Involvement of Acidic Fibroblast Growth Factor in Spinal Cord Injury Repair Processes Revealed by a Proteomics Approach

Abstract

Acidic fibroblast growth factor (aFGF; also known as FGF-1) is a potent neurotrophic factor that affects neuronal survival in the injured spinal cord. However, the pathological changes that occur with spinal cord injury (SCI) and the attribution to aFGF of a neuroprotective effect during SCI are still elusive. In this study, we demonstrated that rat SCI, when treated with aFGF, showed significant functional recovery as indicated by the Basso, Beattie, and Bresnahan locomotor rating scale and the combined behavior score (p < 0.01-0.001). Furthermore proteomics and bioinformatics approaches were adapted to investigate changes in the global protein profile of the damaged spinal cord tissue when experimental rats were treated either with or without aFGF at 24 h after injury. We found that 51 protein spots, resolvable by two-dimensional PAGE, had significant differential expression. Using hierarchical clustering analysis, these proteins were categorized into five major expression patterns. Noticeably proteins involved in the process of secondary injury, such as astrocyte activation (glial fibrillary acidic protein), inflammation (S100B), and scar formation (keratan sulfate proteoglycan lumican), which lead to the blocking of injured spinal cord regeneration, were down-regulated in the contusive spinal cord after treatment with aFGF. We propose that aFGF might initiate a series of biological processes to prevent or attenuate secondary injury and that this, Spinal cord injury (SCI)1 is a costly disease as well as the most frequent cause of mortality and morbidity in every medical care system around the world (1, 2). Traumatic axonal injury is a primary sequela of contusive SCI and is characterized by axonal swelling and disconnection of the ascending sensory and descending motor tracts (3). Contusive SCI seems to initiate a complicated cascade of pathophysiological changes, a process called secondary injury, including fiber deformation, increased vascular permeability, local ischemia, intraneuronal edema, and local demyelination. Moreover traumatic axonal injury typically involves a disruption of the axonal membrane, and this results in up-regulation of the entry of calcium, the influx of which initiates calpain activation (4, 5) and mitochondrial injury/swelling (6), resulting in cytochrome c release and caspase activation (7). Simultaneously the proliferation and hypertrophy of astrocytes around the injury site are characterized by increased immunoreactivity to glial fibrillary acidic proteins (GFAPs) (8).Although many studies have focused on revealing the pathophysiology of SCI, the exact molecular mechanisms and the biochemical pathways that mediate secondary injury remain sketchy (9). Spinal cord injury often causes permanent neurological deficits mostly because the injured neurons lack regenerative ability, and the series of destructive processes that follow SCI results in a second wave of cell death and spreading tissue loss (10). Therefore, studies of the stimulaFrom the ‡Institute

Acid Fibroblast Growth Factor and Peripheral Nerve Grafts Regulate Th2 Cytokine Expression, Macrophage Activation, Polyamine Synthesis, and Neurotrophin Expression in Transected Rat Spinal Cords

“…Previous studies have demonstrated a variety of crucial functions of aFGF in the nervous system (Mason, 2007;Tsai et al, 2008), and intercostal nerve grafts have been implicated in redirecting specific pathways from white to gray matter (Cheng et al, 1996). The present study demonstrated that the repair strategy using both aFGF and nerve grafts modulates macrophage activation, polyamine production, and neurotrophin expression, all of which are important for functional recovery.…”

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury

“…To date, there have been a small number of published reports of proteomic analyses in injured spinal cord tissue (44, 46, [52][53][54][55]. In these studies, 2 dimensional SDS-PAGE based mass spec identified only 61 proteins differentially expressed in injured spinal cord tissue, a relatively low number, which is not surprising because of the limited range of detection.…”

Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial

“…In the proteomics study, aFGF reduces neuronal cell death and inflammatory response after SCI. 12,13,28 Therefore, aFGF may confer neuroprotection and create favorable conditions for axonal regeneration. Based on the findings here, future research should focus on verifying and maximizing the effects of aFGF while limiting side effects by adjustments in dosing and combinations with other strategies like cell replacement therapies 6,22 or lytic enzymes.…”