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Comparative Study
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Ascending Central Canal Dilation and Progressive Ependymal Disruption in a Contusion Model of Rodent Chronic Spinal Cord Injury

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Comparative Study

Ascending Central Canal Dilation and Progressive Ependymal Disruption in a Contusion Model of Rodent Chronic Spinal Cord Injury

Milan Radojicic et al. BMC Neurol.

Abstract

Background: Chronic spinal cord injury (SCI) can lead to an insidious decline in motor and sensory function in individuals even years after the initial injury and is accompanied by a slow and progressive cytoarchitectural destruction. At present, no pathological mechanisms satisfactorily explain the ongoing degeneration.

Methods: Adult female Sprague-Dawley rats were anesthetized laminectomized at T10 and received spinal cord contusion injuries with a force of 250 kilodynes using an Infinite Horizon Impactor. Animals were randomly distributed into 5 groups and killed 1 (n = 4), 28 (n = 4), 120 (n = 4), 450 (n = 5), or 540 (n = 5) days after injury. Morphometric and immunohistochemical studies were then performed on 1 mm block sections, 6 mm cranial and 6 mm caudal to the lesion epicenter. The SPSS 11.5 t test was used to determine differences between quantitative measures.

Results: Here, we document the first report of an ascending central canal dilation and progressive ependymal disruption cranial to the epicenter of injury in a contusion model of chronic SCI, which was characterized by extensive dural fibrosis and intraparenchymal cystic cavitation. Expansion of the central canal lumen beyond a critical diameter corresponded with ependymal cell ciliary loss, an empirically predictable thinning of the ependymal region, and a decrease in cell proliferation in the ependymal region. Large, aneurysmal dilations of the central canal were accompanied by disruptions in the ependymal layer, periependymal edema and gliosis, and destruction of the adjacent neuropil.

Conclusion: Cells of the ependymal region play an important role in CSF homeostasis, cellular signaling and wound repair in the spinal cord. The possible effects of this ascending pathology on ependymal function are discussed. Our studies suggest central canal dilation and ependymal region disruption as steps in the pathogenesis of chronic SCI, identify central canal dilation as a marker of chronic SCI and provide novel targets for therapeutic intervention.

Figures

Figure 1
Figure 1
Quantification of the central canal perimeter +/- 1 mm-5 mm from the lesion epicenter 450 days after injury, with representative toluidine blue stained transverse sections of rat spinal cord for each distance. Extensive dural fibrosis and intraparenchymal cavitations are evident at the epicenter of the injury, which are reminiscent of human syringomyelia. Central canal dilation is more marked cranial to the epicenter of injury and is evident up to 5 mm cranial to epicenter of the injury. Asterisks indicate significance at p < 0.05. Magnification = 10×.
Figure 2
Figure 2
Qualitative changes over time of the post-traumatic central canal lumen, ependymal and periependymal regions at 1 mm cranial to the lesion epicenter. Toluidine blue stained transverse sections of contused rat spinal cords 1 mm cranial to the lesion epicenter are shown in A-H. Low magnification images reveal a progressively increasing central canal lumen from day 1 (A), day 28 (B), day 120 (C) and day 450 (D) following injury. High magnification images reveal progressive thinning of the ependymal region, ependymal ciliary loss, and periependymal edema from day 1 (E), day 28 (F), day 120 (G) and day 450 (H) following injury. Magnification = 40× for A-D, 300× for E-H.
Figure 3
Figure 3
Quantitative changes over time of the post-traumatic central canal lumen, ependymal and periependymal regions at 1 mm cranial to the lesion epicenter. (A) Quantitation of central canal perimeter 1 mm cranial to the lesion epicenter indicates a progressive increase from day 1 to day 450 following injury. (B) Quantitation of ependymal region thickness 1 mm cranial to the lesion epicenter indicates a progressive decrease from day 1 to day 450 following injury. (C) Quantitation of ependymal region nuclear density 1 mm cranial to the lesion epicenter indicates an increase from day 1 to day 28 following injury, then a progressive decrease from day 28 to day 450 following injury. (D) The relation of ependymal region thickness to perimeter of the central canal lumen at all time points. Error bars represent standard error.
Figure 4
Figure 4
Qualitative changes over time of the post-traumatic central canal lumen and ependymal region cellular density at 1 mm-5 mm cranial to the lesion epicenter. Toluidine blue stained transverse sections of contused rat spinal cords from day 1, day 28, day 120 and day 450 following injury at 1 mm (A-D), 3 mm (E-H) and 5 mm (I-L) cranial to the lesion epicenter. Magnification = 40× for A-L.
Figure 5
Figure 5
Quantitative changes over time of the post-traumatic central canal lumen and ependymal region cellular density at 1 mm-5 mm cranial to the lesion epicenter. Quantitation of central canal perimeter and ependymal region thickness from 1 mm-5 mm cranial to the lesion epicenter at day 1 (A), day 28 (B), day 120 (C), and day 450 (D) following injury. Error bars represent standard error.
Figure 6
Figure 6
Transverse sections of the adult rat spinal cord at late time points after injury. Toluidine blue staining 450 days after injury 5 mm (A), 3 mm (B), and 1 mm (C) from the lesion epicenter reveals a progressive dilation of the central canal. Higher power magnification of the cells lining the central canal 5 mm (D), 3 mm (E), and 1 mm (F) from the lesion epicenter reveals a progressive loss of cilia and flattening of ependymal cells at 1 mm from the lesion epicenter (F); these cells also exhibit a more euchromatic appearing nucleus. (G) BrdU immunolabeling of the central canal at 540 days after injury 5 mm from lesion epicenter reveals BrdU immunoreactivity with a mild dilation of the central canal. (H) BrdU immunolabeling of the central canal 3 mm from lesion epicenter also reveals BrdU immunoreactivity with a moderate dilation of the central canal, but with more dispersion of cells around the canal. (I) BrdU immunolabeling of the central canal 1 mm from lesion epicenter shows diminished BrdU reactivity with severe dilation of the central canal. Hematoxylin and eosin staining at 540 days after injury 5 mm (J), 3 mm (K), and 1 mm (L) from the lesion epicenter reveals a progressive dilation of the central canal; note that the continuity of cells bordering the central canal is disrupted 1 mm from the lesion epicenter (arrow in L). Magnification = 40× for A&B, 30× for C, 300× for D-F, 40× for G-L.
Figure 7
Figure 7
The progressive dilation of the central canal with time after spinal cord injury results in a loss of ependymal region cellular density. (A) Total ependymal region cell counts increase with enlarging central canal area up until a critical point. Thereafter, the absolute cell number decreases. (B) Cellular coverage of the central canal similarly decreases with enlarging central canal. Transverse toluidine blue stained sections of the adult rat spinal cord 450 days after injury demonstrating the evolution of the ependymal region cell changes are depicted in C-E. Mild (C) and moderate (D) central canal dilations are associated with an increasing ependymal region nuclear count. Large, aneurysmal dilation of the central canal (E) is accompanied by flattening of the ependymal cell layer, ependymal ciliary loss and disruptions in the continuity of cells lining the canal. Note the periependymal edema and gliosis, macrophage infiltration and loss of adjacent neuropil. Magnification = 60× for C-E.

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