Tanshinone IIA improves hypoxic ischemic encephalopathy through TLR‑4‑mediated NF‑κB signal pathway

Fang,Chengzhi; Xie,Lili; Liu,Chunmei; Fu,Chunhua; Ye,Wei; Liu,Hong; Zhang,Binghong

doi:10.3892/mmr.2018.9227

Tanshinone IIA improves hypoxic ischemic encephalopathy through TLR‑4‑mediated NF‑κB signal pathway

Authors:
- Chengzhi Fang
- Lili Xie
- Chunmei Liu
- Chunhua Fu
- Wei Ye
- Hong Liu
- Binghong Zhang
View Affiliations

Affiliations: Department of Neonatology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
Published online on: June 26, 2018 https://doi.org/10.3892/mmr.2018.9227
Pages: 1899-1908
Copyright: © Fang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hypoxic ischemic encephalopathy (HIE) is the most common brain injury following hypoxia and/or ischemia caused by various factors during the perinatal period, resulting in detrimental neurological deficits in the nervous system. Tanshinone IIA (Tan‑IIA) is a potential agent for the treatment of cardiovascular and cerebrovascular diseases. In this study, the efficacy of Tan‑IIA was investigated in a newborn mouse model of HIE. The dynamic mechanism of Tan‑IIA was also investigated in the central nervous system of neonate mice. Intravenous injection of Tan‑IIA (5 mg/kg) was administered and changes in oxidative stress, inflammation and apoptosis‑associated proteins in neurons. Histology and immunohistochemistry was used to determine infarct volume and the number of damaged neurons by Fluoro‑Jade C staining. The effects of Tan‑IIA on mice with HIE were evaluated by body weight, brain water content, neurobehavioral tests and blood‑brain barrier permeability. The results demonstrated that the apoptosis rate was decreased following Tan‑IIA administration. Expression levels of pro‑apoptotic proteins, caspase‑3 and caspase‑9 and P53 were downregulated. Expression of Bcl‑2 anti‑apoptotic proteins was upregulated by Tan‑IIA treatment in neuro. Results also found that Tan‑IIA treatment decreased production of inflammatory cytokines such as interleukin‑1, tumor necrosis factor‑α, C‑X‑C motif chemokine 10, and chemokine (C‑C motif) ligand 12. Oxidative stress was also reduced by Tan‑IIA in neurons, as determined by the expression levels of superoxide dismutase, glutathione and catalase, and the production of reactive oxygen species. The results demonstrated that Tan‑IIA treatment reduced the infarct volume and the number of damaged neurons. Furthermore, body weight, brain water content and blood‑brain barrier permeability were markedly improved by Tan‑IIA treatment of newborn mice following HIE. Furthermore, the results indicated that Tan‑IIA decreased Toll‑like receptor‑4 (TLR‑4) and nuclear factor‑κB (NF‑κB) expression in neurons. TLR‑4 treatment of neuronal cell in vitro addition stimulated NF‑κB activity, and further enhanced the production of inflammatory cytokines and oxidative stress levels in neurons. In conclusion, these results suggest that Tan‑IIA treatment is beneficial for improvement of HIE through TLR‑4‑mediated NF‑κB signaling.

View Figures

View References

1	Hochwald O, Jabr M, Osiovich H, Miller SP, McNamara PJ and Lavoie PM: Preferential cephalic redistribution of left ventricular cardiac output during therapeutic hypothermia for perinatal hypoxic-ischemic encephalopathy. J Pediatr. 164:999–1004.e1. 2014. View Article : Google Scholar : PubMed/NCBI
2	Looney AM, Ahearne C, Boylan GB and Murray DM: Glial Fibrillary acidic protein is not an early marker of injury in perinatal asphyxia and Hypoxic-ischemic encephalopathy. Front Neurol. 6:2642015. View Article : Google Scholar : PubMed/NCBI
3	Khan RH, Islam MS, Haque SA, Hossain MA, Islam MN, Khaleque MA, Chowdhury B and Chowdhury MA: Correlation between grades of intraventricular hemorrhage and severity of hypoxic ischemic encephalopathy in perinatal asphyxia. Mymensingh Med J. 23:7–12. 2014.PubMed/NCBI
4	Tagin M, Abdel-Hady H, Rahman Ur S, Azzopardi DV and Gunn AJ: Neuroprotection for perinatal hypoxic ischemic encephalopathy in low-and Middle-income countries. J Pediatr. 167:25–28. 2015. View Article : Google Scholar : PubMed/NCBI
5	Li H, Han W, Wang H, Ding F, Xiao L, Shi R, Ai L and Huang Z: Tanshinone IIA inhibits Glutamate-induced oxidative toxicity through prevention of mitochondrial dysfunction and suppression of MAPK activation in SH-SY5Y human neuroblastoma cells. Oxid Med Cell Longev. 2017:45174862017. View Article : Google Scholar : PubMed/NCBI
6	Kim EO, Kang SE, Im CR, Lee JH, Ahn KS, Yang WM, Um JY, Lee SG and Yun M: Tanshinone IIA induces TRAIL sensitization of human lung cancer cells through selective ER stress induction. Int J Oncol. 48:2205–2212. 2016. View Article : Google Scholar : PubMed/NCBI
7	Mao C, Zhang Y, Zhang Y, Cao L, Shao H, Wang L, Zhu L and Xu Z: The effect of tanshinone IIA on the cardiovascular system in ovine fetus in utero. Am J Chin Med. 37:1031–1044. 2009. View Article : Google Scholar : PubMed/NCBI
8	Gao S, Liu Z, Li H, Little PJ, Liu P and Xu S: Cardiovascular actions and therapeutic potential of tanshinone IIA. Atherosclerosis. 220:3–10. 2012. View Article : Google Scholar : PubMed/NCBI
9	Shen JL, Chen YS, Lin JY, Tien YC, Peng WH, Kuo CH, Tzang BS, Wang HL, Tsai FJ, Chou MC, et al: Neuron regeneration and proliferation effects of Danshen and Tanshinone IIA. Evid Based Complement Alternat Med. 2011:3789072011. View Article : Google Scholar : PubMed/NCBI
10	Hernandez-Jimenez M, Sacristan S, Morales C, García-Villanueva M, García-Fernández E, Alcázar A, González VM and Martín ME: Apoptosis-related proteins are potential markers of neonatal hypoxic-ischemic encephalopathy (HIE) injury. Neurosci Lett. 558:143–148. 2014. View Article : Google Scholar : PubMed/NCBI
11	Li SJ, Liu W, Wang JL, Zhang Y, Zhao DJ, Wang TJ and Li YY: The role of TNF-α, IL-6, IL-10, and GDNF in neuronal apoptosis in neonatal rat with hypoxic-ischemic encephalopathy. Eur Rev Med Pharmacol Sci. 18:905–909. 2014.PubMed/NCBI
12	Liu L, Liu C, Lu Y and Jiang Y: ER stress related factor ATF6 and caspase-12 trigger apoptosis in neonatal hypoxic-ischemic encephalopathy. Int J Clin Exp Pathol. 8:6960–6966. 2015.PubMed/NCBI
13	Johnson CT, Burd I, Raghunathan R, Northington FJ and Graham EM: Perinatal inflammation/infection and its association with correction of metabolic acidosis in hypoxic-ischemic encephalopathy. J Perinatol. 36:448–452. 2016. View Article : Google Scholar : PubMed/NCBI
14	Chapados I and Cheung PY: Not all models are created equal: Animal models to study hypoxic-ischemic encephalopathy of the newborn. Commentary on Gelfand SL et al: A new model of oxidative stress in rat pups (Neonatology 2008;94:293-299). Neonatology. 94:300–303. 2008. View Article : Google Scholar : PubMed/NCBI
15	Cikla U, Chanana V, Kintner DB, Udho E, Eickhoff J, Sun W, Marquez S, Covert L, Otles A, Shapiro RA, et al: ERα signaling is required for TrkB-mediated hippocampal neuroprotection in female neonatal mice after hypoxic ischemic encephalopathy(1,2,3). eNeuro. 3:pii2016. View Article : Google Scholar
16	Can MM, Tanboğa IH, Türkyilmaz E, Karabay CY, Akgun T, Koca F, Tokgoz HC, Keles N, Ozkan A, Bezgin T, et al: The risk of false results in the assessment of platelet function in the absence of antiplatelet medication: Comparison of the PFA-100, multiplate electrical impedance aggregometry and verify now assays. Thromb Res. 125:e132–e137. 2010. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time. quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Hashiguchi A, Yano S, Nitta K, Ide W, Hashimoto I, Kamada H and Kuratsu J: Hemisplenial-accompanied by internal border-zone infarction: Clinical relevance of the splenium of the corpus callosum as a border-zone area between anterior and posterior cerebral arteries. J Neurol Neurosurg Psychiatry. 81:704–706. 2010. View Article : Google Scholar : PubMed/NCBI
19	Bechet S, Hill F, Gilheaney Ó and Walshe M: Diagnostic accuracy of the modified Evan's blue dye test in detecting aspiration in patients with tracheostomy: A systematic review of the evidence. Dysphagia. 31:721–729. 2016. View Article : Google Scholar : PubMed/NCBI
20	Farahat FM, Rohlman DS, Storzbach D, Ammerman T and Anger WK: Measures of short-term test-retest reliability of computerized neurobehavioral tests. Neurotoxicology. 24:513–521. 2003. View Article : Google Scholar : PubMed/NCBI
21	Sant'Anna G, Laptook AR, Shankaran S, Bara R, McDonald SA, Higgins RD, Tyson JE, Ehrenkranz RA, Das A, Goldberg RN, et al: Phenobarbital and temperature profile during hypothermia for hypoxic-ischemic encephalopathy. J Child Neurol. 27:451–457. 2012. View Article : Google Scholar : PubMed/NCBI
22	Shankaran S: Hypoxic-ischemic encephalopathy and novel strategies for neuroprotection. Clin Perinatol. 39:919–929. 2012. View Article : Google Scholar : PubMed/NCBI
23	Peliowski-Davidovich A: Hypothermia for newborns with hypoxic ischemic encephalopathy. Paediat Child Health. 17:41–43. 2012. View Article : Google Scholar
24	Barks JD, Liu YQ, Shangguan Y, Li J, Pfau J and Silverstein FS: Impact of indolent inflammation on neonatal hypoxic-ischemic brain injury in mice. Int J Dev Neurosci. 26:57–65. 2008. View Article : Google Scholar : PubMed/NCBI
25	Girard S, Sebire H, Brochu ME, Briota S, Sarret P and Sébire G: Postnatal administration of IL-1Ra exerts neuroprotective effects following perinatal inflammation and/or hypoxic-ischemic injuries. Brain Behav Immun. 26:1331–1339. 2012. View Article : Google Scholar : PubMed/NCBI
26	Aly H, Khashaba MT, El-Ayouty M, El-Sayed O and Hasanein BM: IL-1beta, IL-6 and TNF-alpha and outcomes of neonatal hypoxic ischemic encephalopathy. Brain Dev. 28:178–182. 2006. View Article : Google Scholar : PubMed/NCBI
27	Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O, Than NG, Mittal P, Edwin S, Yoon BH, et al: CXCL10/IP-10: A missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern Fetal Neonatal Med. 20:777–792. 2007. View Article : Google Scholar : PubMed/NCBI
28	Tomita K, Freeman BL, Bronk SF, LeBrasseur NK, White TA, Hirsova P and Ibrahim SH: CXCL10-mediates macrophage, but not other innate immune cells-associated inflammation in murine nonalcoholic steatohepatitis. Sci Rep. 6:287862016. View Article : Google Scholar : PubMed/NCBI
29	Kurian GA, Rajagopal R, Vedantham S and Rajesh M: The role of oxidative stress in myocardial ischemia and reperfusion injury and remodeling: Revisited. Oxid Med Cell Longev. 2016:16564502016. View Article : Google Scholar : PubMed/NCBI
30	Perrone S, Szabo M, Bellieni CV, Longini M, Bangó M, Kelen D, Treszl A, Negro S, Tataranno ML and Buonocore G: Whole body hypothermia and oxidative stress in babies with hypoxic-ischemic brain injury. Pediatr Neurol. 43:236–240. 2010. View Article : Google Scholar : PubMed/NCBI
31	Ten VS, Yao J, Ratner V, Sosunov S, Fraser DA, Botto M, Sivasankar B, Morgan BP, Silverstein S, Stark R, et al: Complement component c1q mediates mitochondria-driven oxidative stress in neonatal hypoxic-ischemic brain injury. J Neurosci. 30:2077–2087. 2010. View Article : Google Scholar : PubMed/NCBI
32	Demarest TG, Schuh RA, Waddell J, McKenna MC and Fiskum G: Sex-dependent mitochondrial respiratory impairment and oxidative stress in a rat model of neonatal hypoxic-ischemic encephalopathy. J Neurochem. 137:714–729. 2016. View Article : Google Scholar : PubMed/NCBI
33	Wang Y, Tu L, Li Y, Chen D and Wang S: Notoginsenoside R1 protects against neonatal cerebral Hypoxic-ischemic injury through estrogen Receptor-dependent activation of endoplasmic reticulum stress pathways. J Pharmacol Exp Ther. 357:591–605. 2016. View Article : Google Scholar : PubMed/NCBI
34	Kong D, Zhu J, Liu Q, Jiang Y, Xu L, Luo N, Zhao Z, Zhai Q, Zhang H, Zhu M and Liu X: Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos, necroptosis, and apoptosis, but not autophagy. Cell Mol Neurobiol. 37:303–313. 2017. View Article : Google Scholar : PubMed/NCBI
35	Yan SZ, Wang XL, Wang HY, Dong P and Zhao YS: Effects of umbilical cord blood mononuclear cells transplantation via lateral ventricle on the neural apoptosis and the expression of Bax and Bcl-2 proteins in neonatal rats with hypoxic-ischemic brain damage. Zhongguo Dang Dai Er Ke Za Zhi. 18:862–866. 2016.(In Chinese). PubMed/NCBI
36	Liang ZQ, Li YL, Zhao XL, Han R, Wang XX, Wang Y, Chase TN, Bennett MC and Qin ZH: NF-kappaB contributes to 6-hydroxydopamine-induced apoptosis of nigral dopaminergic neurons through p53. Brain Res. 1145:190–203. 2007. View Article : Google Scholar : PubMed/NCBI
37	Kairisalo M, Korhonen L, Sepp M, Pruunsild P, Kukkonen JP, Kivinen J, Timmusk T, Blomgren K and Lindholm D: NF-kappaB-dependent regulation of brain-derived neurotrophic factor in hippocampal neurons by X-linked inhibitor of apoptosis protein. Eur J Neurosci. 30:958–966. 2009. View Article : Google Scholar : PubMed/NCBI
38	Ulbrich F, Lerach T, Biermann J, Kaufmann KB, Lagreze WA, Buerkle H, Loop T and Goebel U: Argon mediates protection by interleukin-8 suppression via a TLR2/TLR4/STAT3/NF-κB pathway in a model of apoptosis in neuroblastoma cells in vitro and following ischemia-reperfusion injury in rat retina in vivo. J Neurochem. 138:859–873. 2016. View Article : Google Scholar : PubMed/NCBI