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The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy

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Abstract

This study aimed to investigate the synergic effects of tetramethylpyrazine phosphate (TMPP) and borneol (BO) for protecting against ischemia in the cortex and hippocampus. A rat model of global cerebral ischemia-reperfusion (GCIR) was induced by four-vessel occlusion. The results showed that TMPP (13.3 mg/kg), BO (0.16 g/kg), and their combination improved the ultrastructure of neurons, reduced the apoptosis index, and reduced the intracellular calcium content in both the cortex and hippocampus. TMPP and the combined treatment increased cortex autophagy by modulating phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) in the pAMPK-mammalian target of rapamycin (mTOR)-Unc-51-like kinase 1 (ULK1) signaling pathway, whereas BO only regulated ULK1. Moreover, BO increased neuron autophagy in the hippocampus by modulating mTOR, whereas TMPP targeted both mTOR and Beclin1. Similarly, the combination targeted both pAMPK and Beclin1. All three treatments decreased the expression of p53 and caspase-3 in the two areas. Additionally, TMPP and the combined therapy regulated Bax and Bcl-2. These results demonstrated the synergic effects between TMPP and BO for treating ischemia-reperfusion injury in the cortex and hippocampus regions. Their neuroprotective effects could be partly attributed to switching from apoptosis to protective autophagy. Additionally, the potential mechanism triggering this switching could be ascribed to the reduction of intracellular calcium content.

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References

  • Alers S, Löffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32:2–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang CY, Kao TK, Chen WY, Ou YC, Li JR, Liao SL, Raung SL, Chen CJ (2015) Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats. Biochem Biophys Res Commun 463:421–427

    Article  CAS  PubMed  Google Scholar 

  • Chen TT, Du YJ, Liu XL, Zhu HB (2008) Inhibitory action of hydroxysafflor yellow A on inflammatory signal transduction pathway related factors in rats with cerebral cortex ischemia. Yao Xue Xue Bao 43:570–575

    CAS  PubMed  Google Scholar 

  • Descloux C, Ginet V, Clarke PGH, Puyal J (2015) Neuronal death after perinatal cerebral hypoxia-ischemia: focus on autophagy-mediated cell death. Int J Dev Neurosci 45:75–85

    Article  CAS  PubMed  Google Scholar 

  • Ge XH, Zhu GJ, Geng DQ, Zhang HZ, He JM, Guo AZ, Ma LL, Yu DH (2017) Metformin protects the brain against ischemia/reperfusion injury through PI3K/Akt1/JNK3 signaling pathways in rats. Physiol Behav 170:115–123

    Article  CAS  PubMed  Google Scholar 

  • Guo SK, Chen KJ, Qian ZH, Weng WL, Qian MY (1983) Tetramethylpyrazine in the treatment of cardiovascular and cerebrovascular diseases. Planta Med 47:89

    Article  CAS  PubMed  Google Scholar 

  • He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herrero-Martin G, Hoyer-Hansen M, Garcia-Garcia C, Fumarola C, Farkas T, Lopez-Rivas A, Jaattela M (2009) TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J 28:677–685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong CX, Ming KW (2003) The clinic research on ameliorating vertigo induced by ischemic of vertebral basilar artery with the treatment with spraying agent of CR and borneol mixture, combined with Shenmai injection. J Pract Med 19:932–933

    Google Scholar 

  • Hong YK, Park SH, Lee S, Hwang S, Lee MJ, Kim D, Lee JH, Han SY, Kim ST, Kim YK, Jeon S, Koo BS, Cho KS (2011) Neuroprotective effect of Su He Xiang Wan in Drosophila models of Alzheimer’s disease. J Ethnopharmacol 134:1028–1032

    Article  PubMed  Google Scholar 

  • Huang P, Wu QH, Rong XL, Lei WW, Bei ML, Han J, Wu LN (2000) Protective effects of borneolum combined with Rhizoma Chuanxiong on cerebral ischemia with reperfusion injury. J Guangzhou Univ Tradit Chin Med 17:323–326

    Google Scholar 

  • Huang P, Wu QH, Rong XL, Han J (2001) Mechanism of borneolum combined with Rhizoma Chuanxiong in counteracting cerebral ischemia with reperfusion injury. J Guangzhou Univ Tradit Chin Med 18:332–334

    Google Scholar 

  • Kao TK, Ou YC, Kuo JS, Chen WY, Liao SL, Wu CW, Chen CJ, Ling NN, Zhang YH, Peng WH (2006) Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats. Neurochem Int 48:166–176

    Article  CAS  PubMed  Google Scholar 

  • Klionsky DJ (2007) Autophagy: from phenomenology to molecular under standing in less than a decade. Nat Rev Mol Cell Biol 8:931–937

    Article  CAS  PubMed  Google Scholar 

  • Kong QX, Wu ZY, Chu X, Liang RQ, Xia M, Li L (2013) Study on the anti-cerebral ischemia effect of borneol and its mechanism. Afr J Tradit Complement Altern Med 11:161–164

    PubMed  PubMed Central  Google Scholar 

  • Lee JC, Won MH (2014) Neuroprotection of antioxidant enzymes against transient global cerebral ischemia in gerbils. Anat Cell Biol 47:149–156

    Article  PubMed  PubMed Central  Google Scholar 

  • Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688

  • Li WL, Yu SP, Ogle ME, Ding XS, Wei L (2008) Enhanced neurogenesis and cell migration following focal ischemia and peripheral stimulation in mice. Dev Neurobiol 68:1474–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li YB, Li XR, Yang T, Wang JX, Zhao XF (2016) The steroid hormone 20-hydroxyecdysone promotes switching from autophagy to apoptosis by increasing intracellular calcium levels. Insect Biochem Mol Biol 79:73–86

  • Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B (1999) Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672–676

    Article  CAS  PubMed  Google Scholar 

  • Liu R, Zhang L, Lan X, Li L, Zhang TT, Sun JH, Du GH (2011) Protection by borneol on cortical neurons against oxygen-glucose deprivation/reperfusion: involvement of anti-oxidation and anti-inflammation through nuclear transcription factor κappaB signaling pathway. Neuroscience 176:408–419

    Article  CAS  PubMed  Google Scholar 

  • Meley D, Bauvy C, Houben-Weerts JH, Dubbelhuis PF, Helmond MT, Codogno P, Meijer AJ (2006) AMP-activated protein kinase and the regulation of autophagic proteolysis. J Biol Chem 281:34870–34879

    Article  CAS  PubMed  Google Scholar 

  • Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873

    Article  CAS  PubMed  Google Scholar 

  • Park KK, Liu K, Hu Y, Kanter JL, He ZG (2012) PTEN/mTOR and axon regeneration. Exp Neurol 223:45–50

    Article  Google Scholar 

  • Pinho J, Alves JN, Oliveira L, Pereira S, Barros J, Machado C, Amorim JM, Santos AF, Ribeiro M, Ferreira C (2016) Orolingual angioedema after thrombolysis is not associated with insular cortex ischemia on pre-thrombolysis CT. J Neurol Sci 369:48–50

    Article  PubMed  Google Scholar 

  • Pinter M, Friedrich P (1988) The calcium-dependent proteolytic system calpain-calpastatin in Drosophila melanogaster. Biochem J 253:467–473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith PF, Darlington CL, Zhen Y (2015) The effects of complete vestibular deafferentation on spatial memory and the hippocampus in the rat: the Dunedin experience. Multisens Res 28:461–485

    Article  PubMed  Google Scholar 

  • Su Y, Li F (2016) Endoplasmic reticulum stress in brain ischemia. Int J Neurosci 126:681–691

    Article  CAS  PubMed  Google Scholar 

  • Sun YW, Jiang J, Zhang ZJ, Yu P, Wang LD, Xu CL, Liu W, Wang YQ (2008) Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke. Bioorg Med Chem 16:8868–8874

    Article  CAS  PubMed  Google Scholar 

  • Tang Q, Han R, Xiao H, Shen J, Luo Q, Li J (2012) Neuroprotective effects of tanshinone IIA and/or tetramethylpyrazine in cerebral ischemic injury in vivo and in vitro. Brain Res 1488:81–91

    Article  CAS  PubMed  Google Scholar 

  • Tian WQ, Peng YG, Cui SY, Yao FZ, Li BG (2015) Effects of electroacupuncture of different intensities on energy metabolism of mitochondria of brain cells in rats with cerebral ischemia-reperfusion injury. Chin J Integr Med 21:618–623

    Article  CAS  PubMed  Google Scholar 

  • Uchiyama Y, Shibata M, Koike M, Yoshimura K, Sasaki M (2008) Autophagy–physiology and pathophysiology. Histochem Cell Biol 129:407–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H (2000) Enhancement of synthetic borneol on ligustrazine resisting aoute hypoxia in mice. Pharmacol Clin Chin Mater Med 16:13–15

    CAS  Google Scholar 

  • Wang Y, Han R, Liang ZQ, Wu JC, Zhang XD, Gu ZL, Qin ZH (2008) An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-aspartate receptor agonist kainic acid. Autophagy 4:214–226

    Article  CAS  PubMed  Google Scholar 

  • Wang LT, Chen BL, Wu CT, Huang KH, Chiang CK, Hwa Liu S (2013) Protective role of AMP-activated protein kinase-evoked autophagy on an in vitro model of ischemia/reperfusion-induced renal tubular cell injury. PLoS One 8:e79814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang GH, Lan R, Zhen XD, Zhang W, Xiang J, Cai DF (2014) An-Gong-Niu-Huang Wan protects against cerebral ischemia induced apoptosis in rats: up-regulation of Bcl-2 and down-regulation of Bax and caspase-3. J Ethnopharmacol 154:156–162

    Article  PubMed  Google Scholar 

  • Wu HY, Tang Y, Gao LY, Sun WX, Hua Y, Yang SB, Zhang ZP, Liao GY, Zhou QG, Luo CX, Zhu DY (2014) The synergetic effect of edaravone and borneol in the rat model of ischemic stroke. Eur J Pharmacol 740:522–531

    Article  CAS  PubMed  Google Scholar 

  • Xu HC (2006) Xiongbing nasal spray for vertebral and basilar arterial insufficiency. Chin J Integr Med Cardio/Cerebrovasc Dis 4:388–390

    Google Scholar 

  • Yu B, Ruan M, Sun Y, Cui XB, Yu Y, Wang LL, Fang TH (2011) Effect of borneol and electroacupuncture on the distribution of hyperforin in the rat brain. Neural Regen Res 6:1876–1882

    CAS  Google Scholar 

  • Yu B, Ruan M, Cui XB, Guo JM, Xu L, Dong XP (2012) Effects of borneol on the pharmacokinetics of geniposide in cortex, hippocampus, hypothalamus and striatum of conscious rat by simultaneous brain microdialysis coupled with UPLC–MS. J Pharm Biomed Anal 77:128–132

    Article  Google Scholar 

  • Yu B, Ruan M, Zhang ZN, Cheng HB, Shen XC (2016) Synergic effect of borneol and ligustrazine on the neuroprotection in global cerebral ischemia/reperfusion injury: a region-specificity study. Evid Based Complement Alternat Med 2016. doi:10.1155/2016/4072809

  • Zhang DS, Fu MD, Song CL, Wang CY, Lin XC, Liu YL (2012) Expressions of apoptosis-related proteins in rats with focal cerebral ischemia after Angong Niuhuang sticker point application. Neural Regen Res 7:2347–2353

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Lan R, Wang J, Li XY, Zhu DN, Ma YZ, Wu JT, Liu ZH (2015) Acupuncture reduced apoptosis and up-regulated BDNF and GDNF expression in hippocampus following hypoxia–ischemia in neonatal rats. J Ethnopharmacol 172:124–132

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Ma J, Jin X, Jia G, Jiang Y, Li C (2017) L-PGDS mediates Vagus nerve stimulation-induced neuroprotection in a rat model of ischemic stroke by suppressing the apoptotic response. Neurochem Res 42:644–655

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Huang G, Chen S, Gou Y, Dong Z, Zhang X (2016) Folic acid deficiency increases brain cell injury via autophagy enhancement after focal cerebral ischemia. J Nutr Biochem 38:41–49

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81573713), the Basic Research Project of Jiangsu Province (BK20151564, BK20150088), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), the Qing Lan Project of Jiangsu Province, the Innovated Team of the Education Department of Guizhou Province (2014–31), the Scientific and Technologic Innovated Team of Guizhou Province (2015–4025), the High Level Innovation Talents (2015–4029), the 2011 Modern Drug of Cooperation Innovation ([2013]04), and the Jiangsu Provincial Key Construction Laboratory (No. SuJiaoKe[2016]8).

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Author notes

  1. Bin Yu and Ming Ruan contributed equally to the work.

Authors and Affiliations

  1. Jiangsu Engineering Laboratory for Research and Industrialization of Empirical Formulae, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Bin Yu, Shi-Wen Huang & Hai-Bo Cheng

  2. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Bin Yu, Tao Liang & Yun Yu

  3. Jiangsu Provincial Key Construction Laboratory of Special Biomass Waste Resource Utilization, School of Food Science, Nanjing Xiaozhuang University, Nanjing, 211117, China

    Ming Ruan

  4. The Key Laboratory of Optimal Utilization of Natural Medicinal Resources, Guizhou Medical University, Huaxi College Station, Guian New District, Guiyang, 550025, China

    Xiang-Chun Shen

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  1. Bin Yu
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Corresponding authors

Correspondence to Hai-Bo Cheng or Xiang-Chun Shen.

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The study was approved by the Animal Ethics Committee of Nanjing University of Chinese Medicine. The care and use of the rats were approved by the Animal Ethics Committee of the Nanjing University of Chinese Medicine, and the experiment was strictly performed according to the guidelines of laboratory animal care (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, 1996).

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The authors declare that they have no conflicts of interests.

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Yu, B., Ruan, M., Liang, T. et al. The Synergic Effect of Tetramethylpyrazine Phosphate and Borneol for Protecting Against Ischemia Injury in Cortex and Hippocampus Regions by Modulating Apoptosis and Autophagy. J Mol Neurosci 63, 70–83 (2017). https://doi.org/10.1007/s12031-017-0958-1

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