Salidroside exerts neuroprotective effects on retrograde neuronal death following neonatal axotomy via activation of PI3K/Akt pathway and deactivation of p38 MAPK pathway.

Abstract

Salidroside, a glucoside of tyrosol, is a powerful active ingredient extracted from the Chinese herb medicine Rhodiola rosea L.. As a neuroprotective agent, the application of salidroside in combination with neural tissue engineering has recently attracted much attention in peripheral nerve repair and reconstruction. However, the cellular and molecular mechanisms by which salidroside promotes nerve regeneration remain to be elucidated. We aim to evaluate the long-term neuroprotective potential of salidroside in an experimental rat model of neonatal sciatic nerve crush injury, with a focus on target-deprived neuronal death and the mechanisms involved. Behavioral analysis showed that salidroside dose-dependently improved voluntary hindlimb behavior and rod rotation ability following neonatal axotomy during an 8-week observation period. According to electrophysiology, Fluoro-Gold retrograde tracing, histological and immunohistochemical analyses, salidroside significantly improved nerve regeneration and reinnervation. Nissle and TUNEL staining, as well as caspase-3 activation assay indicated a beneficial effect of salidroside on retrograde loss and apoptosis of motoneurons within 2 weeks after axotomy. qPCR, ELISA and oxidative stress experiments revealed that salidroside improved the imbalance of spinal microenvironment, including oxidative stress and down-regulation of neurotrophic factors. Western blotting analysis showed that salidroside enhanced the activation of PI3K/Akt and inhibited the p38 MAPK signaling pathway following axotomy. The oxidative stress and axonal disconnection/regeneration models of primary motoneurons in vitro further confirmed the involvement of these two pathways in the neuroprotective effects of salidroside. These data provide a theoretical basis for the application of salidroside in peripheral nerve repair and reconstruction.