Abstract
Introduction: Acute neurological damage from spinal cord injuries is believed to be localised, however it initiates a cascade of secondary events which usually leads to extensive and permanent neurological deficit. The secondary damage begins with the disruption of the blood-spinal cord barrier which unleashes a protracted inflammatory response. This prolonged inflammatory response is the catalyst for the secondary neurodegeneration and limited repair response that occurs in the chronic phase of a spinal cord injury. In this study it was proposed that the acute delivery of the angiogenic growth factors vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) would mediate inflammation and restore the blood spinal cord barrier. This would minimise the formation of glial scar and reduce the extent of secondary degeneration caudal and cranial to the lesion site.
Methods: Adult male Wistar rats (400g) were anesthetised. Complete laminectomies were performed at T10 and the animals were subjected to T10 hemisection. Animals were randomised to a treatment group (Lesion Control (LC), Gel Control (GC) and Angiogenic Gel (AG)) after the spinal cord was cut. Each treatment group had 6 animals sacrificed 3 months post injury. Sections were stained with antibodies to neurofilament 200, glial fibrillary acidic protein, smooth muscle actin (SMA), and fluorescent secondary antibodies and mounted with DAPI. The lesion size was measured from horizontal histological sections of the midline from 5 animals in each group using Axiovision version 4.6.1.0 (Carl Zeiss Imaging Solutions, Germany).
Results: The mean lesion size for the lesion control group was 2.09mm2, 1.97mm2 for the gel control group and 0.45mm2 for the active gel group. A t-test was used to confirm that the differences between the active gel and the two control groups were statistically significant (AG vs LC p= 0.021 AG vs GC p= 0.026). Histology showed a marked improvement of the morphology of the astrocytes in the treatment group over the control groups indicating that the treatment affected the population of reactive astrocytes. SMA staining showed an increased level of revascularisation in the treated lesions.
Discussion: Spinal cords do not heal because of prolonged inflammation which leads to secondary necrotic events, scar formation and the inhibition of regeneration. In this study we present a method for regulating the post lesion inflammatory signals, significantly reducing post-lesion scar formation. We propose the delivery of VEGF/PDGF significantly increases the permeability of the blood spinal cord barrier to neutrophils and macrophages and promotes angiogenesis observed in the lesion site. This may have two major effects on the progression of the spinal cord injury. Firstly, by increasing the initial influx of inflammatory cells it enables the faster removal of damaged tissue and phagocytosis of apoptotic cells thereby restoring the balance in favour of regulated inflammation and results in a finite and reduced inflammation time. Secondly, combination of VEGF and PDGF provides a robust angiogenic response and reduces ischemia, the population of reactive astrocytes and the capacity to form glial scars. These growth factors appear to moderate the secondary degenerative changes that result from the prolonged inflammation and thus promote the inherent capacity for regeneration.
Correspondence should be addressed to Dr Owen Williamson, Editorial Secretary, Spine Society of Australia, 25 Erin Street, Richmond, Victoria 3121, Australia.
