Background: Spinal cord injury (SCI) is heterogeneous in nature and can be complicated by inflammation and scarring in the subarachnoid space (arachnoiditis). The constellation of traumatic injury and arachnoiditis can lead to extensive intraparenchymal cysts or post-traumatic syringomyelia (PTS), due to alterations in fluid flow and pressure dynamics in the subarachnoid space.
Hypothesis: Intrathecal injection of a bioengineered hydrogel containing hyaluronan (HA) will improve functional recovery following severe spinal cord injury associated with arachnoiditis.
Methods: Acute to subacute pathophysiological events were characterized in non-injured sham rats, rats receiving a clip compression/contusion injury (SCI), rats receiving an intrathecal kaolin injection (Arachnoiditis) and in rats receiving SCI plus kaolin injection (PTS). Next, a HA containing hydrogel (HAMC) or artificial cerbralspinal fluid (aCSF) control was injected into the subarachnoid space 24 hours following PTS injury. To assess treatment efficacy, subacute pathophysiology was assessed as was long-term neurobehavioural and neuroanatomical recovery. Finally, in vitro studies examined the effect of HA on TLR4 activation using lipopolysaccharide in primary rat microglial cultures.
Results: PTS animals exhibited a greater parenchymal injury response as compared to the sum of SCI alone or arachnoiditis alone. Injection of HAMC reduced the extent of scarring and inflammation in the subarachnoid space and improved neurobehavioural and neuroanatomical recovery relative to aCSF controls. These improvements were associated with reduced chondroitin sulfate proteoglycan and IL-1α expression and a trend towards and axonal preservation. In vitro studies demonstrated that HA is capable of reducing TLR4 mediated inflammation in microglia.
Conclusions: Acute arachnoiditis potentiates the intensity of intraparenchymal inflammatory and scarring events following SCI. When HAMC was injected intrathecally following PTS injury, it mitigated some of the pernicious effects of arachnoiditis. Part of the therapeutic action of HAMC can be attributed to the ability of HA to reduce TLR4 mediated inflammation in microglia, possibly through an extracellular mechanism.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33923 |
| Date | 10 December 2012 |
| Creators | Austin, James W. |
| Contributors | Fehlings, Michael G. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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