Lipoxin A4 protects against spinal cord injury via regulating Akt/nuclear factor (erythroid-derived 2)-like 2/heme oxygenase-1 signaling

Abstract

Spinal cord injury (SCI) is a devastating physical trauma worldwide. The mechanisms of SCI are still not clear and the effective treatment is limited. Lipoxin A4 (LXA4) possesses anti-inflammatory and neuroprotective effects. The present study was designed to further evaluate the molecular mechanisms of LXA4-induced protective effects in a rat model of SCI. We found that LXA4 increased Basso, Beattie and Bresnahan (BBB) scores, increased mechanical paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) to a radiant heat, reduced the lesion volume, decreased Bax mRNA expression and increased Bcl-2 expression after SCI. The phosphorylation of Akt and protein expression of Nrf2 and HO-1 were reduced after SCI. LXA4 treatment significantly inhibited the reduction of Akt phosphorylation and Nrf2 and HO-1 protein expression. Injection of LY294002 notably inhibited the phosphorylation of Akt, and the expression of total Akt and Nrf2 and HO-1 after SCI in LXA4-treated rats. LY294002 prohibited LXA4-induced effects after SCI. shNrf2 injection markedly decreased both Nrf2 and HO-1 expression in LXA4-treated rats after SCI. ZnPP notably decreased HO-1 expression but did not markedly affect Nrf2 expression. shNrf2 and ZnPP prohibited LXA4-induced increase of BBB scores, and PWT and PWL, decrease of lesion volume of spinal cord, reduction of Bax expression and increase of Bcl-2 expression. The results indicate that LXA4 protects against SCI through Akt/Nrf2/HO-1 signaling. The data provide novel insights into the mechanisms of LXA4-mediated neuprotective effects against SCI and suggest that LXA4 may be a potential therapeutic agent for SCI and its associated complications.

Keywords: Akt; HO-1; Lipoxin A4; Nrf2; Spinal cord injury.