Low-Dose Fractionated Irradiation Promotes Axonal Regeneration Beyond Reactive Gliosis and Facilitates Locomotor Function Recovery After Spinal Cord Injury in Beagle Dogs

Abstract

Injury to the adult central nervous system (CNS) results in the formation of glial scar tissues. Glial scar-induced failure of regenerative axon pathfinding may limit axon regrowth beyond the lesion site and cause incorrect reinnervation and dystrophic appearance of stalled growth after CNS trauma. Glial scars also upregulate chondroitin sulfate proteoglycans (CSPGs) and expression of proinflammatory factor(s) that form a barrier to axonal regeneration. Therefore, interventions for glial scarring are an attractive strategy for augmenting axonal sprouting and regeneration and overcoming the physical and molecular barriers impeding functional repair. The glial reaction occurs shortly after spinal cord injury (SCI) and can persist for days or weeks with upregulation of cell cycle proteins. In this study, we utilized Beagle dogs to establish a preclinical SCI model and examine the efficacy of low-dose fractionated irradiation (LDI) treatment, which was performed once a day for 14 days (2 Gy per dose, 28 Gy in total). LDI is a stable method for suppressing cell activation and proliferation through interference in the cell cycle. Our results demonstrated that LDI could reduce astrocyte and microglia activation/proliferation and attenuate CSPGs and IL-1β expression. LDI also promoted and provided a pathway for long-distance axon regeneration beyond the lesion site, induced reinnervation of axonal targets, and restored locomotor function after SCI in Beagle dogs. Taken together, our findings suggest that LDI would be a promising therapeutic strategy for targeting glial scarring, promoting axon regeneration, and facilitating reconstruction of functional circuits after SCI.

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