SARM1 Inhibition Maintains Axonal Integrity After Rat Sciatic Nerve Transection and Repair.

Abstract

Sterile alpha and TlR motif containing-1 (SARM1) protein has been demonstrated to play a critical role in the initiation of Wallerian degeneration after nerve injury. The goal of this study was to assess whether blockade of SARM1 activity inhibits Wallerian degeneration following nerve transection, potentially promoting more rapid recovery of axonal function. An adeno-associated virus plasmid encoded with a dominant-negative SARM1 protein fused with green fluorescent protein to impair SARM1 function, was injected into 24 juvenile rats to create a SARM1 dominant-negative (SARM1-DN) phenotype. Twenty-four control rats were injected with a control plasmid expressing only green fluorescent protein. Three weeks after transfection, the rats underwent unilateral sciatic nerve transection and repair. Walking track analysis and nonsurvival surgeries were performed at 2 days, 2 weeks, or 6 weeks to assess muscle strength and compound nerve action potential. Histomorphologic and electrodiagnostic studies were evaluated with mixed-effect analysis. Histomorphologic analysis showed maintenance of axons in the SARM1-DN animals at 2 weeks, with significantly improved compound nerve action potential amplitude. Muscle testing demonstrated greater gastrocnemius strength in SARM1 DN muscles at 2 days and 2 weeks compared to controls, although this was not maintained at 6 weeks. Inhibition of SARM1 resulted in early increases in number and myelination of axons and action potential after sciatic nerve transection and repair in SARM1-DN rats. SARM1 inhibition may offer the potential to delay Wallerian degeneration following nerve transection and enable earlier functional recovery of motor strength. .