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Tesfaye W Tefera, Karin Borges
Although alterations in energy metabolism are known in ALS, the specific mechanisms leading to energy deficit are not understood. We measured metabolite levels derived from injected [1-13 C]glucose and [1,2-13 C]acetate (i.p.) in cerebral cortex and spinal cord extracts of wild type and hSOD1G93A mice at onset and mid disease stages using high-pressure liquid chromatography,1 H and13 C nuclear magnetic resonance spectroscopy. Levels of spinal and cortical CNS total lactate, [3-13 C]lactate, total alanine and [3-13 C]alanine, but not cortical glucose and [1-13 C]glucose, were reduced mostly at mid stage indicating impaired glycolysis...
January 1, 2018: Journal of Cerebral Blood Flow and Metabolism
Aziza Alrafiah, Evangelia Karyka, Ian Coldicott, Kayleigh Iremonger, Katherin E Lewis, Ke Ning, Mimoun Azzouz
Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene ( SMN1 ), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons...
June 15, 2018: Molecular Therapy. Methods & Clinical Development
Luigi Cavanna, Pietro Seghini, Camilla Di Nunzio, Elena Orlandi, Emanuele Michieletti, Elisa Maria Stroppa, Patrizia Mordenti, Chiara Citterio, Stefano Vecchia, Adriano Zangrandi
Central nervous system (CNS) metastases from cancers of the gastrointestinal tract (GIT) are rare, and occur in 0.16-0.69% of patients with gastric or gastro-esophageal (GE) junction cancer. Overexpression of the human epidermal growth factor 2 (HER-2) is associated with poor prognosis in the absence of HER-2-targeted therapy, and with an increased incidence of CNS metastases in patients with breast cancer. The role of HER-2 overexpression in CNS metastases is not well known in gastric adenocarcinoma. The purpose of the present retrospective study was to assess the incidence of CNS metastases and to evaluate the associations between the CNS and HER-2 status in a series of consecutive patients with gastric or GE junction cancer...
April 2018: Oncology Letters
Magdalini Tsintou, Kyriakos Dalamagkas, Alexander Seifalian
Central Nervous System (CNS) repair has been a challenge, due to limited CNS tissue regenerative capacity. The emerging tools that neural engineering has to offer have opened new pathways towards the discovery of novel therapeutic approaches for CNS disorders. Collagen has been a preferable material for neural tissue engineering due to its similarity to the extracellular matrix, its biocompatibility, and antigenicity. The aim was to compare properties of a plastically compressed collagen hydrogel with the ones of a promising collagen-genipin injectable hydrogel and a collagen-only hydrogel for clinical CNS therapy applications...
2018: International Journal of Biomaterials
Srikant Rangaraju, Syed Ali Raza, Noel Xiang'An Li, Ranjita Betarbet, Eric B Dammer, Duc Duong, James J Lah, Nicholas T Seyfried, Allan I Levey
In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as Aβ in Alzheimer's disease (AD). While CD11b+ CD45low microglia account for the majority of CNS MPs, a small population of CD11b+ CD45high CNS MPs is also recognized in AD that surround Aβ plaques. These transcriptionally and pathologically unique CD45high cells have unclear origin and undefined phagocytic characteristics...
2018: Frontiers in Immunology
Phillip Mackie, Joe Lebowitz, Leila Saadatpour, Emily Nickoloff, Peter Gaskill, Habibeh Khoshbouei
The second-most common neurodegenerative disease, Parkinson Disease (PD) has three hallmarks: dysfunctional dopamine transmission due, at least in part, to dopamine neuron degeneration; intracellular inclusions of α-synuclein aggregates; and neuroinflammation. The origin and interplay of these features remains a puzzle, as does the underlying mechanism of PD pathogenesis and progression. When viewed in the context of neuroimmunology, dopamine also plays a role in regulating peripheral immune cells. Intriguingly, plasma dopamine levels are altered in PD, suggesting collateral dysregulation of peripheral dopamine transmission...
March 15, 2018: Brain, Behavior, and Immunity
Yana Li, Shuna Sun, Zhiwen Ding, Chunjie Yang, Guoping Zhang, Qiu Jiang, Yunzeng Zou
Fibroblast growth factor binding proteins (FGFBPs) are a class of secreted proteoglycans that function as an extracellular chaperone for locally stored FGFs and enhance FGF signaling. To date, all three human FGFBP genes have been identified and one orthologue fgfbp1a has been studied in zebrafish embryos. Here, we described the cloning and expression patterns of four novel FGFBP orthologues in zebrafish, fgfbp1b, fgfbp2a, fgfbp2b, and fgfbp3. Quantitative PCR and whole-mount in situ hybridization results showed that all transcripts except fgfbp2a are initially expressed in a maternal manner...
March 15, 2018: Gene
Despoina Angeliki Stavropoulou, Emiel Van Reckem, Stefaan De Smet, Luc De Vuyst, Frédéric Leroy
Coagulase-negative staphylococci (CNS) are involved in colour and flavour formation of fermented meats. Their communities are established either spontaneously, as in some artisan-type products, or using a starter culture. The latter usually consists of Staphylococcus carnosus and/or Staphylococcus xylosus strains, although strains from other CNS species also have potential for application. However, it is not entirely clear how the fitness of alternative starter cultures within a fermented meat matrix compares to conventional ones and how this may be affected by processing conditions...
March 12, 2018: International Journal of Food Microbiology
Danica M Sutherland, Pavithra Aravamudhan, Terence S Dermody
Viruses are constantly engaged in a molecular arms race with the host, where efficient and tactical use of cellular receptors benefits critical steps in infection. Receptor use dictates initiation, establishment, and spread of viral infection to new tissues and hosts. Mammalian orthoreoviruses (reoviruses) are pervasive pathogens that use multiple receptors to overcome protective host barriers to disseminate from sites of initial infection and cause disease in young mammals. In particular, reovirus invades the central nervous system (CNS) with serotype-dependent tropism and disease...
2018: Advances in Virus Research
Freja Aksel Jacobsen, Alexander N Scherer, Jeppe Mouritsen, Hera Bragadóttir, B Thomas Bäckström, Samra Sardar, Dan Holmberg, Anthony J Koleske, Åsa Andersson
Multiple sclerosis is a neuroinflammatory degenerative disease, caused by activated immune cells infiltrating the CNS. The disease etiology involves both genetic and environmental factors. The mouse genetic locus, Eae27, linked to disease development in the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis, was studied in order to identify contributing disease susceptibility factors and potential drug targets for multiple sclerosis. Studies of an Eae27 congenic mouse strain, revealed that genetic variation within Eae27 influences EAE development...
March 17, 2018: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
Ilana Neuberger, Jacquelyn Garcia, Mariana L Meyers, Tamara Feygin, Dorothy I Bulas, David M Mirsky
Congenital central nervous system (CNS) infections are a cause of significant morbidity and mortality. The recent Zika virus outbreak raised awareness of congenital CNS infections. Imaging can be effective in diagnosing the presence and severity of infection. In this paper we review the clinical presentations and imaging characteristics of several common and less common congenital CNS infections.
April 2018: Pediatric Radiology
Cheng Wang, Xianlin Han, Fang Liu, Tucker A Patterson, Joseph P Hanig, Merle G Paule, William Slikker
Adverse effects related to central nervous system (CNS) function in pediatric populations may, at times, be difficult, if not impossible to evaluate. Prolonged anesthetic exposure affects brain excitability and anesthesia during the most sensitive developmental stages and has been associated with mitochondrial dysfunction, aberrant lipid metabolism and synaptogenesis, subsequent neuronal damage, as well as long-term behavioral deficits. There has been limited research evaluating whether and how anesthetic agents affect cellular lipids, the most abundant components of the brain other than water...
March 14, 2018: Toxicology and Applied Pharmacology
Nazia Karsan, Eric B Gonzales, Gregory Dussor
Acid-sensing ion channels (ASICs) are a family of ion channels, consisting of four members; ASIC1 to 4. These channels are sensitive to changes in pH and are expressed throughout the central and peripheral nervous systems-including brain, spinal cord, and sensory ganglia. They have been implicated in a number of neurological conditions such as stroke and cerebral ischemia, traumatic brain injury, and epilepsy, and more recently in migraine. Their expression within areas of interest in the brain in migraine, such as the hypothalamus and PAG, their demonstrated involvement in preclinical models of meningeal afferent signaling, and their role in cortical spreading depression (the electrophysiological correlate of migraine aura), has enhanced research interest into these channels as potential therapeutic targets in migraine...
March 16, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Irving Zucker
Breastfeeding women are excluded from clinical trials of psychoactive drugs because of ethical concerns. Animal testing, which often is predictive of adverse effects in humans, represents the only avenue available for assessing drug safety for human offspring exposed to drugs during lactation. I determined whether behavioral outcomes for children exposed during breastfeeding to antidepressants, anxiolytics, antipsychotics, anti-seizure medications, analgesics, sedatives, and marijuana can be predicted by rodent studies of offspring exposed to drugs during lactation...
March 16, 2018: Psychopharmacology
Patrick Belikan, Ulrike Bühler, Christina Wolf, Gautam K Pramanik, René Gollan, Frauke Zipp, Volker Siffrin
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Myelin-specific CD4+ Th lymphocytes are known to play a major role in both MS and its animal model experimental autoimmune encephalomyelitis (EAE). CCR7 is a critical element for immune cell trafficking and recirculation, that is, lymph node homing, under homeostatic conditions; blocking CCR7+ central memory cells from egress of lymph nodes is a therapeutic approach in MS. To define the effect of CD4+ T cell-specific constitutive deletion of CCR7 in the priming and effector phase in EAE, we used an active EAE approach in T cell reconstituted Rag1-/- mice, as well as adoptive transfer EAE, in which mice received in vitro-primed CCR7-/- or CCR7+/+ myelin Ag TCR-transgenic 2d2 Th17 cells...
March 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Dongyan Shi, Tongguan Tian, Shu Yao, Kelei Cao, Xingxing Zhu, Mingshun Zhang, Shuang Wen, Longjun Li, Meiqing Shi, Hong Zhou
Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) severely impacts patients' quality of life and leads to a poor prognosis. The current therapeutic protocol, corticosteroid administration, can also induce neuropsychiatric disorders. FTY720 is an immunomodulator that selectively confines lymphocytes in lymph nodes and reduces autoreactive T cell recruitment to the central nervous system (CNS). This study aimed to identify a novel therapeutic strategy for NPSLE. B6.MRL-lpr mice were treated with oral administration of FTY720 (2 mg/kg) three times per week for 12 weeks, to evaluate its efficacy in a model of NPSLE...
March 13, 2018: Brain, Behavior, and Immunity
Nicholas Beazley-Long, Catherine Elizabeth Moss, William Robert Ashby, Samuel Marcus Bestall, Fatimah Almahasneh, Alexandra Margaret Durrant, Andrew Vaughan Benest, Zoe Blackley, Kurt Ballmer-Hofer, Masanori Hirashima, Richard Phillip Hulse, David Owen Bates, Lucy Frances Donaldson
Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation...
March 13, 2018: Brain, Behavior, and Immunity
Andrea K H Stavoe, Erika L F Holzbaur
Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein...
March 13, 2018: Neuroscience Letters
Houfu Liu, Kelly Dong, Wandong Zhang, Scott G Summerfield, Georg C Terstappen
Recent years have seen a paradigm shift away from optimizing the brain:blood concentration ratio toward the more relevant brain:blood unbound concentration ratio (Kp,uu,br ) in CNS drug discovery. Here, we review the recent developments in the in silico and in vitro model systems to predict the Kp,uu,br of discovery compounds with special emphasis on the in-vitro-in-vivo correlation. We also discuss clinical 'translation' of rodent Kp,uu,br and highlight the future directions for improvement in brain penetration prediction...
March 13, 2018: Drug Discovery Today
Moumita Datta, Ori Staszewski, Elena Raschi, Maximilian Frosch, Nora Hagemeyer, Tuan Leng Tay, Thomas Blank, Mario Kreutzfeldt, Doron Merkler, Stephanie Ziegler-Waldkirch, Patrick Matthias, Melanie Meyer-Luehmann, Marco Prinz
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival...
March 7, 2018: Immunity
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