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https://www.readbyqxmd.com/read/28213588/a-differential-autophagy-dependent-response-to-dna-double-strand-brakes-in-bone-marrow-mesenchymal-stem-cells-from-sporadic-als-patients
#1
Shane Wald-Altman, Edward Pichinuk, Or Kakhlon, Miguel Weil
Amyotrophic Lateral Sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors leading to neuromuscular degeneration and pathophysiological implications in non-neural systems. Our previous work showed abnormal transcriptional expression levels of biomarker genes in non-neuronal cell samples from ALS patients. The same genes proved to be differentially expressed in brain, spinal cord and muscle of the SOD1(G93A) ALS mouse model. These observations support the pathophysiological relevance of the ALS biomarkers discovered in human mesenchymal stem cells (hMSC) isolated from bone marrow samples of ALS patients (ALS-hMSC)...
February 16, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28212525/ablation-of-ferroptosis-regulator-glutathione-peroxidase-4-in-forebrain-neurons-promotes-cognitive-impairment-and-neurodegeneration
#2
William Sealy Hambright, Rene Solano Fonseca, Liuji Chen, Ren Na, Qitao Ran
Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis...
February 1, 2017: Redox Biology
https://www.readbyqxmd.com/read/28211895/electroacupuncture-attenuates-cfa-induced-inflammatory-pain-by-suppressing-nav1-8-through-s100b-trpv1-opioid-and-adenosine-pathways-in-mice
#3
Hsien-Yin Liao, Ching-Liang Hsieh, Chun-Ping Huang, Yi-Wen Lin
Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund's adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28210902/deletion-of-mammalian-sterile-20-like-kinase-1-attenuates-neuronal-loss-and-improves-locomotor-function-in-a-mouse-model-of-spinal-cord-trauma
#4
Pan-Feng Wang, Da-Yuan Xu, Yuntong Zhang, Xiao-Bin Liu, Yan Xia, Pan-Yu Zhou, Qing-Ge Fu, Shuo-Gui Xu
Neuronal cell death following spinal cord injury (SCI) is an important contributor to neurological deficits. The purpose of our work was to delineate the function of mammalian sterile 20-like kinase 1 (Mst1), a pro-apoptotic kinase and key mediator of apoptotic signaling, in the pathogenesis of an experimental mouse model of SCI. Male mice received a mid-thoracic spinal contusion injury, and it was found that phosphorylation of Mst1 at the injured site was enhanced significantly following SCI. Furthermore, when compared to the wild-type controls, Mst1-deficient mice displayed improved locomotor function by increased Basso mouse scale score...
February 16, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28210054/sagittal-plane-spinal-mobility-is-associated-with-dynamic-balance-ability-of-community-dwelling-elderly-people
#5
Yahiko Takeuchi
[Purpose] The purpose of this study was to clarify the correlation between the range of spinal mobility on the sagittal plane and the dynamic balance ability of elderly people living in communities. [Subjects and Methods] The persons studied were 31 healthy elderly people living in the community (16 females and 15 males). The range of mobility of the participants' spines in the sagittal plane was measured by using a spinal mouse(®). Balance ability was evaluated by using Functional reach (FR), Timed up and go (TUG), and Maximum walking speed (MWS)...
January 2017: Journal of Physical Therapy Science
https://www.readbyqxmd.com/read/28209777/cd6-as-a-potential-target-for-treating-multiple-sclerosis
#6
Yan Li, Nora G Singer, Joy Whitbred, Michael A Bowen, David A Fox, Feng Lin
CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS...
February 16, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28205575/cu-ii-atsm-improves-the-neurological-phenotype-and-survival-of-sod1-g93a-mice-and-selectively-increases-enzymatically-active-sod1-in-the-spinal-cord
#7
James B Hilton, Stephen W Mercer, Nastasia K H Lim, Noel G Faux, Gojko Buncic, Joseph S Beckman, Blaine R Roberts, Paul S Donnelly, Anthony R White, Peter J Crouch
Ubiquitous expression of mutant Cu/Zn-superoxide dismutase (SOD1) selectively affects motor neurons in the central nervous system (CNS), causing the adult-onset degenerative disease amyotrophic lateral sclerosis (ALS). The CNS-specific impact of ubiquitous mutant SOD1 expression is recapitulated in transgenic mouse models of the disease. Here we present outcomes for the metallo-complex Cu(II)(atsm) tested for therapeutic efficacy in mice expressing SOD1(G93A) on a mixed genetic background. Oral administration of Cu(II)(atsm) delayed the onset of neurological symptoms, improved locomotive capacity and extended overall survival...
February 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28202084/aprepitant-limits-in-vivo-neuroinflammatory-responses-in-a-rhesus-model-of-lyme-neuroborreliosis
#8
Alejandra N Martinez, Amanda R Burmeister, Geeta Ramesh, Lara Doyle-Meyers, Ian Marriott, Mario T Philipp
BACKGROUND: Substance P (SP) is produced at high levels in the central nervous system (CNS), and its target receptor, neurokinin 1 receptor (NK-1R), is expressed by glia and leukocytes. This tachykinin functions to exacerbate inflammatory responses at peripheral sites. Moreover, SP/NK-1R interactions have recently been associated with severe neuroinflammation and neuronal damage. We have previously demonstrated that NK-1R antagonists can limit neuroinflammatory damage in a mouse model of bacterial meningitis...
February 15, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28199834/early-administration-of-gabapentinoids-improves-motor-recovery-after-human-spinal-cord-injury
#9
Freda M Warner, Jacquelyn J Cragg, Catherine R Jutzeler, Frank Röhrich, Norbert Weidner, Marion Saur, Doris D Maier, Christian Schuld, Armin Curt, John K Kramer
The anticonvulsant pregabalin promotes neural regeneration in a mouse model of spinal cord injury (SCI). We have also previously observed that anticonvulsants improve motor outcomes following human SCI. The present study examined the optimal timing and type of anticonvulsants administered in a large, prospective, multi-center, cohort study in acute SCI. Mixed-effects regression techniques were used to model total motor scores at 1, 3, 6, and 12 months post injury. We found that early (not late) administration of anticonvulsants significantly improved motor recovery (6...
February 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/28199829/preclinical-efficacy-failure-of-human-cns-derived-stem-cells-for-use-in-the-pathway-study-of%C3%A2-cervical-spinal-cord-injury
#10
Aileen J Anderson, Katja M Piltti, Mitra J Hooshmand, Rebecca A Nishi, Brian J Cummings
We previously showed the efficacy of multiple research cell lines (RCLs) of human CNS neural stem cells (HuCNS-SCs) in mouse and rat models of thoracic spinal cord injury (SCI), supporting a thoracic SCI clinical trial. Experts recommend in vivo preclinical testing of the intended clinical cell lot/line (CCL) in models with validity for the planned clinical target. We therefore tested the efficacy of two HuCNS-SC lines in cervical SCI: one RCL, and one CCL intended for use in the Pathway Study of cervical SCI in man...
February 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/28197100/rho-kinase-inhibition-with-fasudil-in-the-sod1-g93a-mouse-model-of-amyotrophic-lateral-sclerosis-symptomatic-treatment-potential-after-disease-onset
#11
René Günther, Alexander Balck, Jan C Koch, Tobias Nientiedt, Michael Sereda, Mathias Bähr, Paul Lingor, Lars Tönges
Despite an improved understanding of the genetic background and the pathomechanisms of amyotrophic lateral sclerosis (ALS) no novel disease-modifying therapies have been successfully implemented in clinical routine. Riluzole still remains the only clinically approved substance in human ALS treatment with limited efficacy. We have previously identified pharmacological rho kinase (ROCK) inhibitors as orally applicable substances in SOD1.G93A transgenic ALS mice (SOD1(G93A)), which are able to extend survival time and improve motor function after presymptomatic treatment...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28195039/speed-and-segmentation-control-mechanisms-characterized-in-rhythmically-active-circuits-created-from-spinal-neurons-produced-from-genetically-tagged-embryonic-stem-cells
#12
Matthew J Sternfeld, Christopher A Hinckley, Niall J Moore, Matthew T Pankratz, Kathryn L Hilde, Shawn P Driscoll, Marito Hayashi, Neal D Amin, Dario Bonanomi, Wesley D Gifford, Kamal Sharma, Martyn Goulding, Samuel L Pfaff
Flexible neural networks, such as the interconnected spinal neurons that control distinct motor actions, can switch their activity to produce different behaviors. Both excitatory (E) and inhibitory (I) spinal neurons are necessary for motor behavior, but the influence of recruiting different ratios of E-to-I cells remains unclear. We constructed synthetic microphysical neural networks, called circuitoids, using precise combinations of spinal neuron subtypes derived from mouse stem cells. Circuitoids of purified excitatory interneurons were sufficient to generate oscillatory bursts with properties similar to in vivo central pattern generators...
February 14, 2017: ELife
https://www.readbyqxmd.com/read/28192080/evo-engineering-and-the-cellular-and-molecular-origins-of-the-vertebrate-spinal-cord
#13
REVIEW
Ben Steventon, Alfonso Martinez Arias
The formation of the spinal cord during early embryonic development in vertebrate embryos is a continuous process that begins at gastrulation and continues through to the completion of somitogenesis. Despite the conserved usage of patterning mechanisms and gene regulatory networks that act to generate specific spinal cord progenitors, there now exists two seemingly disparate models to account for their action. In the first, a posteriorly localized signalling source transforms previously anterior-specified neural plate into the spinal cord...
February 9, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28191872/spatiotemporal-correlation-of-spinal-network-dynamics-underlying-spasms-in-chronic-spinalized-mice
#14
Carmelo Bellardita, Vittorio Caggiano, Roberto Leiras, Vanessa Caldeira, Andrea Fuchs, Julien Bouvier, Peter Löw, Ole Kiehn
Spasms after spinal cord injury (SCI) are debilitating involuntary muscle contractions that have been associated with increased motor neuron excitability and decreased inhibition. However, whether spasms involve activation of premotor spinal excitatory neuronal circuits is unknown. Here we use mouse genetics, electrophysiology, imaging and optogenetics to directly target major classes of spinal interneurons as well as motor neurons during spasms in a mouse model of chronic SCI. We find that assemblies of excitatory spinal interneurons are recruited by sensory input into functional circuits to generate persistent neural activity, which interacts with both the graded expression of plateau potentials in motor neurons to generate spasms, and inhibitory interneurons to curtail them...
February 13, 2017: ELife
https://www.readbyqxmd.com/read/28188847/pharmacological-inhibition-of-spinal-cord-injury-stimulated-ribosomal-biogenesis-does-not-affect-locomotor-outcome
#15
Ewa Kilanczyk, Kariena R Andres, Justin Hallgren, Sujata Saraswat Ohri, Marikki Laiho, Scott R Whittemore, Michal Hetman
After unresolved endoplasmic reticulum stress, recovery of protein synthesis including increased expression of ribosomal components and translation factors may induce cell death. Using a mouse model of moderate contusive spinal cord injury (SCI) at the T9 level, upregulation of ribosomal biogenesis was observed in the injury epicenter at 24h after trauma. Such upregulation coincided with endoplasmic reticulum stress response as previously reported in this model. It was also accompanied by changes in expression of many other genes associated with translational regulation...
February 7, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28187742/regulatory-role-of-cytosolic-phospholipase-a2-alpha-in-the-induction-of-cd40-in-microglia
#16
Yafa Fetfet Malada-Edelstein, Nurit Hadad, Rachel Levy
BACKGROUND: The aberrant expression of CD40, a co-stimulatory receptor found on the antigen-presenting cells, is involved in the pathogenesis of various degenerative diseases. Our previous study demonstrated that the reduction of cytosolic phospholipase A2 alpha (cPLA2α) protein overexpression and activation in the spinal cord of a mouse model of ALS, hmSOD1 G93A, inhibited CD40 upregulation in microglia. The present study was designed to determine whether cPLA2α has a direct, participatory role in the molecular events leading to CD40 induction...
February 10, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28177520/broad-spectrum-efficacy-with-ly2969822-an-oral-prodrug-of-metabotropic-glutamate-2-3-mglu2-3-receptor-agonist-ly2934747-in-rodent-pain-models
#17
Michael P Johnson, Mark A Muhlhauser, Eric S Nisenbaum, Rosa M A Simmons, Beth M Forster, Kelly L Knopp, Lijuan Yang, Denise Morrow, Dominic L Li, Jeffrey D Kennedy, Steven Swanson, James A Monn
BACKGROUND AND PURPOSE: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. EXPERIMENTAL APPROACH: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent, and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioral assessments of allodynia, hyperalgesia, or nocifensive behaviors in preclinical pain models were determined after administration of LY2969822 of 0...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28172892/effect-of-genetic-background-on-the-phenotype-of-the-smn2b-mouse-model-of-spinal-muscular-atrophy
#18
Mehdi Eshraghi, Emily McFall, Sabrina Gibeault, Rashmi Kothary
No abstract text is available yet for this article.
October 15, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28167615/the-familial-dysautonomia-disease-gene-ikbkap-elp1-is-required-in-the-developing-and-adult-central-nervous-system
#19
Marta Chaverra, Lynn George, Marc Mergy, Hannah Waller, Katharine Kujawa, Connor Murnion, Ezekiel Sharples, Julian Thorne, Nathaniel Podgajny, Andrea Grindeland, Yumi Ueki, Steven Eiger, Cassie Cusick, A Michael Babcock, George A Carlson, Frances Lefcort
Hereditary sensory and autonomic neuropathies (HSANs) are a genetically and clinically diverse group of disorders defined by peripheral nervous system (PNS) dysfunction. HSAN Type III, Familial Dysautonomia (FD), results from a single base mutation in the gene IKBKAP that encodes a scaffolding unit for a multi-subunit complex Elongator. Since mutations in other Elongator subunits (ELP2-4) are associated with central nervous system (CNS) disorders, the goal of this study was to investigate a potential CNS requirement for Ikbkap/Elp1 The sensory and autonomic pathophysiology of FD is fatal, with the majority of patients dying by age 40...
February 6, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28148646/microcircuit-formation-following-transplantation-of-mouse-embryonic-stem-cell-derived-neurons-into-peripheral-nerve
#20
Philippe Magown, Victor F Rafuse, Robert M Brownstone
Motoneurons derived from embryonic stem cells can be transplanted into the tibial nerve, where they extend axons to functionally innervate target muscle. Here, we studied spontaneous muscle contractions in these grafts three months following transplantation. One-half of the transplanted grafts generated rhythmic muscle contractions of variable patterns, either spontaneously or in response to brief electrical stimulation. Activity generated by transplanted embryonic stem cell-derived neurons was driven by glutamate and was modulated by muscarinic and GABAergic/glycinergic transmission...
February 1, 2017: Journal of Neurophysiology
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