Astrocytic and Vascular Remodeling in the Injured Adult Rat Spinal Cord after Chondroitinase ABC Treatment

Abstract

Upregulation of extracellular chondroitin sulfate proteoglycans (CSPG) is a primary cause for the failure of axons to regenerate after spinal cord injury (SCI), and the beneficial effect of their degradation by chondroitinase ABC (ChABC) is widely documented. Little is known, however, about the effect of ChABC treatment on astrogliosis and revascularization, two important factors influencing axon regrowth. This was investigated in the present study. Immediately after a spinal cord hemisection at thoracic level 8-9, we injected ChABC intrathecally at the sacral level, repeated three times until 10 days post-injury. Our results show an effective cleavage of CSPG glycosaminoglycan chains and stimulation of axonal remodeling within the injury site, accompanied by an extended period of astrocyte remodeling (up to 4 weeks). Interestingly, ChABC treatment favored an orientation of astrocytic processes directed toward the injury, in close association with axons at the lesion entry zone, suggesting a correlation between axon and astrocyte remodeling. Further, during the first weeks post-injury, ChABC treatment affected the morphology of laminin-positive blood vessel basement membranes and vessel-independent laminin deposits: hypertrophied blood vessels with detached or duplicated basement membrane were more numerous than in lesioned untreated animals. In contrast, at later time points, laminin expression increased and became more directly associated with newly formed blood vessels, the size of which tended to be closer to that found in intact tissue. Our data reinforce the idea that ChABC injection in combination with other synergistic treatments is a promising therapeutic strategy for SCI repair.

Molecular mechanisms of scar-sourced axon growth inhibitors

“…tPA deletion attenuated neurite outgrowth and sensory/motor functional recovery due to ChABC treatment and coadministration of ChABC and plasmin reversed the effects of tPA deficiency. ChABC treatment induced an extended period of astrocyte remodeling (up to 4 weeks) and a favored orientation of astrocytic processes directed toward injury area, which might become guidance bridges for regenerating axons (Milbreta et al, 2014). ChABC treatment affected morphology of laminin-positive blood vessel basement membranes and vessel-independent laminin deposits.…”

Rehabilitative Surgery

“…Orlando et al, however, showed that full digestion of motor cortex CSPG by ChABC aggravated motor deficits, suggesting that too much plasticity is not beneficial [246]. Milbreta et al found that ChABC altered astrocytic and vascular structure in injured spinal cords [226]. ChABC also promotes remyelination [185].…”

Vascular endothelial growth factor activates neural stem cells through epidermal growth factor receptor signal after spinal cord injury

“…In the intact spinal cord, NSCs are confined within the ependymal cell population and remain quiescent, and the expression of nestin is restricted . Our previous study shows that spinal cord NSCs are activated and proliferate robustly after SCI, using nestin immunofluorescence to represent NSCs .…”