Oligodendroglial apoptosis occurs along degenerating axons and is associated with FAS and p75 expression following spinal cord injury in the rat
Section snippets
Spinal cord injury
All experimental protocols of this study were approved by the animal care committee of the Toronto Western Hospital Research Institute in accordance with the policies established in the guide to the care and use of experimental animals prepared by the Canadian Council of Animal Care. All efforts were made to minimize the number of animals used and their suffering.
SCI at C7–T1 was performed using the clip compression model in adult female Wistar rats (220–260 g; Charles River Laboratories,
DNA electrophoresis
To demonstrate the occurrence of internucleosomal DNA fragmentation characteristic of apoptotic cell degeneration, we electrophoresed 35S-labeled DNA isolated from normal and injured spinal cord in 1.5% agarose (Fig. 1). DNA isolated from injured tissue exhibited prominent banding of degraded DNA at lower molecular weights, (a characteristic of apoptosis resulting from internucleosomal DNA fragmentation), with a concomitant non-banding smear of DNA typical of necrotic degeneration. DNA from
Discussion
In this study we show using agarose electrophoresis, TUNEL and electron microscopy that apoptosis occurs following cervical SCI in the rat clip compression model. To date, this work is the first to demonstrate apoptosis in an animal model of cervical SCI, the most commonly injured level in humans.70 Ultrastructural data and double labeling immunomicroscopy revealed that most of the apoptotic cells are oligodendrocytes, and that these cells are spatially associated with degenerating axons. This
Acknowledgements
This work was supported by a Premier's Research Excellence Award Grant, Medical Research Council/Canadian Neurotrauma Research Program Grant and a Cervical Spine Research Society Grant. S. Casha is supported by an Ontario Neurotrauma Foundation Fellowship Award. M. G. Fehlings is the recipient of an Ontario Ministry of Health Career Scientist Award.
References (82)
- et al.
Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death
Brain Res.
(1998) - et al.
The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury
Expl Neurol.
(1995) - et al.
Amyloid precursor protein (βAPP) as a marker for axonal injury after head injury
Neurosci. Lett.
(1993) - et al.
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem. biophys. Res. Commun.
(1984) - et al.
In situ detection of fragmented DNA (TUNEL assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: a cautionary note
Hepatology
(1995) Spinal cord blood flow after acute experimental cord injury in dogs
J. Neurol. Sci.
(1976)- et al.
Blockade of glutamate receptors unmasks neuronal apoptosis after oxygen-glucose deprivation in vitro
Neuroscience
(1995) - et al.
Amyloid peptide and a 3-kDa fragment are derived by distinct cellular mechanisms
J. biol. Chem.
(1993) - et al.
Induction and its spread of apoptosis in rat spinal cord after mechanical trauma
Neurosci. Lett.
(1996) - et al.
Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage
Brain Res.
(1990)
Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease
Trends Neurosci.
Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta amyloid precursor protein
Neuron
The amyloid precursor protein of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth
Neuron
FLICE induced apoptosis in a cell-free system
J. biol. Chem.
Fas has a crucial role in the progression of experimental autoimmune encephalomyelitis
Molec. Immun.
Expression of fas antigen in the normal mouse brain
Biochem. biophys. Res. Commun.
A simplification of the protein assay method of Lowry et al. which is more generally applicable
Analyt Biochem.
Neuronal cell death
Neuron
In vitro aging of beta-amyloid protein causes peptide aggergation and neurotoxicity
Brain Res.
Inhibition of fas death signals by FLIPs
Curr. Opin. Immunol.
Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO-1/Fas) ligand expression in microglial cells
Fedn Eur.biochem. Socs Lett.
Mechanism of gammadelta T cell-induced human oligodendrocyte cytotoxicity: relevance to multiple sclerosis
J. Neuroimmunol.
Mechanisms of secondary injury to spinal cord axons in vitro: role of Na+, Na(+)-K(+)-ATPase, the Na(+)-H+ exchanger, and the Na(+)-Ca2+ exchanger
J. Neurosci.
The effect of the sodium channel blocker QX-314 on recovery after acute spinal cord injury
J. Neurotrauma
Role of NMDA and non-NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury
J. Neurosci.
Death receptors: signaling and modulation
Science
The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death
J. Cell Biol.
CD95-CD95L: Can the brain learn from the immune system?
Trends Neurosci.
Models of spinal cord injury: Part 3. Dynamic load technique
Neurosurgery
Mechanical factors in experimental spinal cord injury
J. Am. Paraplegia Soc.
Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75
Nature
Neurotrophins: the biological paradox of survival factors eliciting apoptosis
Cell Death Differ.
Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx
Science
DNA damage and repair in central nervous system injury: National Institute of Neurological Disorders and Stroke Workshop Summary
Stroke
Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia
J. Neurosci.
Neurotrophins and their trk receptors in cultured cells of the glial lineage and in white matter of the central nervous system
J. Molec. Neurosci.
Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys
Nat. Med.
Apoptosis and DNA degeneration induced by 1-methyl-4-phenylpyridinium in neurons
Biochem. biophys. Res. Commun.
A new method for testing the force of clips for aneurysms or experimental spinal cord compression
J. Neurosurg.
Multiple sclerosis: Fas signaling in oligodendrocyte cell death
J. exp. Med.
Apoptosis after traumatic human spinal cord injury
J. Neurosurg.
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2021, Journal of Chemical NeuroanatomyCitation Excerpt :The death of neurons and glial cells occur after SCI due to the initial mechanical damages and through a secondary injury cascade (Sobrido-Cameán and Barreiro-Iglesias, 2018). Oligodendrocytes respond to SCI by differentiation and production of myelin, but are susceptible to death due to both necrosis and apoptosis (Casha et al., 2001; Almad et al., 2011). Stem cells are an effective treatment for SCI because of their neuroregenerative and neuroprotective properties.