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Damage to myelin and oligodendrocytes: a role in chronic outcomes following traumatic brain injury?

Maxwell WL - Brain Sci (2013)

Bottom Line: However, the biomechanism(s) of continued loss of axons is obscure.Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI.As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy, College of Medicine, Veterinary Medicine and Biological Sciences, University of Glasgow, Glasgow G12 8QQ, UK. William.Maxwell@Glasgow.ac.uk.

ABSTRACT
There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve fibers in adult guinea-pigs was used to test the hypothesis that damage to the myelin sheath and oligodendrocytes of the optic nerve fibers may contribute to, or facilitate, the continuance of axonal loss. Myelin dislocations occur within internodal myelin of larger axons within 1-2 h of TBI. The myelin dislocations contain elevated levels of free calcium. The volume of myelin dislocations increase with greater survival and are associated with disruption of the axonal cytoskeleton leading to secondary axotomy. Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI. As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter.

No MeSH data available.


Related in: MedlinePlus

Longitudinal sections of an axonal swelling (a) and several degeneration bulbs (b). Material in (a) from an animal killed at 7 days after injury. The axonal swelling is formed by aggregation of large numbers of membranous organelles which accumulate at a locus of loss of fast axonal transport. The volume of axoplasm increases from the caliber of the axon (ax) and is completely enclosed by direct continuation of the internodal myelin sheath. The cytoplasm of the swelling is packed with numerous, randomly orientated mitochondria (m). At one region a constriction of the caliber of the axonal swelling occurs. This is the site at which the axonal swelling breaks the axon into two fragments when axonal disconnection occurs. The axon has then completed secondary axotomy and both fragments will die back some 600–800 µm on either side of the site of disconnection over the ensuing 48 h [23]. The surrounding tissue has widely separated cell processes and is suggestive of edema. Several aggregates of loosely organised membrane fragments (◊) occur in the enlarged extracellular space. An exrample of nerve fiber undergoing “dark degeneration” occurs at the bottom of this field. Magnification 2800×. (b) Longitudinal sections of terminal bulbs obtained from a 4 week posttrauma survival animal processed with the pyroantimonate technique. There is little evidence suggestive of edema. Numerous, closely spaced myelin intrusions and/or external protrusions occur within myelin sheaths of both nerve fibers or the myelin remnants adjacent to the large caliber terminal bulbs. The rounded, bulbous profile of the bulbs is enveloped by a remnant of the myelin sheath and probably represents myelin from a more proximal region of the degenerating nerve fibre during retraction of the terminal bulbs subsequent to axotomy. Mitochondria within both of the bulbs and parts of recognizable nerve fibers contain focal, electron dense aggregates of pyroantimonate precipitate—see inside the dotted ovals for example. There are also widespread aggregates of pyroantimonate precipitate at foci of extracellular fluid. Magnification 1875×.
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brainsci-03-01374-f010: Longitudinal sections of an axonal swelling (a) and several degeneration bulbs (b). Material in (a) from an animal killed at 7 days after injury. The axonal swelling is formed by aggregation of large numbers of membranous organelles which accumulate at a locus of loss of fast axonal transport. The volume of axoplasm increases from the caliber of the axon (ax) and is completely enclosed by direct continuation of the internodal myelin sheath. The cytoplasm of the swelling is packed with numerous, randomly orientated mitochondria (m). At one region a constriction of the caliber of the axonal swelling occurs. This is the site at which the axonal swelling breaks the axon into two fragments when axonal disconnection occurs. The axon has then completed secondary axotomy and both fragments will die back some 600–800 µm on either side of the site of disconnection over the ensuing 48 h [23]. The surrounding tissue has widely separated cell processes and is suggestive of edema. Several aggregates of loosely organised membrane fragments (◊) occur in the enlarged extracellular space. An exrample of nerve fiber undergoing “dark degeneration” occurs at the bottom of this field. Magnification 2800×. (b) Longitudinal sections of terminal bulbs obtained from a 4 week posttrauma survival animal processed with the pyroantimonate technique. There is little evidence suggestive of edema. Numerous, closely spaced myelin intrusions and/or external protrusions occur within myelin sheaths of both nerve fibers or the myelin remnants adjacent to the large caliber terminal bulbs. The rounded, bulbous profile of the bulbs is enveloped by a remnant of the myelin sheath and probably represents myelin from a more proximal region of the degenerating nerve fibre during retraction of the terminal bulbs subsequent to axotomy. Mitochondria within both of the bulbs and parts of recognizable nerve fibers contain focal, electron dense aggregates of pyroantimonate precipitate—see inside the dotted ovals for example. There are also widespread aggregates of pyroantimonate precipitate at foci of extracellular fluid. Magnification 1875×.

Mentions: In the guinea pig optic nerve stretch injury model of TAI classic degeneration bulbs may be encountered in any specimen from 7 days and later survivals. Two examples are illustrated in Figure 10a,b. The specimen in Figure 10a was obtained at 7 days post-trauma, while that in Figure 10b was obtained at 4 weeks post-injury. In the latter, the number of rounded, darkly stained, myelin intrusions is very high within the myelin sheaths of all sizes of nerve fiber as well as in the myelin remnants in relation to the terminal degeneration bulbs. The pericellular tissue fluid internal to the remnants of the myelin sheath (top) and within the extracellular space related to the bulbs contains pyroantimonate precipitate. Mitochondria within degeneration bulbs frequently also contain small foci of precipitate. In Figure 10a, the 7 day survival animal, the extracellular space is enlarged such that cell processes are widely separated and aggregates of membranous debris (◊) occur and is suggestive of tissue edema. A nerve fiber with the pathological characteristics of “dark degeneration” may be seen at the bottom of the figure (arrow).


Damage to myelin and oligodendrocytes: a role in chronic outcomes following traumatic brain injury?

Maxwell WL - Brain Sci (2013)

Longitudinal sections of an axonal swelling (a) and several degeneration bulbs (b). Material in (a) from an animal killed at 7 days after injury. The axonal swelling is formed by aggregation of large numbers of membranous organelles which accumulate at a locus of loss of fast axonal transport. The volume of axoplasm increases from the caliber of the axon (ax) and is completely enclosed by direct continuation of the internodal myelin sheath. The cytoplasm of the swelling is packed with numerous, randomly orientated mitochondria (m). At one region a constriction of the caliber of the axonal swelling occurs. This is the site at which the axonal swelling breaks the axon into two fragments when axonal disconnection occurs. The axon has then completed secondary axotomy and both fragments will die back some 600–800 µm on either side of the site of disconnection over the ensuing 48 h [23]. The surrounding tissue has widely separated cell processes and is suggestive of edema. Several aggregates of loosely organised membrane fragments (◊) occur in the enlarged extracellular space. An exrample of nerve fiber undergoing “dark degeneration” occurs at the bottom of this field. Magnification 2800×. (b) Longitudinal sections of terminal bulbs obtained from a 4 week posttrauma survival animal processed with the pyroantimonate technique. There is little evidence suggestive of edema. Numerous, closely spaced myelin intrusions and/or external protrusions occur within myelin sheaths of both nerve fibers or the myelin remnants adjacent to the large caliber terminal bulbs. The rounded, bulbous profile of the bulbs is enveloped by a remnant of the myelin sheath and probably represents myelin from a more proximal region of the degenerating nerve fibre during retraction of the terminal bulbs subsequent to axotomy. Mitochondria within both of the bulbs and parts of recognizable nerve fibers contain focal, electron dense aggregates of pyroantimonate precipitate—see inside the dotted ovals for example. There are also widespread aggregates of pyroantimonate precipitate at foci of extracellular fluid. Magnification 1875×.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061868&req=5

brainsci-03-01374-f010: Longitudinal sections of an axonal swelling (a) and several degeneration bulbs (b). Material in (a) from an animal killed at 7 days after injury. The axonal swelling is formed by aggregation of large numbers of membranous organelles which accumulate at a locus of loss of fast axonal transport. The volume of axoplasm increases from the caliber of the axon (ax) and is completely enclosed by direct continuation of the internodal myelin sheath. The cytoplasm of the swelling is packed with numerous, randomly orientated mitochondria (m). At one region a constriction of the caliber of the axonal swelling occurs. This is the site at which the axonal swelling breaks the axon into two fragments when axonal disconnection occurs. The axon has then completed secondary axotomy and both fragments will die back some 600–800 µm on either side of the site of disconnection over the ensuing 48 h [23]. The surrounding tissue has widely separated cell processes and is suggestive of edema. Several aggregates of loosely organised membrane fragments (◊) occur in the enlarged extracellular space. An exrample of nerve fiber undergoing “dark degeneration” occurs at the bottom of this field. Magnification 2800×. (b) Longitudinal sections of terminal bulbs obtained from a 4 week posttrauma survival animal processed with the pyroantimonate technique. There is little evidence suggestive of edema. Numerous, closely spaced myelin intrusions and/or external protrusions occur within myelin sheaths of both nerve fibers or the myelin remnants adjacent to the large caliber terminal bulbs. The rounded, bulbous profile of the bulbs is enveloped by a remnant of the myelin sheath and probably represents myelin from a more proximal region of the degenerating nerve fibre during retraction of the terminal bulbs subsequent to axotomy. Mitochondria within both of the bulbs and parts of recognizable nerve fibers contain focal, electron dense aggregates of pyroantimonate precipitate—see inside the dotted ovals for example. There are also widespread aggregates of pyroantimonate precipitate at foci of extracellular fluid. Magnification 1875×.
Mentions: In the guinea pig optic nerve stretch injury model of TAI classic degeneration bulbs may be encountered in any specimen from 7 days and later survivals. Two examples are illustrated in Figure 10a,b. The specimen in Figure 10a was obtained at 7 days post-trauma, while that in Figure 10b was obtained at 4 weeks post-injury. In the latter, the number of rounded, darkly stained, myelin intrusions is very high within the myelin sheaths of all sizes of nerve fiber as well as in the myelin remnants in relation to the terminal degeneration bulbs. The pericellular tissue fluid internal to the remnants of the myelin sheath (top) and within the extracellular space related to the bulbs contains pyroantimonate precipitate. Mitochondria within degeneration bulbs frequently also contain small foci of precipitate. In Figure 10a, the 7 day survival animal, the extracellular space is enlarged such that cell processes are widely separated and aggregates of membranous debris (◊) occur and is suggestive of tissue edema. A nerve fiber with the pathological characteristics of “dark degeneration” may be seen at the bottom of the figure (arrow).

Bottom Line: However, the biomechanism(s) of continued loss of axons is obscure.Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI.As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter.

View Article: PubMed Central - PubMed

Affiliation: Department of Human Anatomy, College of Medicine, Veterinary Medicine and Biological Sciences, University of Glasgow, Glasgow G12 8QQ, UK. William.Maxwell@Glasgow.ac.uk.

ABSTRACT
There is increasing evidence in the experimental and clinical traumatic brain injury (TBI) literature that loss of central myelinated nerve fibers continues over the chronic post-traumatic phase after injury. However, the biomechanism(s) of continued loss of axons is obscure. Stretch-injury to optic nerve fibers in adult guinea-pigs was used to test the hypothesis that damage to the myelin sheath and oligodendrocytes of the optic nerve fibers may contribute to, or facilitate, the continuance of axonal loss. Myelin dislocations occur within internodal myelin of larger axons within 1-2 h of TBI. The myelin dislocations contain elevated levels of free calcium. The volume of myelin dislocations increase with greater survival and are associated with disruption of the axonal cytoskeleton leading to secondary axotomy. Waves of Ca2+ depolarization or spreading depression extend from the initial locus injury for perhaps hundreds of microns after TBI. As astrocytes and oligodendrocytes are connected via gap junctions, it is hypothesized that spreading depression results in depolarization of central glia, disrupt axonal ionic homeostasis, injure axonal mitochondria and allow the onset of axonal degeneration throughout an increasing volume of brain tissue; and contribute toward post-traumatic continued loss of white matter.

No MeSH data available.


Related in: MedlinePlus