Mulberrin (Mul) reduces spinal cord injury (SCI)-induced apoptosis, inflammation and oxidative stress in rats via miroRNA-337 by targeting Nrf-2

Abstract

Spinal cord injury (SCI) is a major reason of paralysis, disability and even death in severe cases. Mulberrin (Mul) is a major compound of ramulus mori and turned out that it has potent ability on tyrosinase inhibition. Ramulus mori has been reported to possess anti-inflammation, anti-oxidative stress and anti-apoptosis effects. However, the effects of Mul on SCI progression and the underlying molecular mechanism have never been elucidated before. Here, we established a SCI rat model, which subsequently received Mul treatment. The findings showed that Mul treatment improved the functional recovery of SCI rats, along with reduced spinal cord water contents and myeloperoxidase (MPO) activity. SCI-induced apoptosis was attenuated by Mul, as evidenced by the reduced TUNEL-positive cells, and the decreased pro-apoptotic signals expressions, while increased anti-apoptotic molecule. Further, Mul inhibited inflammatory response in the spinal cord tissues of SCI rats through inactivating nuclear factor-kappa B (NF-κB) pathway. Oxidative stress was also decreased by Mul treatment in SCI mice, associated with the up-regulation of heme oxygenase-1 (HO-1)/nuclear factor E2-related factor 2 (HO-1/Nrf-2) pathway. Significantly, SCI rats showed high expression of miR-337 in spinal cord tissue samples. Astrocytes (AST) stimulated by LPS also had higher expression of miR-337. Nrf-2 was found to be a direct target for miR-337. Over-expressing miR-337 markedly reduced Nrf-2 expression in AST, whereas inhibiting miR-337, Nrf-2 expressions were significantly increased. In vitro, AST transfected with miR-337 inhibitor showed attenuated inflammation, apoptosis and oxidative stress in LPS-treated AST, which was, intriguingly, abolished by Nrf-2 knockdown. Together, the findings above indicated that Mul could attenuate SCI by reducing miR-337 expressions to reduce apoptosis, inflammation and oxidative stress via regulating Nrf-2.

Keywords: Mulberrin (Mul); Nrf-2; Spinal cord injury (SCI); miR-337.