SIRT1 Inhibition Improves Age-related Shift in Wallerian Degeneration
Zhongyu Li, MD, PhD;Tiefu Liu, PhD2; Jiaozhong Cai, BS; Thomas L. Smith, PhD
Wake Forest Baptist Medical Center, Winston-Salem, NC
Introduction:
The underlining molecular mechanisms of poor neurologic recovery after peripheral nerve injury in adults remain unclear. Cellular energy NAD+-dependent SIRT1 deacetylase coordinates Wallerian degeneration (WD) after peripheral nerve injury by reprogramming immunometabolic genes and posttranslational modifications of signal proteins and metabolic key enzymes. We hypothesize that age-associated shift in Wallerian degeneration is SIRT1 dependent, pharmacological inhibition of SIRT1 acutely after peripehral nerve injury may improve Wallerian degeneration process in adult animals.
Material & Methods: Sciatic nerve crush model was produced in young (2-month old) and adult (12-month old) Lewis rats. Sciatic nerve samples were harvested at 1, 3 or 10 days after crush and continuous sections distal to the marked injury site were made for histology and immunohistochemistry studies. Inflammatory gene expression of sciatic nerve tissues were analyzed using qRT-PCR. The effect of NAD+ downstream effector SIRT1 on WD generation was studied by administrating SIRT1 specific inhibitor EX-527 or vehicle after nerve crush injury.
Results: In contrast to young animals, adult rats displayed an initial immune suppressive response after axonal crush with attenuated expression of pro-inflammatory genes (TNF-α, MCP-1) and delayed recruitment and activation of hematogenous macrophages. These modifications of WD in adult animals were positively correlated with baseline axonal expression of SIRT1. Pharmacological inhibition of SIRT1 by EX-527 restores pro-inflammatory MCP-1 gene expression (Figure 1).
Conclusion: Aging alters the process of WD after peripheral nerve injury. Inhibition of SIRT1 improves WD. Rejuvenation of WD by modulating SIRT1 activity could be a potential adjunct therapeutic strategy for the treatment of peripheral nerve injury in adult patients.
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