Curcumin Inhibits TLR2/4-NF-κB Signaling Pathway and Attenuates Brain Damage in Permanent Focal Cerebral Ischemia in Rats
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Toll-like receptors 2 and 4 (TLR2/4) and the downstream nuclear factor-kappa B (NF-κB) signaling pathway, which mediate the inflammatory reaction in cerebral ischemia, were demonstrated to be involved in the extension of cerebral infarction and the aggravation of ischemic brain damage. Reports showed that curcumin provides neuroprotection against ischemic brain damage. In this study, we investigated whether curcumin inhibits the activation of TLR2/4-NF-κB signaling pathway in rats of permanent focal cerebral ischemia. Adult male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO). Curcumin was administered by intraperitoneal injection twice at 2 and 12 h after the onset of ischemia. Neurological deficit scores, cerebral infarct size, morphological characteristic, and cerebral water content were measured after 24 h of pMCAO. The enzymatic activity of myeloperoxidase (MPO) was assessed after 24 h of pMCAO. Expression of TLR2 and TLR4 in ischemic brain was determined by western blot. Expression of NF-κB p65 in ischemic brain was detected by immunohistochemistry and western blot. The release of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in blood was examined by ELISA. Curcumin significantly reduced neurological deficit scores, cerebral infarct size, neuronal damage, cerebral water content, and MPO activity. It also inhibited the expression of TLR2/4 and decreased the expression and activity of NF-κB p65 in rat brain. In addition, curcumin attenuated the release of TNF-α and IL-1β in blood. Our results suggest that curcumin reduces inflammatory reaction and brain damage in a rat model of permanent focal cerebral ischemia. The neuroprotective effect and anti-inflammatory property of curcumin in cerebral ischemia might be associated with the inhibition of TLR2/4-NF-κB signaling pathway.
KEY WORDScerebral ischemia inflammation interleukin-1β myeloperoxidase nuclear factor-kappa B toll-like receptors tumor necrosis factor-α curcumin
The National Natural Science Foundation of China (81100987), the Natural Science Foundation of Fujian Province of China (2011J05066), the Doctoral Program Foundation of Institutions of Higher Education of China (20113518120005), the Clinical Key Subject (Neurosurgery) Funding of Fujian Medical University, and the Key Laboratory (Neurosurgical Department) Funding from the Affiliated Union Hospital of Fujian Medical University supported this work.
- 5.Ziegler, G., D. Harhausen, C. Schepers, O. Hoffmann, C. Rohr, V. Prinz, J. König, H. Lehrach, W. Nietfeld, and G. Trendelenburg. 2007. TLR2 has a detrimental role in mouse transient focal cerebral ischemia. Biochemical and Biophysical Research Communications 359: 574–579.PubMedCrossRefGoogle Scholar
- 7.Tang, S.C., T.V. Arumugam, X. Xu, A. Cheng, M.R. Mughal, D.G. Jo, J.D. Lathia, D.A. Siler, S. Chigurupati, X. Ouyang, T. Magnus, S. Camandola, and M.P. Mattson. 2007. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proceedings of the National Academy of Sciences of the United States of America 104: 13798–13803.PubMedCrossRefPubMedCentralGoogle Scholar
- 8.Tu, X.K., W.Z. Yang, S.S. Shi, C.H. Wang, G.L. Zhang, T.R. Ni, C.M. Chen, R. Wang, J.W. Jia, and Q.M. Song. 2010. Spatio-temporal distribution of inflammatory reaction and expression of TLR2/4 signaling pathway in rat brain following permanent focal cerebral ischemia. Neurochemical Research 35: 1147–1155.PubMedCrossRefGoogle Scholar
- 13.Ahmad, N., S. Umar, M. Ashafaq, M. Akhtar, Z. Iqbal, M. Samim, and F.J. Ahmad. 2013. A comparative study of PNIPAM nanoparticles of curcumin, demethoxycurcumin, and bisdemethoxycurcumin and their effects on oxidative stress markers in experimental stroke. Protoplasma 250: 1327–1338.PubMedCrossRefGoogle Scholar
- 20.Wang, Y.F., Y.T. Gu, G.H. Qin, L. Zhong, and Y.N. Meng. 2013. Curcumin ameliorates the permeability of the blood-brain barrier during hypoxia by upregulating heme oxygenase-1 expression in brain microvascular endothelial cells. Journal of Molecular Neuroscience 51: 344–351.PubMedCrossRefGoogle Scholar
- 21.Singh, R., J. Bullard, M. Kalra, S. Assefa, A.K. Kaul, K. Vonfeldt, S.C. Strom, R.S. Conrad, H.L. Sharp, and R. Kaul. 2011. Status of bacterial colonization, Toll-like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers. Clinical Immunology 138: 41–49.PubMedCrossRefGoogle Scholar