Protective effect of tanshinone IIA on the brain and its therapeutic time window in rat models of cerebral ischemia-reperfusion

Tang,Qiqiang; Han,Ruodong; Xiao,Han; Li,Jun; Shen,Jilong; Luo,Qingli

doi:10.3892/etm.2014.1936

Protective effect of tanshinone IIA on the brain and its therapeutic time window in rat models of cerebral ischemia-reperfusion

Authors:
- Qiqiang Tang
- Ruodong Han
- Han Xiao
- Jun Li
- Jilong Shen
- Qingli Luo
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Affiliations: Department of Neurology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, Anhui 230022, P.R. China, Department of Neurology, Affiliated Provincial Hospital, Anhui Medical University, Hefei, Anhui 230022, P.R. China, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, P.R. China, nstitute of Clinical Pharmacology, Anhui Medical University, The Key Laboratories of Zoonoses and Pathogen Biology, Hefei, Anhui 230022, P.R. China
Published online on: August 27, 2014 https://doi.org/10.3892/etm.2014.1936
Pages: 1616-1622

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Abstract

The aims of the present study were to investigate the protective effect of tanshinone IIA on the brain and its therapeutic time window in a rat model of cerebral ischemia‑reperfusion. The rat model of cerebral ischemia‑reperfusion was established by suture occlusion. In an initial experiment, male Sprague‑Dawley (SD) rats were randomly divided into control cerebral ischemia-reperfusion rat model, tanshinone IIA1 (TSA1), tanshinone IIA4 (TSA4), tanshinone IIA6 (TSA6) and tanshinone IIA12 (TSA12) groups (n=8 per group). The rats in the control group were given 4 ml phosphate-buffered saline (PBS) intraperitoneally following suture occlusion. The other groups were respectively treated with 25 mg/kg tanshinone IIA intraperitoneally at 1, 4, 6 and 12 h following the initiation of reperfusion and once a day for a total of three days. The grades of neurologic impairment and volume of cerebral infarction of each group were measured 72 h after suture occlusion. In another experiment, 16 male SD rats were randomly divided into a 6 h reperfusion group and a 24 h reperfusion group following drug administration. The rats in each group were further divided into a control subgroup (4 ml PBS) and a tanshinone IIA subgroup (25 mg/kg). The rats were immediately administered their respective treatments following the establishment of the model. The rats were decapitated 6 and 24 h after the initiation of reperfusion. The expression levels of cytoplasmic thioredoxin (Trx-1) and mitochondrial thioredoxin (Trx-2) in the ischemic penumbra were determined by western blot analysis. The nitric oxide (NO) levels, and total NO synthase (tNOS) and inducible NO synthase (iNOS) activities in the rat blood were measured using a reagent kit. The changes in cerebral blood flow were evaluated by Doppler imaging. The grade of neurological impairment of the TSA1 group was statistically lower than that of the other groups (P<0.05). The cerebral infarction volume results showed that the volumes of infarction in the TSA1 and TSA4 groups were lower than those in the other groups (P<0.05). Tanshinone IIA significantly increased cerebral blood flow compared with that of the control group (P<0.05). Moreover, tanshinone IIA significantly increased the expression levels of Trx-1 and Trx-2 compared with those in the control group (P<0.05). Tanshinone IIA significantly decreased the NO levels and iNOS and tNOS activities compared with those of the control group (P<0.05). However, the iNOS activity in the rats in the 6 h reperfusion group was not statistically significantly different from that of the respective control group (P>0.05). Tanshinone IIA has a protective effect on the cranial nerves when administered during the initial stages of cerebral ischemia. This protective effect is associated with an improvement of cerebral blood flow as well as an increase in anti‑oxygen radical and anti-inflammatory activities.

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1	Chollet F, Cramer SC, Stinear C, et al: Pharmacological therapies in post stroke recovery: recommendations for future clinical trials. J Neurol. (Epub ahead of print). 2013.PubMed/NCBI
2	Candelario-Jalil E: Injury and repair mechanisms in ischemic stroke: considerations for the development of novel neurotherapeutics. Curr Opin Investig Drugs. 10:644–654. 2009.PubMed/NCBI
3	Lo EH, Dalkara T and Moskowitz MA: Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci. 4:399–415. 2003. View Article : Google Scholar : PubMed/NCBI
4	Mustacich D and Powis G: Thioredoxin reductase. Biochem J. 346(Pt 1): 1–8. 2000. View Article : Google Scholar
5	Kishimoto K, Li RC, Zhang J, et al: Cytosolic phospholipase A2 alpha amplifies early cyclooxygenase-2 expression, oxidative stress and MAP kinase phosphorylation after cerebral ischemia in mice. J Neuroinflammation. 7:422010.
6	Stoyanova II and Lazarov NE: Localization of nitric oxide synthase in rat trigeminal primary afferent neurons using NADPH-diaphorase histochemistry. J Mol Histol. 36:187–193. 2005. View Article : Google Scholar
7	Bredt DS and Snyder SH: Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum. Proc Natl Acad Sci USA. 86:9030–9033. 1989. View Article : Google Scholar : PubMed/NCBI
8	Kawase M, Kinouchi H, Kato I, et al: Inducible nitric oxide synthase following hypoxia in rat cultured glial cells. Brain Res. 738:319–322. 1996. View Article : Google Scholar : PubMed/NCBI
9	Hirota K, Nakamura H, Masutani H and Yodoi J: Thioredoxin superfamily and thioredoxin-inducing agents. Ann N Y Acad Sci. 957:189–199. 2002. View Article : Google Scholar : PubMed/NCBI
10	Berk BC: Novel approaches to treat oxidative stress and cardiovascular diseases. Trans Am Clin Climatol Assoc. 118:209–214. 2007.PubMed/NCBI
11	Billiet L, Furman C, Cuaz-Pérolin C, et al: Thioredoxin-1 and its natural inhibitor, vitamin D3 up-regulated protein 1, are differentially regulated by PPARalpha in human macrophages. J Mol Biol. 384:564–576. 2008. View Article : Google Scholar : PubMed/NCBI
12	Watson HW, Yang X, Choi YE, Jones DP and Kehrer JP: Thioredoxin and its role in toxicology. Toxicol Sci. 78:3–14. 2004. View Article : Google Scholar
13	Xu W, Yang J and Wu LM: Cardioprotective effects of tanshinone IIA on myocardial ischemia injury in rats. Pharmazie. 64:332–336. 2009.PubMed/NCBI
14	Lam BY, Lo AC, Sun X, Luo HW, Chung SK and Sucher NJ: Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice. Phytomedicine. 10:286–291. 2003. View Article : Google Scholar : PubMed/NCBI
15	Dong K, Xu W, Yang J, Qiao H and Wu L: Neuroprotective effects of Tanshinone IIA on permanent focal cerebral ischemia in mice. Phytother Res. 23:608–613. 2009. View Article : Google Scholar : PubMed/NCBI
16	Adams JD, Wang R, Yang J and Lien EJ: Preclinical and clinical examinations of Salvia miltiorrhiza and its tanshinones in ischemic conditions. Chin Med. 1:32006. View Article : Google Scholar
17	Liu LL, Zhang XL, Wang L, et al: The neuroprotective effects of Tanshinone IIA are associated with induced nuclear translocation of TORC1 and upregulated expression of TORC1, pCREB and BDNF in the acute stage of ischemic stroke. Brain Res Bull. 82:228–233. 2010. View Article : Google Scholar
18	Chen X, Zhou ZW, Xue CC, Li XX and Zhou SF: Role of P-glycoprotein in restricting the brain penetration of tanshinone IIA, a major active constituent from the root of Salvia miltiorrhiza Bunge, across the blood-brain barrier. Xenobiotica. 37:635–678. 2007. View Article : Google Scholar : PubMed/NCBI
19	National Research Council. Guide for the care and use of laboratory animals. 8th edition. The National Academies Press; Washington, DC: pp. 1–246. 2001
20	Engel O, Kolodziej S, Dirnagl U and Prinz V: Modeling stroke in mice - middle cerebral artery occlusion with the filament model. J Vis Exp. 47:e24232011.PubMed/NCBI
21	Longa EZ, Weinstein PR, Carlson S and Cummins R: Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 20:84–91. 1989. View Article : Google Scholar : PubMed/NCBI
22	Hoffman GE, Merchenthaler I and Zup SL: Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine. 29:217–231. 2006. View Article : Google Scholar : PubMed/NCBI
23	Wang LN, Zhang XJ, Liu LL, et al: Tanshinone IIA down-regulates HMGB1, RAGE, TLR4, NF-kappaB expression, ameliorates BBB permeability and endothelial cell function, and protects rat brains against focal ischemia. Brain Res. 1321:143–151. 2010. View Article : Google Scholar : PubMed/NCBI
24	Tang C, Xue HL, Bai CL, Fu R and Wu AH: The effects of Tanshinone IIA on blood-brain barrier and brain edema after transient middle cerebral artery occlusion in rats. Phytomedicine. 17:1145–1149. 2010. View Article : Google Scholar : PubMed/NCBI
25	Chen D, Tang J, Khatibi NH, et al: Treatment with Z-ligustilide, a component of Angelica sinensis, reduces brain injury after a subarachnoid hemorrhage in rats. J Pharmacol Exp Ther. 337:663–672. 2011.PubMed/NCBI
26	Cavallucci V and D’Amelio M: Matter of life and death: the pharmacological approaches targeting apoposis in brain diseases. Curr Pharm Des. 17:215–229. 2011. View Article : Google Scholar : PubMed/NCBI
27	Nizamutdinova IT, Jin YC, Kim JS, et al: Paeonol and paeoniflorin, the main active principles of Paeonia albiflora, protect the heart from myocardial ischemia/reperfusion injury in rats. Planta Med. 74:14–18. 2008.PubMed/NCBI
28	Liu Y, Wang L, Li X, Lv C, Feng D and Luo Z: Tanshinone IIA improves impaired nerve functions in experimental diabetic rats. Biochem Biophys Res Commun. 399:49–54. 2010. View Article : Google Scholar : PubMed/NCBI
29	Zhang WJ, Feng J, Zhou R, et al: Tanshinone IIA protects the human blood-brain barrier model from leukocyte-associated hypoxia-reoxygenation injury. Eur J Pharmacol. 648:146–152. 2010. View Article : Google Scholar : PubMed/NCBI
30	Anctil M, Poulain I and Pelletier C: Nitric oxide modulates peristaltic muscle activity associated with fluid circulation in the sea pansy Renilla koellikeri. J Exp Biol. 208:2005–2017. 2005. View Article : Google Scholar : PubMed/NCBI
31	Das KC: Thioredoxin system in premature and newborn biology. Antioxid Redox Signal. 6:177–184. 2004. View Article : Google Scholar : PubMed/NCBI
32	Nalvarte I, Damdimopoulos AE and Spyrou G: Human mitochondrial thioredoxin reductase reduces cytochrome c and confers resistance to complex III inhibition. Free Rad Biol Med. 36:1270–1278. 2004. View Article : Google Scholar : PubMed/NCBI
33	Liu R1, Gao M, Yang ZH, et al: Pinocembrin protects rat brain against oxidation and apoptosis induced by ischemia-reperfusion both in vivo and in vitro. Brain Res. 1216:104–15. 2008. View Article : Google Scholar : PubMed/NCBI
34	Dohare P, Varma S and Ray M: Curcuma oil modulates the nitric oxide system response to cerebral ischemia/reperfusion injury. Nitric Oxide. 19:1–11. 2008. View Article : Google Scholar : PubMed/NCBI
35	Blomgren K and Hagberg H: Free radicals, mitochondria, and hypoxia-ischemia in the developing brain. Free Radic Biol Med. 40:388–97. 2006. View Article : Google Scholar : PubMed/NCBI
36	Han JD: The investigation of nerveprotective effect and mechanism of TongLuoHuaTan capsule and its active ingredient on cerebral ischemia reperfusion injury. Beijing University of Chinese Medicine; Doctoral dissertation. 2012