Abstract
Chondroitin sulphate proteoglycans (CSPGs) are major components to impeding axonal regeneration, condense in the extracellular-matrix to form perineuronal nets (PNNs) which interdigitate with axonal contacts. Each CSPG comprises a core protein with covalently attached chondroitin-sulfate glycosaminoglycan side chains (CS moieties). In the past, the representative treatment for CSPGs were chondroitinase-ABC which destroys all CS moieties. However, recent rodents researches found some CS moieties promote axon regeneration rather than inhibit axon regeneration. Using a canine model of spinal cord injury (SCI), which is a superior translational model for progressing rodent data into clinical practice, we showed that specific sulfation patterns of CS moieties play different role in modulation of axon re-growth. Upregulated CS-A expression occurred at 1-day post-SCI, earlier than CS-C expression which was increased at 14-days post-SCI. CS-A was mainly colocalized with astrocytes but CS-C was upregulated in both astrocytes and neurons/axons. Treatment with low-dose fractionated irradiation (LDI) significantly inhibited the expressions of astrocyte-associated CS-A and CS-A-enriched PNNs, but no inhibitory effect on CS-C and CS-C-enriched PNNs. There was a positive correlation between a reduction of CS-A-enriched PNNs and an increase of serotonergic (5-hydroxytryptamine, 5-HT) axonal sprouting. Increased serotonergic axon sprouting proximal to the lesion accompanied 5HT receptor up regulation following LDI treatment. Furthermore, LDI treatment promoted hindlimb motor function recovery following SCI. Taken together, our findings show that specific sulfation patterns of CS moieties and CSPG-enriched PNNs involved in carrying instructions for regulating axonal regeneration and that LDI treatment may be an efficacious strategy for treating SCI.
Low-Dose Fractionated Irradiation Selectivly Regulate CSPGs and PNNs, Promote Serotonergic Axonal Regeneration
