DOCSLIB.ORG

The Role of SARM1 in Traumatic Axonopathy in the Mouse Visual System

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of SARM1 in Traumatic Axonopathy in the Mouse Visual System The role of SARM1 in traumatic axonopathy in the mouse visual system. Youngrim Lee,1 Athanasios S. Alexandris,1 Mohamed Lehar4, Jiwon Ryu,1 Zahra Alam1, Payton Flores1, Vassilis E. Koliatsos1,2,3 Departments of Pathology,1 Neurology,2 and Psychiatry and Behavioral Sciences,3 Otolaryngology-HNS4 | Johns Hopkins University School of Medicine | Baltimore, MD Introduction & Aims Methods Results Traumatic brain injury (TBI) has been a major cause of adult mortality and permanent Stereological analysis. disability, including cognitive, psychosocial, and physical deficits. One of the main Unbiased and efficient estimation of intact and damaged myelinated axons in the ON 2. Significant axon loss and ongoing pathology are present in both genotype groups after TBI. neuropathologies contributing to the permanent disability in TBI patients is traumatic was performed by an investigator blinded to experimental groups, using Stereo The number of intact axons significantly decreases while the number of damaged axons dramatically increases at 21 days axonal injury (TAI). TAI is a primary axonal insult resulted from rotational acceleration of Investigator® software (Microbrightfield Inc., Williston, VT) under 100x magnification. after IA-TBI in both WT and SARM1 KO mice. It is also important to note that the SARM1 KO mice have greater number of the head typically during motor vehicle crashes and high-impact falls. TAI initiates and Systematic random sampling was chosen with the following sampling parameters: intact axons than WT mice at baseline (p = 0.0018). Additionally, a significant loss of total axons is present after IA-TBI in both genotype groups. Bar graphs show means with standard deviation (SD). An independent t-Test was used to determine triggers an axonal program of self-destruction called Wallerian degeneration (WD), counting frame size (4 x 4μm), grid size (17.89 x 17.89μm), sampling fraction (4%). The statistically significant differences between the means in addition to one-tailed p values. A p value <0.05 was considered as total number of axons was automatically estimated by the software (Koschade et al., which results in distal axon fragmentation and degeneration. However, the initiation of statistically significant. WT n = 8 sham, n = 10 IA-TBI; SARM1 KO n = 8 sham, n = 9 IA-TBI. WD requires the activation of Sterile alpha and TIR motif containing 1 (SARM1), which is 2019). a key regulator in a conserved axon death pathway involved in WD (Koliatsos & The criteria for intact and damaged axons: Alexandris, 2019). • Intact axon is featured with organized cytoskeletal structure and compact Thus, this SARM1-mediated axon death pathway has been investigated as a target for myelin. Thickness of myelin is proportional to axon diameter. acute interventions that could mitigate axonal degeneration and preserve neurological • Damaged axon is characterized by collapsed cytoskeleton (darkening of function following TBI. Previous studies have demonstrated the protective effect of axoplasm) and/or abnormal myelin (i.e. myelin thickening, myelin outfolding, SARM1 genetic deletion against axon degeneration in corpus callosum (CC) and disintegration of myelin sheath). corticospinal tract (CST) of mice subjected to injury in a closed head TBI model at early phase post-injury time points (Henninger et al., 2016; Ziogas et al., 2018; Armstrong et al., 2019). In contrast, there was no axonal protection observed in CC of the TBI-induced Results mice at late phase post-injury time point (Armstrong et al., 2019). 1. A significant population of the damaged axons is present in the ON of both Although there has been studies focusing on WD in the optic nerve (ON) stretch-injury WT and SARM1 KO mice on day 21 post IA-TBI injury, indicating the model of TBI (Maxwell et al., 2015), there has not been studies investigating the effect of presence of ongoing degeneration. A and B show the population of the intact axons. 3. SARM1 deletion reduces ongoing pathology afterTBI. SARM1 deletion on axon degeneration after TBI in ON. Therefore, we conducted a On the other hand, C and D show many profiles of the damaged axons, including myelin To determine the protective effect of SARM1 deletion on axon degeneration unbiasedly, it was essential to normalize the baselines of WT and SARM1 KO. Thus, the intact axon survival rate was calculated by comparing to shams per genotype. The stereological analysis to assess the protective effect of SARM1 deletion on traumatic outfoldings (Blue arrows), disintegration of myelin sheath (green arrows), and darkening of intact axon survival rate is higher in SARM1 KO mice than the one in WT mice; however, the difference in the intact axon axonopathy of the mouse ON after impact acceleration TBI in the long term. axoplasm (yellow arrows). All pictures were taken under 100x magnification using a light survival rate between two groups is not statistically significant (p = 0.10). On the other hand, the percentage of damage axons microscope. *The scale bar indicates 50μm. is significantly lower in SARM1 KO mice than the one in WT mice (p=0.022), meaning that SARM1 deletion protects against Materials and Methods WT SARM1 KO chronic pathology after TBI. A B Experimental animals. The subjects of the experiment were 10 weeks old male mice (n=35) and divided into 2 genotype groups: WT (Sarm1+/+) (n=16) and SARM1 KO (Sarm1-/- ) mice (n=19). Subsequently, each genotype group was separated into two SHAM groups: Sham group and injury group exposed to the impact acceleration (IA) method of TBI (IA-TBI group). C D Impact acceleration (IA) model of TBI. IA injury was produced under gas anesthesia with 2% isoflurane. A 5-mm-diameter steel disc was glued on the IA-TBI exposed cranium between bregma and lambda. 50g brass weight was dropped from a height of 85cm through the Plexiglas tube onto the disk glued on mouse that was Conclusions placed prone on a foam bed and secured with tape under References a Plexiglas tube (Xu et al., 2016). 1. Henninger, Nils, et al. “Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.” • TAI leads to ongoing axon degeneration over the course of weeks on the ON of Brain, vol. 139, 2016, p. 1094-1105. mice after IA-TBI. Tissue preparation and Toluidine blue staining. 2. Koliatsos & Alexandris. “Wallerian degeneration as a therapeutic target in traumatic brain injury.” Curr Opin Neurol. 2019 Dec;32(6):786-795. 3. Koschade, Sebastian E., et al. “Efficient determination of axon number in the optic nerve: A stereological approach.” Experimental Eye Research, Injury group of mice were perfused 21 days post IA-TBI as well as sham mice. ONs were vol. 186, 2019, p. 107710. • The protective effect of SARM1 deletion is absent on primary traumatic dissected from the mice and subsequently, post-fixed with 4% paraformaldehyde and 4. Marion, Christina M., et al. “Sarm1 Deletion Reduces Axon Damage, Demyelination, and White Matter Atrophy after Experimental Traumatic Brain Injury.” Experimental Neurology, vol. 321, 2019, p. 113040. axonopathy on the ON of IA-TBI mice. 0.2% glutaraldehyde, treated with 1% osmium tetroxide, and stained en bloc with 1% 5. Maxwell, William L., et al. “Wallerian Degeneration in the Optic Nerve. Stretch-Injury Model of Traumatic Brain Injury: A Stereological Analysis.” Jouranl of Neurotrauma, Vol. 32, No.11,2015. • Sarm-1 deletion reduces the burden of chronic pathology on the ON at 3 weeks uranyl acetate by order. Then semithin sections (1um) were cut transversely from 6. Xu, Leyan, et al., “Repetitive mild traumatic brain injury with impact acceleration in themouse: Multifocal axonopathy, neuroinflammation, segments of ONs proximal to the optic chiasm. Subsequently, sections were stained andneurodegeneration in the visual system.” Experimental Neurology, Vol. 275, 2016, p.436-449. after TBI. 7. Ziogas, Nikolaos K. & Koliatsos, Vassilis E. “Primary Traumatic Axonopathy in Mice Subjected to Impact Acceleration: A Reappraisal of Pathology with 1% toluidine blue. and Mechanisms with High-Resolution Anatomical Methods.” The journal of Neuroscience , 2018, p. 4031– 4047..
Load more

Recommended publications
  • Wallerian Degeneration and Inflammation in Rat Peripheral Nerve Detected by in Vivo MR Imaging
    741 Wallerian Degeneration and Inflammation in Rat Peripheral Nerve Detected by in Vivo MR Imaging DavidS. Titelbaum 1 To investigate the role of MR imaging in wallerian degeneration, a series of animal Joel L. Frazier 2 models of increasingly complex peripheral nerve injury were studied by in vivo MR. Robert I. Grossman 1 Proximal tibial nerves in brown Norway rats were either crushed, transected (neurotomy), Peter M. Joseph 1 or transected and grafted with Lewis rat (allograft) or brown Norway (isograft) donor Leonard T. Yu 2 nerves. The nerves distal to the site of injury were imaged at intervals of 0-54 days after surgery. Subsequent histologic analysis was obtained and correlated with MR Eleanor A. Kassab 1 3 findings. Crush injury, neurotomy, and nerve grafting all resulted in high signal intensity William F. Hickey along the course of the nerve observed on long TR/TE sequences, corresponding to 2 Don LaRossa edema and myelin breakdown from wallerian degeneration. The abnormal signal inten­ 4 Mark J. Brown sity resolved by 30 days after crush injury and by 45-54 days after neurotomy, when the active changes of wallerian degeneration had subsided. These changes were not seen in sham-operated rats. Our findings suggest that MR is capable of identifying traumatic neuropathy in a peripheral nerve undergoing active wallerian degeneration. The severity of injury may be reflected by the corresponding duration of signal abnormality. With the present methods, MR did not distinguish inflammatory from simple posttraumatic neuropathy. Wallerian degeneration is the axonal degeneration and loss of myelin that occurs when an axon is separated from its cell body.
    [Show full text]
  • Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury Rachel E
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2014 Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury Rachel E. Bennett Washington University School of Medicine David L. Brody Washington University School of Medicine Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Bennett, Rachel E. and Brody, David L., ,"Acute reduction of microglia does not alter axonal injury in a mouse model of repetitive concussive traumatic brain injury." Journal of Neurotrauma.31,9. 1647-1663. (2014). https://digitalcommons.wustl.edu/open_access_pubs/4711 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. JOURNAL OF NEUROTRAUMA 31:1647–1663 (October 1, 2014) ª Mary Ann Liebert, Inc. DOI: 10.1089/neu.2013.3320 Acute Reduction of Microglia Does Not Alter Axonal Injury in a Mouse Model of Repetitive Concussive Traumatic Brain Injury Rachel E. Bennett and David L. Brody Abstract The pathological processes that lead to long-term consequences of multiple concussions are unclear. Primary mechanical damage to axons during concussion is likely to contribute to dysfunction. Secondary damage has been hypothesized to be induced or exacerbated by inflammation. The main inflammatory cells in the brain are microglia, a type of macrophage. This research sought to determine the contribution of microglia to axon degeneration after repetitive closed-skull traumatic brain injury (rcTBI) using CD11b-TK (thymidine kinase) mice, a valganciclovir-inducible model of macrophage depletion.
    [Show full text]
  • Evidence That Wallerian Degeneration and Localized Axon Degeneration Induced by Local Neurotrophin Deprivation Do Not Involve Caspases
    The Journal of Neuroscience, February 15, 2000, 20(4):1333–1341 Evidence That Wallerian Degeneration and Localized Axon Degeneration Induced by Local Neurotrophin Deprivation Do Not Involve Caspases John T. Finn,1 Miguel Weil,1 Fabienne Archer,2 Robert Siman,3 Anu Srinivasan,4 and Martin C. Raff1 1Medical Research Council Laboratory for Molecular Cell Biology and Biology Department and 2Department of Physiology, University College London, London WC1E 6BT, United Kingdom, 3Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6084, and 4Idun Pharmaceuticals, Inc., La Jolla, California 92037 The selective degeneration of an axon, without the death of the not activated in the axon during either form of degeneration, parent neuron, can occur in response to injury, in a variety of although it is activated in the dying cell body of the same metabolic, toxic, and inflammatory disorders, and during nor- neurons. Moreover, caspase inhibitors do not inhibit or retard mal development. Recent evidence suggests that some forms either form of axon degeneration, although they inhibit apopto- of axon degeneration involve an active and regulated program sis of the same neurons. Finally, we cannot detect cleaved of self-destruction rather than a passive “wasting away” and in substrates of caspase-3 and its close relatives immunocyto- this respect and others resemble apoptosis. Here we investi- chemically or caspase activity biochemically in axons undergo- gate whether selective axon degeneration depends on some of ing Wallerian degeneration. Our results suggest that a neuron the molecular machinery that mediates apoptosis, namely, the contains at least two molecularly distinct self-destruction pro- caspase family of cysteine proteases.
    [Show full text]
  • Effects of NAD+ in Caenorhabditis Elegans Models of Neuronal Damage
    biomolecules Review Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage Yuri Lee 1, Hyeseon Jeong 1, Kyung Hwan Park 1 and Kyung Won Kim 1,2,3,* 1 Department of Life Science, Hallym University, Chuncheon 24252, Korea; [email protected] (Y.L.); [email protected] (H.J.); [email protected] (K.H.P.) 2 Convergence Program of Material Science for Medicine and Pharmaceutics, Hallym University, Chuncheon 24252, Korea 3 Multidisciplinary Genome Institute, Hallym University, Chuncheon 24252, Korea * Correspondence: [email protected]; Tel.: +82-33-248-2091 Received: 1 April 2020; Accepted: 30 June 2020; Published: 2 July 2020 Abstract: Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage. Keywords: NAD+; Nmnat; NMAT-2; PARP; C. elegans; neuroprotection; axon regeneration 1. NAD+ Biosynthesis Pathway in C. elegans Nicotinamide adenine dinucleotide (NAD+) is found in all living cells and plays an essential role in many fundamental biological processes, such as metabolism, cell signaling, gene expression, and DNA repair [1].
    [Show full text]
  • Diffuse Axonal Injury and Oxidative Stress: a Comprehensive Review
    International Journal of Molecular Sciences Review Diffuse Axonal Injury and Oxidative Stress: A Comprehensive Review Alessandro Frati 1,2, Daniela Cerretani 3, Anna Ida Fiaschi 3, Paola Frati 1,4, Vittorio Gatto 4, Raffaele La Russa 1,4 ID , Alessandro Pesce 2, Enrica Pinchi 4, Alessandro Santurro 4 ID , Flavia Fraschetti 2 and Vittorio Fineschi 1,4,* 1 Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Via Atinense 18, 86077 Pozzilli, Italy; [email protected] (A.F.); [email protected] (P.F.); [email protected] (R.L.R.) 2 Department of Neurosciences, Mental Health, and Sensory Organs, Sant’Andrea Hospital, Sapienza University of Rome, Via di Grottarossa 1035, 00189 Rome, Italy; [email protected] (A.P.); fl[email protected] (F.F.) 3 Department of Medicine, Surgery and Neuroscience, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy; [email protected] (D.C.); annaida.fi[email protected] (A.I.F.) 4 Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00185 Rome, Italy; [email protected] (V.G.); [email protected] (E.P.); [email protected] (A.S.) * Correspondence: vfi[email protected]; Tel.: +39-06-49912-722; Fax: +39-06-4455-335 Received: 16 September 2017; Accepted: 28 November 2017; Published: 2 December 2017 Abstract: Traumatic brain injury (TBI) is one of the world’s leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death.
    [Show full text]
  • Wallerian Degeneration: Morphological and Molecular Changes
    1. Neurology & Neurotherapy Open Access Journal Wallerian Degeneration: Morphological and Molecular Changes Mehrnaz Moattari1, Farahnaz Moattari2, Gholamreza Kaka3*, Homa Review Article Mohseni Kouchesfahani1*, Majid Naghdi4 and Seyed Homayoon Volume 3 Issue 2 Sadraie3 Received Date: July 15, 2018 Published Date: August 20, 2018 1Department of Animal Biology, Kharazmi University, Iran 2Faculty of Agriculture and Natural Resources, Persian Gulf University, Iran 3Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Iran 4Fasa University of Medical Science, Iran *Corresponding authors: Homa Mohseni Kouchesfahani, Department of Animal Biology, Faculty of Biological Science, Kharazmi University, PO Box: 15719-14911, Tehran, Iran, Fax: +982126127286; Tel: +989123844874; Email: [email protected]; [email protected] Gholamreza Kaka, Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Aghdasie, Artesh Boulevard, Artesh Square, PO Box: 19568-37173, Tehran, Iran, Fax: +982126127286; Tel: +989123844874; Email: [email protected]; [email protected] Abstract Wallerian degeneration is a process that follows damage to the nerve fiber. Instantly after the initial injury, Wallerian degeneration begins at the distal stump. The axon breaks down, retraction of the myelin sheath happens and the axoplasm is surrounded within ellipsoids of myelin. In respond to loss of axons by disruption of their myelin sheaths, myelin genes are down regulated and Schwann cells dedifferentiated. Schwann cells
    [Show full text]
  • Wallerian-Like Degeneration of Central Neurons After Synchronized and Geometrically Registered Mass Axotomy in a Three-Compartmental Microfluidic Chip
    Neurotox Res (2011) 19:149–161 DOI 10.1007/s12640-010-9152-8 Wallerian-Like Degeneration of Central Neurons After Synchronized and Geometrically Registered Mass Axotomy in a Three-Compartmental Microfluidic Chip Devrim Kilinc • Jean-Michel Peyrin • Vanessa Soubeyre • Se´bastien Magnifico • Laure Saias • Jean-Louis Viovy • Bernard Brugg Received: 3 August 2009 / Revised: 15 October 2009 / Accepted: 12 January 2010 / Published online: 17 February 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Degeneration of central axons may occur fol- neurons exhibit rapid Wallerian-like distal degeneration lowing injury or due to various diseases and it involves but no somatic death following central axotomy. Distal complex molecular mechanisms that need to be elucidated. axons show progressive degeneration leading to axonal Existing in vitro axotomy models are difficult to perform, beading and cytoskeletal fragmentation within a few hours and they provide limited information on the localization of after axotomy. Degeneration is asynchronous, reminiscent events along the axon. We present here a novel experi- of in vivo Wallerian degeneration. Axonal cytoskeletal mental model system, based on microfluidic isolation, fragmentation is significantly delayed with nicotinamide which consists of three distinct compartments, intercon- adenine dinucleotide pretreatment, but it does not change nected by parallel microchannels allowing axon outgrowth. when distal calpain or caspase activity is inhibited. These Neurons cultured in one compartment successfully elon- findings, consistent with previous experiments in vivo, gated their axons to cross a short central compartment and confirm the power and biological relevance of this micro- invade the outermost compartment. This design provides fluidic architecture.
    [Show full text]
  • Emergence of the Wallerian Degeneration Pathway As A
    [Downloaded free from http://www.nrronline.org on Monday, December 14, 2020, IP: 193.60.240.99] Perspective between WD in the peripheral nervous system Emergence of the Wallerian and central nervous system, namely in the inflammatory response to injury and the time required to clear myelin debris by different glial degeneration pathway as a cells, the axon death pathway discussed above controls degeneration of both peripheral nervous mechanism of secondary brain injury system and central nervous system axons. One of these diseases is traumatic brain injury (TBI) (Hill et al., 2016). An estimated 10 million people per year Ciaran Scott Hill*, Andrea Loreto suffer a TBI; it is one of the leading causes of death in many parts of the world and can have profound individual and socioeconomic consequences. TBI Augustus Volney Waller was a renowned murine knockout of the ortholog Sarm1 (sterile α differs from many traditional diseases in so far British neurophysiologist who birthed the axon and Toll/Interleukin 1 receptor motif containing as it is not primarily driven by genetic mutation degeneration field in 1850 by describing curdling protein 1) demonstrated robust protection or an aberration of normal physiology. Instead it and fragmentation of the glossopharyngeal and against axotomy induced degeneration in cortical is an acquired insult caused by an external force hypoglossal cranial nerves of a frog following a neurons and dorsal root ganglion neurons. In at a single moment in time. What follows can be transection injury. The degeneration of axons vivo, Sarm1 deletion preserved the distal sciatic understood in terms of subsequent biological after a transection injury is now known as nerve morphology, synaptic structure and motor consequences of that initial act – known as Wallerian degeneration (WD).
    [Show full text]
  • MR Imaging of Wallerian Degeneration in the Brainstem: Temporal Relationships
    897 MR Imaging of Wallerian Degeneration in the Brainstem: Temporal Relationships Yuichi Inoue 1 Degeneration of the myelin sheath and axon distal to the most proximal site of axonal Yasumasa Matsumura2 interruption secondary to axonal disease has been called wallerian degeneration. On Teruo Fukuda1 MR imaging, wallerian degeneration of the pyramidal tract can be observed as an Yutaka Nemoto1 abnormal signal intensity, showing prolonged T1 and T2 relaxation times that correspond to the corticospinal tract, with or without shrinkage of the ipsilateral cerebral peduncle Nobuyuki Shirahata3 and pons. Review of MR studies in 150 cases of supratentorial cerebrovascular accidents Tosihisa Suzuki4 1 showed abnormal signal alterations in the ipsilateral brainstem in 33 of the cases. Miyuki Shakudo Abnormal intensity in the ipsilateral brainstem was seen as early as 5 weeks after the 1 Satoshi Yawata supratentorial ictus and was fully evident after 10 weeks in all 33 cases. Signal 2 Shigeko Tanaka alterations were strongest at about 3-6 months when compared with alterations seen Kazumasa Takemoto5 at 10 weeks or even 10 months after the ictus. Shrinkage of the ipsilateral brainstem Yasuto Onoyama 1 appeared as early as 8 months and was demonstrated in all cases 13 months after the ictus. MR seems to be the most effective technique for early detection of wallerian degen­ eration and may provide insight into its pathophysiological and chemical changes. AJNR 11:897-902, September/October 1990 Wallerian degeneration is the process of disintegration that affects an axon and its myelin sheath after its connection with the cell body has been interrupted [1 ).
    [Show full text]
  • Peripheral Nerve Regeneration and Muscle Reinnervation
    International Journal of Molecular Sciences Review Peripheral Nerve Regeneration and Muscle Reinnervation Tessa Gordon Department of Surgery, University of Toronto, Division of Plastic Reconstructive Surgery, 06.9706 Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; [email protected]; Tel.: +1-(416)-813-7654 (ext. 328443) or +1-647-678-1314; Fax: +1-(416)-813-6637 Received: 19 October 2020; Accepted: 10 November 2020; Published: 17 November 2020 Abstract: Injured peripheral nerves but not central nerves have the capacity to regenerate and reinnervate their target organs. After the two most severe peripheral nerve injuries of six types, crush and transection injuries, nerve fibers distal to the injury site undergo Wallerian degeneration. The denervated Schwann cells (SCs) proliferate, elongate and line the endoneurial tubes to guide and support regenerating axons. The axons emerge from the stump of the viable nerve attached to the neuronal soma. The SCs downregulate myelin-associated genes and concurrently, upregulate growth-associated genes that include neurotrophic factors as do the injured neurons. However, the gene expression is transient and progressively fails to support axon regeneration within the SC-containing endoneurial tubes. Moreover, despite some preference of regenerating motor and sensory axons to “find” their appropriate pathways, the axons fail to enter their original endoneurial tubes and to reinnervate original target organs, obstacles to functional recovery that confront nerve surgeons. Several surgical manipulations in clinical use, including nerve and tendon transfers, the potential for brief low-frequency electrical stimulation proximal to nerve repair, and local FK506 application to accelerate axon outgrowth, are encouraging as is the continuing research to elucidate the molecular basis of nerve regeneration.
    [Show full text]
  • Axonotmesis of the Sciatic Nerve
    Diagnostic and Interventional Imaging (2012) 93, 398—400 LETTER / Neurology Axonotmesis of the sciatic nerve a,∗ b c c M. Ohana , S. Quijano-Roy , F. Colas , C. Lebreton , c c C. Vallée , R.-Y. Carlier a Radiology Department, Nouvel Hôpital Civil, Strasbourg University Hospitals, 1, place de l’Hôpital, 67000 Strasbourg, France b Paediatrics Department, Raymond-Poincaré Hospital, 104, boulevard Raymond-Poincaré, 92380 Garches, France c Radiology Department, Raymond-Poincaré Hospital, 104, boulevard Raymond-Poincaré, 92380 Garches, France Case report KEYWORDS Peripheral nerve; We report the case of an eight-year old girl who was admitted for aftercare and rehabilita- MRI; tion one month after a serious head injury that required a four-day stay in intensive care. Axonotmesis Initial investigations did not show any evidence of post-traumatic injury. During her admission, she developed significant pain in the left buttock radiating to the lower limb associated with a sensorimotor deficit. These disabling pains persisted at rest. The clinical examination revealed that the patient had great difficulty walking, presenting a limp, a tender point on palpation of the left buttock radiating to the thigh and the leg along a posterolateral course, with hyperaesthesia in the whole area. Extension of the leg and both flexion and extension of the foot were impossible; hip flexion was normal. Hypoaesthesia was noted on the inside of the left leg and foot. The left patellar and Achilles reflexes were absent. Vital signs were normal. First-line magnetic resonance imaging (MRI) of the lumbar spine did not reveal any abnormalities. An MRI of the pelvis and lower limbs was then carried out and this highlighted involve- ment of the sciatic nerve along its whole extra-perineal course (Fig.
    [Show full text]
  • Wallerian Degeneration of the Superior Cerebellar Peduncle
    Letters (1000 mg at days 0 and 14). She continued to experience wors- Funding/Support: This study was supported by the Huayi and Siuling Zhang ening lower extremity weakness. Eventually,she received 6 plas- Discovery Fund. mapheresis treatments with minimal improvement. Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; During the entire period of follow-up at our center, she re- preparation, review, or approval of the manuscript; and decision to submit the quired 20 to 30 mg daily of oral prednisone. Neurological ex- manuscript for publication. amination prior to the onset of HiCy therapy revealed sym- 1. Valiyil R, Casciola-Rosen L, Hong G, Mammen A, Christopher-Stine L. metrically reduced arm abduction (4−/5) and hip flexion Rituximab therapy for myopathy associated with anti-signal recognition particle strength (2/5) and her CK level was 2920 U/L. Given progres- antibodies: a case series. Arthritis Care Res (Hoboken). 2010;62(9):1328-1334. sive muscle weakness in the absence of a robust response to 2. DeZern AE, Petri M, Drachman DB, et al. High-dose cyclophosphamide without stem cell rescue in 207 patients with aplastic anemia and other any immunosuppression, she was treated with HiCy, 50 mg/kg autoimmune diseases. Medicine (Baltimore). 2011;90(2):89-98. per day, for 4 consecutive days and supportive care, as previ- 3. Krishnan C, Kaplin AI, Brodsky RA, et al. Reduction of disease activity and 2 ously described. Although she developed neutropenic fever disability with high-dose cyclophosphamide in patients with aggressive multiple 9 days later, she recovered successfully.
    [Show full text]