scholarly journals Regulatory Forum Opinion Piece*: Effective Sectioning of Spinal Cord during Regulatory-type Nonclinical Toxicity Studies

2017 ◽  
Vol 45 (5) ◽  
pp. 580-583 ◽  
Author(s):  
Brad Bolon
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
White Matter ◽  
Best Practices ◽  
Gray Matter ◽  
Vertical Plane ◽  
Toxicity Studies ◽  
Regulatory Guidelines ◽  
Motor Tracts ◽  
Regulatory Type

Regulatory guidelines for nonclinical neurotoxicity testing require spinal cord evaluation but do not specify a trimming scheme. The Society of Toxicologic Pathology (STP) “best practices” for nervous system sampling during nonclinical general toxicity studies recommend that spinal cord be assessed in both longitudinal/oblique and transverse sections. This article defines possible longitudinal/oblique orientations, describes their benefits and challenges, and provides an expert recommendation regarding suitable trimming planes. Longitudinal parasagittal (LP) sections follow a vertical plane just lateral to the midline, revealing sensory and motor tracts but little gray matter. Longitudinal horizontal sections transect only sensory or motor tracts and variable quantities of gray matter. Oblique vertical (OV) sections angle across the spinal cord from side to side. Oblique transverse (OT) sections slant through from top (dorsal [posterior]) to bottom (ventral [anterior]). Compared to longitudinal planes, oblique orientations demonstrate considerably more gray matter and white matter. Current STP “best practices” explicitly recommend the LP and OV options; the OT orientation also will yield suitable sections while permitting assessment of anatomic symmetry. Selection among the LP, OT, and OV planes should be at the discretion of the study pathologist. The bilaterally symmetrical OT sections likely will be analyzed most easily by nonneuropathologists.

scholarly journals An Attenuated Variant of the GDVII Strain of Theiler’s Virus Does Not Persist and Does Not Infect the White Matter of the Central Nervous System

1999 ◽  
Vol 73 (1) ◽  
pp. 801-804 ◽  
Author(s):  
Nadine Jarousse ◽  
Ekaterina G. Viktorova ◽  
Evgeny V. Pilipenko ◽  
Vadim I. Agol ◽  
Michel Brahic
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
White Matter ◽  
Gray Matter ◽  
Noncoding Region ◽  
Theiler's Virus ◽  
Recombinant Viruses ◽  
Central Nervous Systems ◽  
The Central Nervous System

ABSTRACT The DA strain of Theiler’s virus causes a persistent and demyelinating infection of the white matter of spinal cord, whereas the GDVII strain causes a fatal gray-matter encephalomyelitis. Studies with recombinant viruses showed that this difference in phenotype is controlled mainly by the capsid. However, conflicting results regarding the existence of determinants of persistence in the capsid of the GDVII strain have been published. Here we show that a GDVII virus whose neurovirulence has been attenuated by an insertion in the 5′ noncoding region does not persist in the central nervous systems of mice. Furthermore, this virus infects the gray matter efficiently, but not the white matter. These results confirm the absence of determinants of persistence in the GDVII capsid. They suggest that the DA capsid controls persistence by allowing the virus to infect cells in the white matter of the spinal cord.

NG2 cells generate oligodendrocytes and gray matter astrocytes in the spinal cord

2008 ◽  
Vol 4 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Xiaoqin Zhu ◽  
Robert A. Hill ◽  
Akiko Nishiyama
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
White Matter ◽  
Glial Cell ◽  
Gray Matter ◽  
Ng2 Cells ◽  
Protoplasmic Astrocytes

NG2 cells represent a unique glial cell population that is distributed widely throughout the developing and adult CNS and is distinct from astrocytes, mature oligodendrocytes and microglia. The ability of NG2 cells to differentiate into myelinating oligodendrocytes has been documented in vivo and in vitro. We reported recently that NG2 cells in the forebrain differentiate into myelinating oligodendrocytes but into a subpopulation of protoplasmic astrocytes (Zhu et al., 2008). However, the in vivo fate of NG2 cells in the spinal cord and cerebellum has remained unknown. To investigate the fate of NG2 cells in caudal central nervous system (CNS) regions in vivo, we examined the phenotype of cells that express EGFP in mice that are double transgenic for NG2CreBAC and the Cre reporter Z/EG. The fate of NG2 cells can be studied in these mice by permanent expression of EGFP in cells that have undergone Cre-mediated recombination in NG2 cells. We find that NG2 cells give rise to oligodendrocytes in both gray and white matter of the spinal cord and cerebellum, and to protoplasmic astrocytes in the gray matter of the spinal cord. However, NG2 cells do not give rise to astrocytes in the white matter of the spinal cord and cerebellum. These observations indicate that NG2 cells serve as precursor cells for oligodendrocytes and a subpopulation of protoplasmic astrocytes throughout the rostrocaudal axis of the CNS.

scholarly journals Widespread distribution of the major polypeptide component of MAP 1 (microtubule-associated protein 1) in the nervous system.

1984 ◽  
Vol 98 (1) ◽  
pp. 320-330 ◽  
Author(s):  
G S Bloom ◽  
T A Schoenfeld ◽  
R B Vallee
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Cerebral Cortex ◽  
White Matter ◽  
Rat Brain ◽  
Brain Tissue ◽  
Gray Matter ◽  
Neuronal Morphology ◽  
Double Labeling ◽  
Brain And Spinal Cord

We prepared a monoclonal antibody to microtubule-associated protein 1 (MAP 1), one of the two major high molecular weight MAP found in microtubules isolated from brain tissue. We found that MAP 1 can be resolved by SDS PAGE into three electrophoretic bands, which we have designated MAP 1A, MAP 1B, and MAP 1C in order of increasing electrophoretic mobility. Our antibody recognized exclusively MAP 1A, the most abundant and largest MAP 1 polypeptide. To determine the distribution of MAP 1A in nervous system tissues and cells, we examined tissue sections from rat brain and spinal cord, as well as primary cultures of newborn rat brain by immunofluorescence microscopy. Anti-MAP 1A stained white matter and gray matter regions, while a polyclonal anti-MAP 2 antibody previously prepared in this laboratory stained only gray matter. This confirmed our earlier biochemical results, which indicated that MAP 1 is more uniformly distributed in brain tissue than MAP 2 (Vallee, R.B., 1982, J. Cell Biol., 92:435-442). To determine the identity of cells and cellular processes immunoreactive with anti-MAP 1A, we examined a variety of brain and spinal cord regions. Fibrous staining of white matter by anti-MAP 1A was generally observed. This was due in part to immunoreactivity of axons, as judged by examination of axonal fiber tracts in the cerebral cortex and of large myelinated axons in the spinal cord and in spinal nerve roots. Cells with the morphology of oligodendrocytes were brightly labeled in white matter. Intense staining of Purkinje cell dendrites in the cerebellar cortex and of the apical dendrites of pyramidal cells in the cerebral cortex was observed. By double-labeling with antibodies to MAP 1A and MAP 2, the presence of both MAP in identical dendrites and neuronal perikarya was found. In primary brain cell cultures anti-MAP 2 stained predominantly cells of neuronal morphology. In contrast, anti-MAP 1A stained nearly all cells. Included among these were neurons, oligodendrocytes and astrocytes as determined by double-labeling with anti-MAP 1A in combination with antibody to MAP 2, myelin basic protein or glial fibrillary acidic protein, respectively. These results indicate that in contrast to MAP 2, which is specifically enriched in dendrites and perikarya of neurons, MAP 1A is widely distributed in the nervous system.

scholarly journals Upregulation of EphA Receptor Expression in the Injured Adult Rat Spinal Cord

2002 ◽  
Vol 11 (3) ◽  
pp. 229-239 ◽  
Author(s):  
Christopher A. Willson ◽  
Margarita Irizarry-Ramírez ◽  
Hope E. Gaskins ◽  
Lillian Cruz-Orengo ◽  
Johnny D. Figueroa ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Gray Matter ◽  
Receptor Expression ◽  
Axonal Guidance ◽  
Receptor Subtypes ◽  
Rat Spinal Cord ◽  
Functional Connections ◽  
Cord Injury ◽  
Epha Receptor

After spinal cord injury (SCI), the inability of supraspinal neurons to regenerate or reform functional connections is likely due to proteins in the surrounding microenvironment restricting regeneration. EphAs are a family of receptor tyrosine kinases that are involved in axonal guidance during development. These receptors and their ligands, the Ephrins, act via repulsive mechanisms to guide growing axons towards their appropriate targets and allow for the correct developmental connections to be made. In the present study, we investigated whether EphA receptor expression changed after a thoracic contusion SCI. Our results indicate that several EphA molecules are upregulated after SCI. Using semiquantitative RT-PCR to investigate mRNA expression after SCI, we found that EphA3, A4, and A7 mRNAs were upregulated. EphA3, A4, A6, and A8 receptor immunoreactivity increased in the ventrolateral white matter (VWM) at the injury epicenter. EphA7 had the highest level of immunoreactivity in both control and injured rat spinal cord. EphA receptor expression in the white matter originated from glial cells as coexpression in both astrocytes and oligodendrocytes was observed. In contrast, gray matter expression was localized to neurons of the ventral gray matter (motor neurons) and dorsal horn. After SCI, specific EphA receptor subtypes are upregulated and these increases may create an environment that is unfavorable for neurite outgrowth and functional regeneration.

Presence and significance of CD-95 (Fas/APO1) expression after spinal cord injury

2001 ◽  
Vol 94 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Mercedes Zurita ◽  
Jesús Vaquero ◽  
Isabel Zurita
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Gray Matter ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Content Type ◽  
Cord Injury ◽  
Positive Immunostaining ◽  
Fine Print

Object. A glycoprotein, CD95 (Fas/APO1) is widely considered to be implicated in the development of apoptosis in a number of tissues. Based on the hypothesis that apoptosis is related to cell death after spinal cord injury (SCI), the authors studied the presence and distribution of CD95 (Fas/APO1)-positive cells in injured spinal cord tissue for the purpose of determining the significance of this protein during the early phases of SCI. Methods. The presence and distribution of cells showing positive immunostaining for CD95 (Fas/APO1) were studied 1, 4, 8, 24, 48, and 72 hours and 1, 2, and 4 weeks after induction of experimental SCI in rats. Studies were conducted using a monoclonal antibody to the CD95 (Fas/APO1) protein. Positivity for CD95 (Fas/APO1) was observed in apoptotic cells, mainly in the gray matter, 1 hour after trauma, and the number of immunostained cells increased for the first 8 hours, at which time the protein was expressed in both gray and white matter. From 24 to 72 hours postinjury, the number of immunostained cells decreased in the gray matter, but increased in the white matter. From then on, there were fewer CD95 (Fas/APO1)-positive cells, but some cells in the white matter still exhibited positive immunostaining 1 and 2 weeks after injury. At 4 weeks, there remained no CD95 (Fas/APO1)-positive cells in injured spinal cord. Conclusions. These findings indicate that CD95 (Fas/APO1) is expressed after SCI, suggesting a role for this protein in the development of apoptosis after trauma and the possibility of a new therapeutic approach to SCI based on blocking the CD95 (Fas/APO1) system.

Effects of Glycine Administration on Canine Experimental Spinal Spasticity and the Levels of Glycine, Glutamate, and Aspartate in the Lumbar Spinal Cord

Neurosurgery ◽  
1979 ◽  
Vol 4 (2) ◽  
pp. 152-156 ◽  
Author(s):  
J. E. Smith ◽  
P. V. Hall ◽  
M. R. Galvin ◽  
A. R. Jones ◽  
R. L. Campbell
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Gray Matter ◽  
Clinical Signs ◽  
Spinal Cord Transection ◽  
Lumbar Spinal Cord ◽  
Central Gray Matter ◽  
Central Gray ◽  
Lumbar Spinal

Abstract Twelve female mongrel dogs were made paraplegic by midthoracic spinal cord transection. Beginning at 9 weeks posttransection, either glycine (50 mg/kg) or saline was injected intramuscularly each day and the signs of spinal spasticity were assessed clinically. After treating the dogs for 3 weeks, we removed the lumbar enlargement of each dog and microdissected it into gray and white areas which we assayed for glycine, glutamate, and aspartate content. Some of the clinical signs of spasticity improved in the animals injected with glycine compared to the saline-injected controls. The content of glycine was significantly elevated in the central gray matter and ventral medial white matter of the glycinetreated dogs. The levels of glutamate were also significantly elevated in the central, lateral ventral, and medial ventral gray matter and in the dorsal lateral and ventral medial white matter of the glycine-treated dogs. The possible role of these segmental putative neurotransmitters in spinal spasticity is discussed.

scholarly journals A Neuropathy in Goats Caused by Experimental Coyotillo (Karwinskia humboldtiana) Poisoning

1970 ◽  
Vol 7 (5) ◽  
pp. 435-447 ◽  
Author(s):  
K. M. Charlton ◽  
K. R. Pierce ◽  
R. W. Storts ◽  
C. H. Bridges
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
White Matter ◽  
Light Microscopy ◽  
Clinical Signs ◽  
Close Correlation ◽  
Axonal Dystrophy ◽  
The Central Nervous System ◽  
Oral Doses

Twenty-two goats were poisoned with daily oral doses of ground coyotillo fruits and were killed at various times after the first day of dosing. The morphologic features and distribution of lesions in the central nervous system were studied by light microscopy. An axonal dystrophy occurred in several of the goats given high daily doses. Swellings occurred along axons of Purkinje cells in the cerebellum and in the white matter of the spinal cord. There was a fairly close correlation between the occurrence of clinical signs suggestive of the neocerebellar syndrome and the occurrence and distribution of lesions in the cerebellum.

Effect of aminophylline and isoproterenol on spinal cord blood flow after impact injury

1980 ◽  
Vol 53 (3) ◽  
pp. 385-390 ◽  
Author(s):  
Diana Dow-Edwards ◽  
Vincent DeCrescito ◽  
John J. Tomasula ◽  
Eugene S. Flamm
Keyword(s):  
Spinal Cord ◽  
Blood Flow ◽  
White Matter ◽  
Cord Blood ◽  
Gray Matter ◽  
Adenosine Monophosphate ◽  
Spinal Cord Blood Flow ◽  
Content Type ◽  
Cord Injury ◽  
Matter Flow

✓ A study of the effects of spinal cord injury upon spinal cord blood flow was carried out in cats. A 400 gm-cm impact produced an overall reduction in spinal cord blood flow of 24% in the white matter and 30% in the gray matter, as determined by 14C-antipyrine autoradiography. At the level of the injury, white-matter flow was 8.1 ml/100 gm/min, a reduction of 49%, and in the gray matter, 12.5 ml/100 gm/min, a reduction of 76%. Treatment with aminophylline and isoproterenol improved the overall blood flow in the spinal cord. At the level of the injury, white-matter flow after this treatment was no longer significantly different from control values. The gray-matter flow remained decreased to 26.2 ml/100 gm/min, a reduction of only 47%. It is proposed that aminophylline and isoproterenol may increase cyclic adenosine monophosphate (AMP) and prevent platelet aggregation along the endothelial surfaces of the microcirculation, and may thereby help to maintain improved perfusion of the injured spinal cord.

scholarly journals Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) Model

2019 ◽  
Author(s):  
Niranjan Khadka ◽  
Xijie Liu ◽  
Hans Zander ◽  
Jaiti Swami ◽  
Evan Rogers ◽  
...  
Keyword(s):  
Spinal Cord ◽  
White Matter ◽  
Open Source ◽  
Electric Fields ◽  
Epidural Space ◽  
Gray Matter ◽  
Spinal Cord Stimulation ◽  
Clinical Trial Design ◽  
Element Model ◽  
Scs Model

AbstractObjectiveComputational current flow models of spinal cord stimulation (SCS) are widely used in device development, clinical trial design, and patient programming. Proprietary models of varied sophistication have been developed. An open-source model with state-of-the-art precision would serve as a standard for SCS simulation.ApproachWe developed a sophisticated SCS modeling platform, named Realistic Anatomically Detailed Open-Source Spinal Cord Stimulation (RADO-SCS) model. This platform consists of realistic and detailed spinal cord and ancillary tissues anatomy derived based on prior imaging and cadaveric studies. Represented tissues within the T9-T11 spine levels include vertebrae, intravertebral discs, epidural space, dura, CSF, white-matter, gray-matter, dorsal and ventral roots and rootlets, dorsal root ganglion, sympathetic chain, thoracic aorta, epidural space vasculature, white-matter vasculature, and thorax. As an exemplary, a bipolar SCS montage was simulated to illustrate the model workflow from the electric field calculated from a finite element model (FEM) to activation thresholds predicted for individual axons populating the spinal cord.Main ResultsCompared to prior models, RADO-SCS meets or exceeds detail for every tissue compartment. The resulting electric fields in white and gray-matter, and axon model activation thresholds are broadly consistent with prior stimulations.SignificanceThe RADO-SCS can be used to simulate any SCS approach with both unprecedented resolution (precision) and transparency (reproducibility). Freely available online, the RADO-SCS will be updated continuously with version control.

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