Age-related shift of Wallerian degeneration after peripheral nerve injury
Zhongyu Li, MD, PhD1; Tiefu Liu, PhD2; Thomas L. Smith, PhD3; Jiaozhong Cai, BS2; (1)Department of Orthopaedic Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, (2)Wake Forest School of Medicine, Winston-salem, NC, (3)Orthopaedic Surgery, Wake Forest School of Medicine, Winston-Salem, NC
Introduction: It is well known that age natively influence peripheral nerve regeneration after injury, however, the underlining molecular mechanisms remain unclear. Wallerian degeneration is the essential part of the nerve regeneration by attracting and activating macrophages to clear myelin debris. This study tested the hypothesis that inflammatory response to nerve injury decreases with age resulting in delayed and/or decreased macrophage recruitment and activation, and therefore limiting axonal regrowth.
Material & Methods: In 15 young (2 months) and 15 adult (12 months) Lewis rats, unilateral sciatic nerve crush injury was induced. Both sciatic nerves from each animal were harvested at one, three, and ten days after injury. Immunohistochemistry was performed for MCP-1. ED-1, CD14 & CD68 and qRT-PCR was doned using Taqman (Applied Biosystems) for MCP-1, TNF-? and IL-10 as target genes and Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as endogenous control. Two-way ANOVA was used for analysis the effect of age on the overall gene expression.
Results: Young animals showed significantly earlier (started on day 1 and maintained through day 10) and stronger MCP-1 and TNF-? expression than adults animals (P<0.01, Figure 1). In contrast, adult animals had stronger expression of IL-10 after crush injury. This delayed and weaker proinflammatory cytokine expression correlated with delaying in nuclear count increases and recruitment of homogeneous macrophages (ED1 positive).
The significant reduction and delay of inflammatory cytokine expression and macrophage recruitment in adult animals after nerve injury indicates that age negatively impacts the rate of myelin clearance during Wallerian degeneration. This age-related shift in Wallerian degeneration may be in part contributing to the decline of nerve regeneration potential in adults.
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