Sialidase enhances spinal axon outgrowth in vivo

Abstract

The adult CNS is an inhibitory environment for axon outgrowth, severely limiting recovery from traumatic injury. This limitation is due, in part, to endogenous axon regeneration inhibitors (ARIs) that accumulate at CNS injury sites. ARIs include myelin-associated glycoprotein, Nogo, oligodendrocyte-myelin glycoprotein, and chondroitin sulfate proteoglycans (CSPGs). Some ARIs bind to specific receptors on the axon growth cone to halt outgrowth. Reversing or blocking the actions of ARIs may promote recovery after CNS injury. We report that treatment with sialidase, an enzyme that cleaves one class of axonal receptors for myelinassociated glycoprotein, enhances spinal axon outgrowth into implanted peripheral nerve grafts in a rat model of brachial plexus avulsion, a traumatic injury in which nerve roots are torn from the spinal cord. Repair using peripheral nerve grafts is a promising restorative surgical treatment in humans, although functional improvement remains limited. To model brachial plexus avulsion in the rat, C8 nerve roots were cut flush to the spinal cord and a peroneal nerve graft was inserted into the lateral spinal cord at the lesion site. Infusion of Clostridium perfringens sialidase to the injury site markedly increased the number of spinal axons that grew into the graft (2.6-fold). Chondroitinase ABC, an enzyme that cleaves a different ARI (CSPGs), also enhanced axon outgrowth in this model. In contrast, phosphatidylinositol-specific phospholipase C, which cleaves oligodendrocyte-myelin glycoprotein and Nogo receptors, was without benefit. Molecular therapies targeting sialoglycoconjugates and CSPGs may aid functional recovery after brachial plexus avulsion or other nervous system injuries and diseases.axon regeneration ͉ brachial plexus injury ͉ chondroitinase ABC ͉ gangliosides ͉ spinal cord injury

Sialidase enhances recovery from spinal cord contusion injury

“…Supporting this hypothesis are data demonstrating that sialidase reverses the inhibitory effects of MAG on axon outgrowth from some types of neurons in vitro (13,14,17). The increase in serotonergic fibers caudal to the lesion in the current study and our prior observation that sialidase enhanced axon outgrowth from motor neurons into a peripheral nerve graft (19) provide evidence that sialidase treatment enhances axon outgrowth in vivo. However, V. cholerae sialidase has broad specificity for sialic acids in various linkages to lipids and proteins (21).…”

“…Some bacterial sialidases are readily overexpressed as recombinant proteins, are highly stable, and efficiently cleave sialic acid residues from MAG-binding sialoglycans on living neurons without cytotoxicity. Previously, we found that infusion of a recombinant sialidase to the site of a peripheral nerve graft enhanced outgrowth of CNS axons into the graft (19). Here, we report that sialidase enhances motor and autonomic functional recovery and stimulates axon outgrowth after spinal cord contusion injury in the rat, an animal model of the most common type of spinal cord injury in humans (20).…”

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] .…”