References for this Review were identified through searches of PubMed and the Cochrane Library from January, 1985, to November, 2008, by use of the terms “multiple sclerosis”, “axonal degeneration”, and “myelin degeneration”. Articles were also identified through searches of the authors' own archives. References resulting from those searches and from bibliographies cited in retrieved articles were considered. Material was chosen for inclusion if it focused on the latest advances in the
ReviewVirtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis
Introduction
Multiple sclerosis (MS) is an inflammation-mediated demyelinating disease of the CNS, and is the main cause of non-traumatic neurological disability in young adults in North America and Europe.1, 2 The neurological disease course is variable and biphasic. Approximately 85% of affected individuals begin with relapsing-remitting MS (RRMS), which is characterised by a repetitive pattern of rapid onset and reversible neurological deficits. Episodic neurological disability in RRMS is caused by discrete foci of inflammatory demyelination and oedema. As the inflammation and oedema resolve, axonal conduction is largely restored, and the patient recovers. After 8–15 years, most patients with RRMS enter a second disease phase, secondary progressive MS (SPMS), which is characterised by gradual, irreversible neurological decline. Transition to SPMS is an ominous event because treatments are not yet available to combat the physical, cognitive, and quality-of-life deterioration that most patients with SPMS inevitably face. Therefore, prevention of SPMS is a major therapeutic goal of MS research. Axonal degeneration is now generally accepted as the main cause of irreversible neurological disability in patients with MS.3, 4 Accordingly, axonal preservation presents a new opportunity for MS therapeutics, and is the focus of this Review. Repair strategies have been extensively studied and reviewed elsewhere,5 and are thus not discussed here.
MS as a neurodegenerative disease is a recent concept. However, evidence of axonal loss in the brains of patients with MS has been reported sporadically for over a century.6 The paradigm shift to neurodegeneration in MS research was catalysed by several factors, including histological demonstrations of axonal transection and loss in post-mortem MS brains,7, 8, 9, 10 progressive MS brain atrophy,11, 12 and reductions in the neuronal specific marker N-acetyl aspartic acid identified with brain imaging techniques.13, 14, 15 In addition, progressive axonal loss provided a logical and testable explanation for the transition from RRMS to SPMS, as well as for continuous and irreversible neurological decline in SPMS. Finally, mice that are deficient in certain myelin proteins often exhibit late-onset axonal degeneration without significant pathological changes in myelin.16, 17, 18 These data strengthen the hypothesis that long-term axonal survival requires trophic support from oligodendrocytes and/or myelin, and provide evidence that chronically demyelinated axons in MS lesions might degenerate due to loss of glial support.
Section snippets
Neurodegeneration and disability in MS
Two pathological environments in which axonal degeneration have been documented in MS brains are shown in Figure 1, Figure 2. Substantial numbers of axons (over 11 000 per mm3 of brain white matter) are transected in acute inflammatory demyelinating lesions,7 where the axon seems to be a bystander target of the immune-mediated demyelination (figure 1). The axonal transection that occurs early in MS is clinically silent because the human brain has a remarkable ability to compensate for neuronal
Mechanisms of axonal degeneration
In normal myelinated fibres, Na+ channels are concentrated at nodes of Ranvier, allowing the action potential to rapidly jump from node to node. When Na+ enters axoplasm at nodes during electrogenesis, it is rapidly exchanged for extracellular K+ by Na+/K+ ATPase (figure 4). This continuous energy-dependent ion exchange is required for maintenance of axonal polarisation to support the repetitive axonal firing that is essential for most neuronal functions. Thus, myelination not only promotes
Chronic necrosis of demyelinated axons
Despite the large number of transected axons in acute MS lesions, most demyelinated fibres initially survive, and the axonal changes associated with acute inflammatory demyelination are reversed. Clinical recovery from acute attacks also supports the notion of functional recovery of the demyelinated axons. However, the MS brain undergoes continuous atrophy in later stages of the disease when new inflammatory demyelinating lesions are rare.83, 84 Although atrophy is not a specific marker of any
Neuroprotective strategies in MS
Axonal protection in MS has been deemed the therapeutic challenge for the next decade.88 Although immunomodulatory therapy has met with some success, we would argue that in the absence of near complete control of immune and inflammatory attack, neuroprotection will play a very important adjunctive part. Moreover, aggressive immune suppression could result in serious side-effects,89 and indiscriminate anti-inflammatory treatment might inadvertently extinguish the beneficial components of an
Conclusions
We have seen major advances in our understanding of the neuroimmunology of MS in recent years, with the emergence of reasonably effective strategies for controlling certain aspects of the disease. The growing emphasis on axonal degeneration as an underlying cause for permanent and progressive disability in MS is encouraging the research community to better understand the cellular and molecular mechanisms of axonal damage as a way to devise effective neuro-protective and glio-protective
Search strategy and selection criteria
References (109)
Epidemiology of multiple sclerosis
Neurol Clin
(1996)- et al.
Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis
Neuroimage
(2003) - et al.
Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions
Am J Pathol
(2000) - et al.
The role of nitric oxide in multiple sclerosis
Lancet Neurol
(2002) - et al.
Sodium-mediated axonal degeneration in inflammatory demyelinating disease
J Neurol Sci
(2005) - et al.
Depolarization-induced Ca2+ release in ischemic spinal cord white matter involves L-type Ca2+ channel activation of ryanodine receptors
Neuron
(2003) - et al.
Protein serine/threonine phosphatase 1 and 2A associate with and dephosphorylate neurofilaments
Brain Res Mol Brain Res
(1997) - et al.
Calpain-dependent neurofilament breakdown in anoxic and ischemic rat central axons
Neurosci Lett
(2002) Na+ currents that fail to inactivate
Trends Neurosci
(1993)Ions, energy and axonal energy: towards a molecular neurology of multiple sclerosis
Trends Mol Med
(2006)
The link between excitotoxic oligodendroglial death and demyelinating diseases
Trends Neurosci
Hypoxia-like tissue injury as a component of multiple sclerosis lesions
J Neurol Sci
Mechanisms of glutamate release from astrocytes: gap junction “hemichannels”, purinergic receptors and exocytotic release
Neurochem Int
TE-averaged two-dimensional proton spectroscopic imaging of glutamate at 3 T
Neuroimage
Memantine abrogates neurological deficits, but not CNS inflammation, in Lewis rat experimental autoimmune encephalomyelitis
J Neurol Sci
Hypoxia-like tissue injury as a component of multiple sclerosis lesions
J Neurol Sci
Innate and adaptive immune responses can be beneficial for CNS repair
Trends Neurosci
Multiple sclerosis: therapy
Multiple sclerosis
N Engl J Med
Multiple sclerosis as a neuronal disease
Multiple sclerosis: an immune or neurodegenerative disorder?
Annu Rev Neurosci
Paving the axonal highway: from stem cells to myelin repair
Stem Cell Rev
Axonal pathology in multiple sclerosis. A historical note
Brain Pathol
Axonal transection in the lesions of multiple sclerosis
N Engl J Med
Spinal cord axonal loss in multiple sclerosis: a post-mortem study
Neuropathol Appl Neurobiol
Axonal changes in chronic demyelinated cervical spinal cord plaques
Brain
Axonal loss in normal-appearing white matter in a patient with acute MS
Neurology
Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group
Neurology
A longitudinal study of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group (MSCRG)
Neurology
Use of proton magnetic resonance spectroscopy for monitoring disease progression in multiple sclerosis
Ann Neurol
Assessment of lesion pathology in multiple sclerosis using quantitative MRI morphometry and magnetic resonance spectroscopy
Brain
Neurological disability correlates with spinal cord axonal loss and reduce N-acetyl aspartate in chronic multiple sclerosis patients
Ann Neurol
Axonal swellings and degeneration in mice lacking the major proteolipid of myelin
Science
Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination
Nat Genet
Myelin-associated glycoprotein is a myelin signal that modulates the caliber of myelinated axons
J Neurosci
Axonal pathology in multiple sclerosis: relationship to neurologic disability
Curr Opin Neurol
Neurodegeneration in multiple sclerosis: relationship to neurological disability
Neuroscientist
Axonal pathology in myelin disorders
J Neurocytol
Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis
Brain
Cortical motor reorganization after a single clinical attack of multiple sclerosis
Brain
Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine
Brain
Axon-glial signaling and the glial support of axon function
Annu Rev Neurosci
Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients
Ann Neurol
Mitochondrial defects in acute multiple sclerosis lesions
Brain
Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav 1.6 sodium channels and Na+/Ca2+ exchanger
Proc Natl Acad Sci USA
Axonal degeneration in multiple sclerosis: is it time for neuroprotective strategies?
Ann Neurol
Imaging correlates of decreased axonal Na+/K+ ATPase in chronic MS lesions
Ann Neurol
Sodium channel expression within chronic multiple sclerosis plaques
J Neuropathol Exp Neurol
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2023, Translational Neuroimmunology: Multiple Sclerosis: Volume 8