Effect of curcumin on acute spinal cord injury in mice via inhibition of inflammation and TAK1 pathway

Background: Traumatic spinal cord injury (SCI) is damage to the spinal cord that results in damaged spinal cord function. As a natural compound, curcumin has recently been shown to have anti-inflammatory and strong antioxidant activities. To investigate the effect of curcumin against acute spinal cord injury (SCI), we explored its induced effects in SCI mice. Transforming growth factor (TGF)-activated kinase 1 (TAK1) is a member of the MAPKKK family and plays an essential role in TNF, IL-1, and Toll-like receptor (TLR) signaling pathways. Methods: One hundred adult female KM mice were randomly divided into 5 groups (Control, Model, Test-L, Test-M, and Test-H). SCI was induced using the method described by Allen's. Motor function of the hindlimbs was evaluated on days 1, 7, 14, 21, and 28 after the injury using the motor rating test on the Basso mouse scale (BMS). 7 days after SCI, the levels of TNF-alpha, IL-1 beta, and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA); the level of NO was evaluated by Griess assay; and Western blot was used to verify the levels of proteins in the TAK1 pathway. Expressions of GFAP positive cells in injured spinal cord were detected by immunohistochemical staining. Results: The experiment showed that curcumin markedly inhibited SCI-induced production of inflammatory mediators, including TNF-alpha, IL-1 beta, IL-6 (ELISA assay) and nitrite oxide (Griess method) in a concentration-dependent manner. Curcumin decreased the phosphorylation levels of TGF-beta-activated kinase 1 (TAK1) protein, leading to decreased phosphorylation levels of MKK6 and p38 MAPKs, key players in the microglia-mediated inflammatory response. Curcumin also significantly down-regulated the expression levels of the NF-kappa B upstream regulators IkB and IkB kinase (IKK). Additionally, behavior research showed that curcumin-treated mice showed significantly improved functional recovery compared to untreated mice (BMS assay). The expressions of GFAP increased in the injured spinal cord segments, which were decreased by Teat-M and Teat-H at 7d after SCI. Conclusions: Curcumin restores mice hind-limb function that has been reduced by SCI. This occurs by inhibition of TAK1/MKK6/p38MAPK via the TAK1 and NF kappa B pathways and inflammation. These results suggest the therapeutic potential for curcumin in the treatment of SCI. (c) 2017 Published by Elsevier Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.