Abstract
Chondroitin sulfate proteoglycans (CSPGs) are glial scar-associated molecules considered axonal regeneration inhibitors and can be digested by chondroitinase ABC (ChABC) to promote axonal regeneration after spinal cord injury (SCI). We previously demonstrated that intrathecal delivery of low-dose ChABC (1 U) in the acute stage of SCI promoted axonal regrowth and functional recovery. In this study, high-dose ChABC (50 U) introduced via intrathecal delivery induced subarachnoid hemorrhage and death within 48 h. However, most SCI patients are treated in the sub-acute or chronic stages, when the dense glial scar has formed and is minimally digested by intrathecal delivery of ChABC at the injury site. The present study investigated whether intraparenchymal delivery of ChABC in the sub-acute stage of complete spinal cord transection would promote axonal outgrowth and improve functional recovery. We observed no functional recovery following the low-dose ChABC (1 U or 5 U) treatments. Furthermore, animals treated with high-dose ChABC (50 U or 100 U) showed decreased CSPGs levels. The extent and area of the lesion were also dramatically decreased after ChABC treatment. The outgrowth of the regenerating axons was significantly increased, and some partially crossed the lesion site in the ChABC-treated groups. In addition, retrograde Fluoro-Gold (FG) labeling showed that the outgrowing axons could cross the lesion site and reach several brain stem nuclei involved in sensory and motor functions. The Basso, Beattie and Bresnahan (BBB) open field locomotor scores revealed that the ChABC treatment significantly improved functional recovery compared to the control group at eight weeks after treatment. Our study demonstrates that high-dose ChABC treatment in the sub-acute stage of SCI effectively improves glial scar digestion by reducing the lesion size and increasing axonal regrowth to the related functional nuclei, which promotes locomotor recovery. Thus, our results will aid in the treatment of spinal cord injury.
Highlights
Traumatic spinal cord injury (SCI) leads to a loss of sensory and motor function because the damaged axons are unable to regrow
After SCI, a cascade of axonal regeneration inhibitors accumulate at the injury site, including myelin-derived proteins such as myelin-associated glycoprotein (MAG) [1], Nogo-A [2], and oligodendrocyte-myelin glycoprotein (OMgp) [3]; extracellular matrix-derived factors such as repulsive guidance molecules (RGMs), i.e., ephrins and semaphorins [4]; and the reactive astrocyte-derived extracellular matrix molecules chondroitin sulfate proteoglycans (CSPGs) [5, 6], which are the main components of the astroglial scar
To clarify whether the hemorrhage and death were due to the acutestage delivery of high-dose chondroitinase ABC (ChABC), the brains and spinal cords from an additional normal and T8 complete transected rat were harvested without perfusion after two days and compared to those of the high-dose ChABC-treated rats
Summary
Traumatic spinal cord injury (SCI) leads to a loss of sensory and motor function because the damaged axons are unable to regrow. After SCI, a cascade of axonal regeneration inhibitors accumulate at the injury site, including myelin-derived proteins such as myelin-associated glycoprotein (MAG) [1], Nogo-A [2], and oligodendrocyte-myelin glycoprotein (OMgp) [3]; extracellular matrix-derived factors such as repulsive guidance molecules (RGMs), i.e., ephrins and semaphorins [4]; and the reactive astrocyte-derived extracellular matrix molecules chondroitin sulfate proteoglycans (CSPGs) [5, 6], which are the main components of the astroglial scar By eliminating these inhibitors, we may enhance axonal outgrowth and functional recovery after SCI [7]. GAG side chains are the major factors responsible for blocking axon regrowth, and digestion of the GAG side chains by ChABC enhances axonal outgrowth and promotes functional recovery in various animal models [15,16,17]
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