying-Hsuan Li, Jan-Gowth Chang
Dandy-Walker malformation (DWM) has been reported to have heterogeneous causes, including mutations in genes of fibroblast growth factors and in genes in the sonic hedgehog (Shh) signaling pathway. Here, we identified an activating cancerous inhibitor of protein phosphatase 2A (CIP2A) p.D269V mutation, located at the predicted protein-protein interaction groove, as a novel genetic cause of Dandy-Walker variant (DWV). CIP2A has been reported as an oncoprotein promoting tumor survival via inhibition of protein phosphatase 2A (PP2A)...
May 30, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29802157/defect-of-branched-chain-amino-acid-metabolism-promotes-the-development-of-alzheimer-s-disease-by-targeting-the-mtor-signaling
#6
Huajie Li, Dan Ye, Wei Xie, Fei Hua, Yiling Yang, Jian Wu, Aifang Gu, Yi Ren, Keshi Mao
Diabetes is a risk factor for Alzheimer's disease (AD) in humans. Branched-chain amino acids (BCAAs, namely valine, leucine, and isoleucine) metabolic defect is observed in human diabetes, which is associated with insulin resistance. But whether BCAAs connect diabetes and AD remains unknown. Here we show that BCAA metabolic defect may be one of the drivers of the AD. BCAA levels were increased in the blood in human patients and mice with diabetes or AD. BCAAs-eriched diet promoted the development of AD in mice as evidenced by the behavior and pathological analysis...
May 25, 2018: Bioscience Reports
https://www.readbyqxmd.com/read/29793507/targeting-energy-metabolism-via-the-mitochondrial-pyruvate-carrier-as-a-novel-approach-to-attenuate-neurodegeneration
#7
REVIEW
Emmanuel Quansah, Wouter Peelaerts, J William Langston, David K Simon, Jerry Colca, Patrik Brundin
Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria...
May 24, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29780409/beneficial-effects-of-resveratrol-mediated-inhibition-of-the-mtor-pathway-in-spinal-cord-injury
#8
REVIEW
Jingying Zhou, Xue Huo, Benson O A Botchway, Luyao Xu, Xiaofang Meng, Songou Zhang, Xuehong Liu
Spinal cord injury (SCI) causes a high rate of morbidity and disability. The clinical features of SCI are divided into acute, subacute, and chronic phases according to its pathophysiological events. The mammalian target of rapamycin (mTOR) signaling pathway plays an important role in cell death and inflammation in the acute phase and neuroregeneration in the subacute/chronic phases at different times. Resveratrol has the potential of regulating cell growth, proliferation, metabolism, and angiogenesis through the mTOR signaling pathway...
2018: Neural Plasticity
https://www.readbyqxmd.com/read/29778488/the-2016-bernard-sachs-lecture-timing-in-morphogenesis-and-genetic-gradients-during-normal-development-and-in-malformations-of-the-nervous-system
#9
REVIEW
Harvey B Sarnat
Nervous system development is quadradimensional. Both normal ontogenesis and developmental malformations are explained in the context of the fourth dimension, timing. Timing of the onset of either the genetic expression of a mutation or an epigenetic event that may be teratogenic is primordial in determining morphogenesis and the forms of malformations with their functional consequences. Multiple genotypes may cause similar phenotypes or a single genotype with different degrees of retained normal genetic expression may result in variable phenotypes...
March 30, 2018: Pediatric Neurology
https://www.readbyqxmd.com/read/29773580/resistin-inhibits-neuronal-autophagy-through-toll-like-receptor-4
#10
Jie Miao, Yacir Benomar, Sarah Al-Rifai, Ghislaine Poizat, Laure Riffault, Delphine Crepin, Mohammed Taouis
Autophagy is as a non-selective degradation pathway induced in energy-deprived cells and in non-starved cells by participating in cellular inflammatory responses mainly through the elimination of injured and aged mitochondria that constitute an important source of reactive oxygen species. We have previously reported that resistin/TLR4 signaling pathway induces inflammation and insulin resistance in neuronal cell. However, the impact of resistin-induced inflammation on neuronal autophagy is unknown. In the present study, we hypothesized that resistin-induced neuroinflammation could be attributed, at least partially, to the impairment of autophagy pathways in neuronal cells...
May 17, 2018: Journal of Endocrinology
https://www.readbyqxmd.com/read/29770442/current-concepts-in-the-neuropathogenesis-of-mucolipidosis-type-iv
#11
REVIEW
Lauren C Boudewyn, Steven U Walkley
Mucolipidosis type IV (MLIV) is an autosomal recessive, lysosomal storage disorder causing progressively severe intellectual disability, motor and speech deficits, retinal degeneration often culminating in blindness, and systemic disease causing a shortened lifespan. MLIV results from mutations in the gene MCOLN1 encoding the transient receptor potential channel mucolipin-1. It is an ultra-rare disease and is currently known to affect just over 100 diagnosed individuals. The last decade has provided a wealth of research focused on understanding the role of the enigmatic mucolipin-1 protein in cell and brain function and how its absence causes disease...
May 16, 2018: Journal of Neurochemistry
https://www.readbyqxmd.com/read/29763645/agmatine-potentiates-neuroprotective-effects-of-subthreshold-concentrations-of-ketamine-via-mtor-s6-kinase-signaling-pathway
#12
Mauren K Tavares, Suellen Dos Reis, Nicolle Platt, Isabella A Heinrich, Ingrid A V Wolin, Rodrigo B Leal, Manuella P Kaster, Ana Lúcia S Rodrigues, Andiara E Freitas
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most robust neurobiological findings in the pathophysiology of major depressive disorder (MDD) over the last 40 years. The persistent increase in glucocorticoids levels induces morphological and anatomical changes in the brain, especially in the hippocampus. Ketamine represents a major advance for the treatment of MDD, however the psychotomimetic effects of this compound limit its widespread use. Agmatine is a neuromodulator that has been shown to be a putative novel and well-tolerated antidepressant/augmenter drug...
May 12, 2018: Neurochemistry International
https://www.readbyqxmd.com/read/29761115/depdc5-knockdown-causes-mtor-dependent-motor-hyperactivity-in-zebrafish
#13
Hortense de Calbiac, Adriana Dabacan, Elise Marsan, Hervé Tostivint, Gabrielle Devienne, Saeko Ishida, Eric Leguern, Stéphanie Baulac, Raul C Muresan, Edor Kabashi, Sorana Ciura
Objective: DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Methods: Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders...
May 2018: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/29755318/arc-3-utr-splicing-leads-to-dual-and-antagonistic-effects-in-fine-tuning-arc-expression-upon-bdnf-signaling
#14
Chiara Paolantoni, Simona Ricciardi, Veronica De Paolis, Chinenye Okenwa, Caterina Catalanotto, Maria T Ciotti, Antonino Cattaneo, Carlo Cogoni, Corinna Giorgi
Activity-regulated cytoskeletal associated protein (Arc) is an immediate-early gene critically involved in synaptic plasticity and memory consolidation. Arc mRNA is rapidly induced by synaptic activation and a portion is locally translated in dendrites where it modulates synaptic strength. Being an activity-dependent effector of homeostatic balance, regulation of Arc is uniquely tuned to result in short-lived bursts of expression. Cis -Acting elements that control its transitory expression post-transcriptionally reside primarily in Arc mRNA 3' UTR...
2018: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/29751355/targeting-of-microrna-21-5p-protects-against-seizure-damage-in-a-kainic-acid-induced-status-epilepticus-model-via-pten-mtor
#15
Chongyang Tang, Yunhe Gu, Haiyang Wang, Hongmei Wu, Yu Wang, Yao Meng, Zhibin Han, Yifei Gu, Wei Ma, Zhenfeng Jiang, Yuanyuan Song, Meng Na, Dunyue Lu, Zhiguo Lin
OBJECTIVE: Studies have shown that microRNAs play a role in the development of epilepsy by regulating downstream target messenger (m)RNA. The present study aims to determine the changes associated with microRNA-21-5p (miR-21-5p) during epileptogenesis in a kainic acid rat model, and to assess whether the PTEN-mTOR pathway is a target of miR-21-5p. METHOD: Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the quantitative expressions of miR-21-5p and PTEN, and Western blotting was used to test the activity of mTOR in the acute, latent, and chronic stages of epileptogenesis...
May 4, 2018: Epilepsy Research
https://www.readbyqxmd.com/read/29749694/trimethylamine-n-oxide-promotes-brain-aging-and-cognitive-impairment-in-mice
#16
Dang Li, Yilang Ke, Rui Zhan, Changjie Liu, Mingming Zhao, Aiping Zeng, Xiaoyun Shi, Liang Ji, Si Cheng, Bing Pan, Lemin Zheng, Huashan Hong
Gut microbiota can influence the aging process and may modulate aging-related changes in cognitive function. Trimethylamine-N-oxide (TMAO), a metabolite of intestinal flora, has been shown to be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24-week-old senescence-accelerated prone mouse strain 8 (SAMP8) and age-matched senescence-accelerated mouse resistant 1 (SAMR1) mice for 16 weeks...
May 10, 2018: Aging Cell
https://www.readbyqxmd.com/read/29740323/the-selective-antagonism-of-adenosine-a-2b-receptors-reduces-the-synaptic-failure-and-neuronal-death-induced-by-oxygen-and-glucose-deprivation-in-rat-ca1-hippocampus-in-vitro
#17
Irene Fusco, Filippo Ugolini, Daniele Lana, Elisabetta Coppi, Ilaria Dettori, Lisa Gaviano, Daniele Nosi, Federica Cherchi, Felicita Pedata, Maria G Giovannini, Anna M Pugliese
Ischemia is a multifactorial pathology characterized by different events evolving in time. Immediately after the ischemic insult, primary brain damage is due to the massive increase of extracellular glutamate. Adenosine in the brain increases dramatically during ischemia in concentrations able to stimulate all its receptors, A1 , A2A , A2B , and A3 . Although adenosine exerts clear neuroprotective effects through A1 receptors during ischemia, the use of selective A1 receptor agonists is hampered by their undesirable peripheral side effects...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29738527/defensive-effect-of-microrna-200b-c-against-amyloid-beta-peptide-induced-toxicity-in-alzheimer-s-disease-models
#18
Sayuri Higaki, Masashi Muramatsu, Akio Matsuda, Kenji Matsumoto, Jun-Ichi Satoh, Makoto Michikawa, Shumpei Niida
MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice...
2018: PloS One
https://www.readbyqxmd.com/read/29736615/bdnf-reduces-eef2-phosphorylation-and-enhances-novel-protein-synthesis-in-the-growth-cones-of-dorsal-root-ganglia-neurons
#19
Osamu Hoshi, Ayana Sugizaki, Yuichiro Cho, Nobuyuki Takei
The local translation, which is regulated by extracellular stimuli such as guidance molecules, in growth cones of neurons provides a molecular mechanism for axonal development. In this study, we performed immunocytochemistry together with atomic force microscopy to investigate the localization of ribosomal proteins in the growth cones of rat dorsal root ganglion (DRG) neurons. The immunoreactivity of ribosomal protein P0/1/2 and S6, and novel protein synthesis were observed in the central, sterically bulky region of growth cones...
May 7, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29734780/cpkc%C3%AE-modulated-sequential-reactivation-of-mtor-inhibited-autophagic-flux-in-neurons-exposed-to-oxygen-glucose-deprivation-reperfusion
#20
Rongrong Hua, Song Han, Nan Zhang, Qingqing Dai, Ting Liu, Junfa Li
We have reported that conventional protein kinase Cγ (cPKCγ)-modulated neuron-specific autophagy improved the neurological outcome of mice following ischemic stroke through the Akt-mechanistic target of rapamycin (mTOR) pathway. However, its detailed molecular mechanism remains unclear. In this study, primary cortical neurons from postnatal one-day-old C57BL/6J cPKCγ wild-type ( cPKCγ +/+ ) and knockout ( cPKCγ −/− ) mice suffering oxygen glucose deprivation/reperfusion (OGD/R) were used to simulate ischemia/reperfusion injury in vitro...
May 6, 2018: International Journal of Molecular Sciences
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