Sialidase, Chondroitinase ABC, and Combination Therapy after Spinal Cord Contusion Injury

Abstract

Axon regeneration in the central nervous system is severely hampered, limiting functional recovery. This is in part because of endogenous axon regeneration inhibitors that accumulate at the injury site. Therapeutic targeting of these inhibitors and their receptors may facilitate axon outgrowth and enhance recovery. A rat model of spinal cord contusion injury was used to test the effects of two bacterial enzyme therapies that target independent axon regeneration inhibitors, sialidase (Vibrio cholerae) and chondroitinase ABC (ChABC, Proteus vulgaris). The two enzymes, individually and in combination, were infused for 2 weeks via implanted osmotic pumps to the site of a moderate thoracic spinal cord contusion injury. Sialidase was completely stable, whereas ChABC retained > 30% of its activity in vivo over the 2 week infusion period. Immunohistochemistry revealed that infused sialidase acted robustly throughout the spinal cord gray and white matter, whereas ChABC activity was more intense superficially. Sialidase treatment alone resulted in improved behavioral and anatomical outcomes. Rats treated exclusively with sialidase showed significantly increased hindlimb motor function, evidenced by higher Basso Beattie and Bresnahan (BBB) and BBB subscores, and fewer stepping errors on a horizontal ladder. Sialidase-treated rats also had increased serotonergic axons caudal to the injury. ChABC treatment, in contrast, did not enhance functional recovery or alter axon numbers after moderate spinal cord contusion injury, and dampened the response of sialidase in the dual enzyme treatment group. We conclude that sialidase infusion enhanced recovery from spinal cord contusion injury, and that combining sialidase with ChABC failed to improve outcomes.

Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord

“…ChABC acts on chondroitin 4-suphate, chondroitin 6-sulphate, and dermatan sulfated proteogycans, and acts very slowly on hyaluronate. This enzyme has been used to promote axon regeneration in lesioned spinal cord in single and combined treatments (e.g., [34,[53][54][55]). In fact, ChABC has been used in combination with OECs [32,56], and the expression of ChABC has also been directed to Schwann cells [57] and astrocytes [58] with relevant results.…”

Biomaterials for spinal cord repair

“…The enzymes chondroitinase (ChABC) (for review see [148] ) and sialidase [149,150] , or a combination of the two were shown to decrease growth inhibition [151] . Many groups have shown that administration of ChABC is associated with sensory axonal regeneration [152] and functional recovery [148,152,153] when experimentally introduced following SCi.…”

“…Many groups have shown that administration of ChABC is associated with sensory axonal regeneration [152] and functional recovery [148,152,153] when experimentally introduced following SCi. When comparing the two, one group found that sialidase increases axonal regeneration and functional recovery [149][150][151] to a greater degree than either ChABC alone or a sialidase/ChABC combination [151] .…”

“…Many groups have shown that administration of ChABC is associated with sensory axonal regeneration [152] and functional recovery [148,152,153] when experimentally introduced following SCi. When comparing the two, one group found that sialidase increases axonal regeneration and functional recovery [149][150][151] to a greater degree than either ChABC alone or a sialidase/ChABC combination [151] .Alternatively, groups have addressed this issue by incorporating growth-promoting molecules into biomaterials.Largely, this approach involves either presenting cellmatrix-binding ligands or growth factors to enhance regeneration and encourage infiltration of growing axons into and through the lesion site [154] . often, the cell-matrix- [71,[155][156][157][158][159] , neurotrophin-3 [156,159] , nerve growth factor [160][161][162] , and ciliary neurotrophic factor [155,159,163] .…”

Combination of chondroitinase ABC and AAV-NT3 promotes neural plasticity at descending spinal pathways after thoracic contusion in rats

“…ChABC was found to improve function after dorsal lesions of cervical spinal cord (Bradbury et al 2002). In cases of other SCI models, treatment with ChABC alone improved axonal sprouting, although it induced little or no recovery of locomotor function after hemisection (Alilain et al 2011;Hunanyan et al 2010) and contusion (Harris et al 2010;Mountney et al 2013;Tom et al 2009). …”