Axonal Loss In The Pathology Of MS: Consequences For Understanding The Progressive Phase Of The Disease
Bjartmar C, Wujek JR, Trapp BD
J Neurol Sci 2003 Feb 15;206(2):165-71
Lerner Research Institute, Cleveland Clinic Foundation, Department of NeuroSciences, 9500 Euclid Ave., Cleveland, OH 44195, USA
Axonal degeneration has been identified as the major determinant of irreversible Neurological disability in patients with Multiple Sclerosis (MS).
Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory DeMyelination influences Axon Pathology during Relapsing/Remitting MS (RR-MS).
This Axonal Loss remains clinically silent for many years, and irreversible Neurological disability develops when a threshold of Axonal Loss is reached and compensatory CNS resources are exhausted.
Experimental support for this view - the Axonal Hypothesis - is provided by data from various animal models with primary Myelin or Axonal pathology, and from pathological or Magnetic Resonance studies on MS patients.
In mice with Experimental Autoimmune Encephalomyelitis (EAE), 15-30% of Spinal Cord Axons can be lost before permanent Ambulatory Impairment occurs.
During Secondary/Progressive MS (SP-MS), chronically DeMyelinated Axons may degenerate due to lack of Myelin-derived Trophic support.
In addition, we hypothesize that reduced Trophic support from damaged targets or degeneration of Efferent Fibers may trigger preprogrammed NeuroDegenerative mechanisms.
The concept of MS as an Inflammatory NeuroDegenerative Disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of NeuroProtective treatment strategies.
Anti-Inflammatory Strategies To Prevent Axonal Injury In Multiple Sclerosis
Rieckmann P, Maurer M
Curr Opin Neurol 2002 Jun;15(3):361-70
Julius-Maximilians-University, Clinical Research Unit for Multiple Sclerosis and NeuroImmunology, Department of Neurology, Josef-Schneider-Strasse 11, D-97080 Wurzburg, Germany
Axonal injury in Multiple Sclerosis has attracted considerable interest during the past few years. It has been demonstrated in association with inflammation within active lesions, but it is also present in Normal-Appearing White Matter.
Because Axonal Loss appears to be responsible for persistent Neurological deficits in patients with Multiple Sclerosis, treatment strategies to prevent damage to Neurites and restore function are of paramount importance in controlling the disease process.
Some of the currently available ImmunoModulatory therapies may also reduce Axonal damage, as demonstrated using improved imaging technologies, but the precise mechanisms that could protect Axons during the inflammatory attack are yet to be identified.
Factors that are involved in functional impairment of Axonal Conduction and those elements that are responsible for direct structural damage to the Axon are both potential targets for therapeutic interventions.
NeuroTrophins Reduce Degeneration Of Injured Ascending Sensory And CorticoSpinal Motor Axons In Adult Rat Spinal Cord
Sayer FT, Oudega M, Hagg T
Exp Neurol 2002 May;175(1):282-96
University of Louisville, Kentucky Spinal Cord Injury Research Center, Kentucky 40292, USA
Spinal Cord regeneration in adult mammals is limited by Neurite outgrowth inhibitors and insufficient availability of outgrowth-promoting agents.
Formation of degenerative swellings at the proximal ends of severed Axons (Terminal Clubs), which starts early after injury, also may hinder recovery and their rupture may contribute to secondary Spinal Cord damage.
We investigated whether NeuroTrophins would reduce these degenerative processes. Adult rats received a transection of the Dorsal Column Sensory and CorticoSpinal Motor Tracts at T9 and anterograde tracing of the Axons from the Sciatic Nerve and Motor Cortex, respectively.
The highest number of terminal clubs was found at 1 day and approximately half remained present until at least 28 days.
A single injection immediately after injury of a mixture of Nerve Growth Factor, Brain-Derived Neurotrophic Factor and NeuroTrophin-3 into the lesion site, reduced the number of Terminal Clubs in the Sensory System by approximately half at 1 and 7 days (but not 14) after the lesion.
Individual or combinations of two NeuroTrophins were as effective, suggesting that the NeuroTrophins protected similar Axonal populations. The injected NeuroTrophins did not affect degeneration of CorticoSpinal Motor Axons.
A 7-day continuous intrathecal infusion of NeuroTrophin-3 was more effective and also reduced Terminal Club formation of CorticoSpinal Axons by approximately 60%.
Spinal tissue loss was not affected by the NeuroTrophin treatments, suggesting that Terminal Clubs are not major contributors to the pathogenesis of secondary Spinal degeneration during the first two weeks.
Thus, NeuroTrophins can reduce Axonal degeneration in the Spinal Cord after Traumatic Axonal Injury.
Copyright 2002 Elsevier Science (USA).
Patients Lacking The Major CNS Myelin Protein, Proteolipid Protein 1, Develop Length-Dependent Axonal Degeneration In The Absence Of DeMyelination And Inflammation
Garbern JY, Yool DA, Moore GJ, Wilds IB, Faulk MW, Klugmann M, Nave KA, Sistermans EA, van der Knaap MS, Bird TD, Shy ME, Kamholz JA, Griffiths IR
Brain 2002 Mar;125(Pt 3):551-61
Wayne State University School of Medicine, Department of Neurology and Center for Molecular Medicine and Genetics, Detroit, Michigan, USA
Axonal degeneration contributes to clinical disability in the acquired DeMyelinating Disease Multiple Sclerosis.
Axonal degeneration occurs during acute attacks, associated with inflammation, and during the chronic progressive phase of the disease in which inflammation is not prominent.
To explore the importance of interactions between Oligodendrocytes and Axons in the CNS, we analyzed the Brains of rodents and humans with a null mutation in the gene encoding the major CNS Myelin Protein, ProteoLipid Protein (PLP1, previously PLP).
Histological analyses of the CNS of Plp1 null mice and of autopsy material from patients with null PLP1 mutations were performed to evaluate Axonal and Myelin integrity.
In vivo Proton Magnetic Resonance Spectroscopy (MRS) of PLP1 null patients was conducted to measure levels of N-AcetylAspartate (NAA), a marker of Axonal integrity.
Length-dependent Axonal degeneration without DeMyelination was identified in the CNS of Plp1 null mice. Proton MRS of PLP1-deficient patients showed reduced NAA levels, consistent with Axonal loss.
Analysis of patients' Brain tissue also demonstrated a length-dependent pattern of Axonal loss without significant DeMyelination. Therefore, Axonal degeneration occurs in humans as well as mice lacking the major Myelin protein PLP1.
This degeneration is length-dependent, similar to that found in the PNS of patients with the inherited DeMyelinating Neuropathy, CMT1A, but is not associated with significant DeMyelination.
Disruption of PLP1-mediated Axonal - Glial interactions thus probably causes this Axonal degeneration. A similar mechanism may be responsible for Axonal degeneration and clinical disability that occur in patients with Multiple Sclerosis.
Watery And Dark Axons In Wallerian Degeneration Of The Opossum's Optic Nerve: Different Patterns Of CytoSkeletal Breakdown?
Narciso MS, Hokoc JN, Martinez AM
An Acad Bras Cienc 2001 Jun;73(2):231-43
Universidade Federal do Rio de Janeiro, Departamento de Histologia e Embriologia, Instituto de Ciencias Biomedicas, Centro de Ciencias da Saude, Rio de Janeiro, RJ, 21941-590 Brazil
In this paper we report a qualitative morphological analysis of Wallerian Degeneration in a marsupial.
Right Optic Nerves of opossums Didelphis marsupialis were crushed with a fine forceps and after 24, 48, 72, 96 and 168 hours the animals were anaesthetized and perfused with fixative.
The Optic Nerves were immersed in fixative and processed for routine transmission electron microscopy.
Among the early alterations typical of Axonal degeneration, we observed nerve fibers with focal degeneration of the Axoplasmic CytoSkeleton, watery degeneration and dark degeneration, the latter being prevalent at 168 hours after crush.
Our results point to a gradual disintegration of the AxoPlasmic CytoSkeleton, opposed to the previous view of an "all-or-nothing" process (Griffin et al 1995).
We also report that, due to an unknown mechanism, fibers show either a dark or watery pattern of Axonal degeneration, as observed in Axon profiles. We also observed fibers undergoing early Myelin breakdown in the absence of Axonal alterations.
Pathogenesis Of Axonal Degeneration: Parallels Between Wallerian Degeneration And Vincristine Neuropathy
Wang MS, Wu Y, Culver DG, Glass JD
J NeuroPathol Exp Neurol 2000 Jul;59(7):599-606
Emory University School of Medicine, Department of Neurology, Atlanta, Georgia 30322, USA
Peripheral Neuropathies and Wallerian Degeneration share a number of pathological features; the most prominent of which is Axonal degeneration.
We asked whether common PathoPhysiologic mechanisms are involved in these 2 disorders by directly comparing in vitro models of Axonal degeneration after Axotomy or exposure to the NeuroToxin Vincristine.
Embryonic rat Dorsal Root Ganglia (DRG) were allowed to extend Neurites for 5 days in culture, and then were either Axotomized or exposed to 0.01 microM Vincristine. Neurites universally degenerated by 3 days after Axotomy or after 6 days of Vincristine exposure.
The NeuroProtective effects of a low Calcium environment or pharmacologic inhibition of the Cysteine protease Calpain were compared in these 2 models of Axonal degeneration.
Addition of EGTA or growth in zero-Calcium media provided significant protection against Axonal degeneration after either Axotomy or Vincristine exposure.
Treatment with the experimental Calpain Inhibitor AK295 was equally protective in both models. Chronic exposure to AK295 was not toxic to the cultures.
These data suggest that common mechanisms involving Calcium and Calpains are involved in both Axotomy-induced and Vincristine-induced Axonal degeneration.
In addition, Calpain inhibition may provide a strategy for preventing Axonal degeneration and preserving Neurologic function in a variety of PNS and CNS Disorders.