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01-09-2019 | Subarachnoid Hemorrhage | Original Paper

Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models

Authors: Liangmiao Wu, Zhiyang Su, Ling Zha, Zeyu Zhu, Wei Liu, Yewei Sun, Pei Yu, Yuqiang Wang, Gaoxiao Zhang, Zaijun Zhang

Published in: NeuroMolecular Medicine | Issue 3/2019

Abstract

Cerebral vasospasm is one of the deleterious complications after subarachnoid hemorrhage (SAH), leading to delayed cerebral ischemia and permanent neurological deficits or even death. Free radicals and oxidative stress are considered as crucial causes contributing to cerebral vasospasm and brain damage after SAH. Tetramethylpyrazine nitrone (TBN), a derivative of the clinically used anti-stroke drug tetramethylpyrazine armed with a powerful free radical scavenging nitrone moiety, has been reported to prevent brain damage from ischemic stroke. The present study aimed to investigate the effects of TBN on vasospasm and brain damage after SAH. Two experimental SAH models were used, a rat model by endovascular perforation and a rabbit model by intracisternal injection of autologous blood. The effects of TBN on SAH were evaluated assessing basilar artery spasm, neuronal apoptosis, and neurological deficits. TBN treatment significantly attenuated vasospasm, improved neurological behavior functions and reduced the number of apoptotic neurons in both the SAH rats and rabbits. Mechanistically, TBN suppressed the increase in 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immuno-positive cells in the cortex of SAH rat brain. Western blot analyses indicated that TBN effectively reversed the altered expression of Bcl-2, Bax and cytochrome C, and up-regulated nuclear factor erythroid-derived 2-like 2 (Nrf2) and hemeoxygenase-1 (HO-1) protein expressions. In the in vitro studies, TBN inhibited H₂O₂-induced bEnd.3 cell apoptosis and reduced ROS generation. Additionally, TBN alleviated the contraction of rat basilar artery rings induced by H₂O₂ ex vivo. In conclusion, TBN ameliorated SAH-induced cerebral vasospasm and neuronal damage. These effects of TBN may be attributed to its anti-oxidative stress effect and up-regulation of Nrf2/HO-1.

Aladag, M. A., Turkoz, Y., Parlakpinar, H., & Gul, M. (2017). Nebivolol attenuates cerebral vasospasm both by increasing endothelial nitric oxide and by decreasing oxidative stress in an experimental subarachnoid haemorrhage. British Journal of Neurosurgery, 31, 439–445.CrossRefPubMed

Al-Mufti, F., Amuluru, K., Smith, B., Damodara, N., El-Ghanem, M., Singh, I. P., et al. (2017). Emerging markers of early brain injury and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage. World Neurosurgery, 107, 148–159.CrossRefPubMed

Chen, J., Chen, G., Li, J., Qian, C., Mo, H., Gu, C., et al. (2014a). Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: A possible role for the regulation of pro-inflammatory cytokines. Journal of Pineal Research, 57, 340–347.CrossRefPubMed

Chen, J., Wang, L., Wu, C., Hu, Q., Gu, C., Yan, F., et al. (2014b). Melatonin-enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage. Journal of Pineal Research, 56, 12–19.CrossRefPubMed

Cheng, M. F., Song, J. N., Li, D. D., Zhao, Y. L., An, J. Y., Sun, P., et al. (2014). The role of rosiglitazone in the proliferation of vascular smooth muscle cells after experimental subarachnoid hemorrhage. Acta Neurochirurgica (Wien), 156, 2103–2109.CrossRef

Cui, Y., Duan, X., Li, H., Dang, B., Yin, J., Wang, Y., et al. (2016). Hydrogen sulfide ameliorates early brain injury following subarachnoid hemorrhage in rats. Molecular Neurobiology, 53, 3646–3657.CrossRefPubMed

Duan, H., Zhang, J., Li, L., & Bao, S. (2016). Effect of simvastatin on proliferation of vascular smooth muscle cells during delayed cerebral vasospasm after subarachnoid hemorrhage. Turkish Neurosurgery, 26, 538–544.PubMed

Fujii, M., Yan, J., Rolland, W. B., Soejima, Y., Caner, B., & Zhang, J. H. (2013). Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Translational Stroke Research, 4, 432–446.CrossRefPubMedPubMedCentral

Gao, C., Liu, X., Liu, W., Shi, H., Zhao, Z., Chen, H., et al. (2008). Anti-apoptotic and neuroprotective effects of tetramethylpyrazine following subarachnoid hemorrhage in rats. Autonomic Neuroscience, 141, 22–30.CrossRefPubMed

Granger, D. N., & Kvietys, P. R. (2015). Reperfusion injury and reactive oxygen species: The evolution of a concept. Redox Biology, 6, 524–551.CrossRefPubMedPubMedCentral

Guo, B., Xu, D., Duan, H., Du, J., Zhang, Z., Lee, S. M., et al. (2014). Therapeutic effects of multifunctional tetramethylpyrazine nitrone on models of Parkinson’s disease in vitro and in vivo. Biological and Pharmaceutical Bulletin, 37, 274–285.CrossRefPubMed

Hanggi, D., Etminan, N., Aldrich, F., Steiger, H. J., Mayer, S. A., Diringer, M. N., et al. (2017). Randomized, open-label, phase 1/2a study to determine the maximum tolerated dose of intraventricular sustained release nimodipine for subarachnoid hemorrhage (NEWTON [nimodipine microparticles to enhance recovery while reducing toxicity after subarachnoid hemorrhage]). Stroke, 48, 145–151.CrossRefPubMed

Huang, Y. Y., Wu, J. M., Su, T., Zhang, S. Y., & Lin, X. J. (2018). Fasudil, a rho-kinase inhibitor, exerts cardioprotective function in animal models of myocardial ischemia/reperfusion injury: A meta-analysis and review of preclinical evidence and possible mechanisms. Frontiers in Pharmacology, 9, 1083.CrossRefPubMedPubMedCentral

Jiang, Y., Liu, D. W., Han, X. Y., Dong, Y. N., Gao, J., Du, B., et al. (2012). Neuroprotective effects of anti-tumor necrosis factor-alpha antibody on apoptosis following subarachnoid hemorrhage in a rat model. Journal of Clinical Neuroscience, 19, 866–872.CrossRefPubMed

Joshi, G., & Johnson, J. A. (2012). The Nrf2-ARE pathway: a valuable therapeutic target for the treatment of neurodegenerative diseases. Recent Patents on CNS Drug Discovery, 7, 218–229.CrossRefPubMedPubMedCentral

Khurana, V. G., Sohni, Y. R., Mangrum, W. I., McClelland, R. L., O’Kane, D. J., Meyer, F. B., et al. (2004). Section on cerebrovascular surgery: Galbraith Award: Endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) gene polymorphisms predict susceptibility to aneurysmal subarachnoid hemorrhage (SAH) and post-SAH cerebral vasospasm. Clinical Neurosurgery, 51, 343–350.PubMed

Kim, D. E., Suh, Y. S., Lee, M. S., Kim, K. Y., Lee, J. H., Lee, H. S., et al. (2002). Vascular NAD(P)H oxidase triggers delayed cerebral vasospasm after subarachnoid hemorrhage in rats. Stroke, 33, 2687–2691.CrossRefPubMed

Lewen, A., Matz, P., & Chan, P. H. (2000). Free radical pathways in CNS injury. Journal of Neurotrauma, 17, 871–890.CrossRefPubMed

Li, K., Barras, C. D., Chandra, R. V., Kok, H. K., Maingard, J. T., Carter, N. S., et al. (2019). A review on the management of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. World Neurosurgery, 126, 513–527.CrossRef

Li, H., Song, F., Duan, L. R., Sheng, J. J., Xie, Y. H., Yang, Q., et al. (2016a). Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: Roles of Nrf2/HO-1 and PI3 K/Akt pathway. Sci Rep, 6, 23693.CrossRefPubMedPubMedCentral

Li, M., Wang, W., Mai, H., Zhang, X., Wang, J., Gao, Y., et al. (2016b). Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice. Scientific Reports, 6, 35055.CrossRefPubMedPubMedCentral

Love, S. (2003). Apoptosis and brain ischaemia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 27, 267–282.CrossRefPubMed

Luo, C., Yi, B., Chen, Z., Tang, W., Chen, Y., Hu, R., et al. (2011). PKGIα inhibits the proliferation of cerebral arterial smooth muscle cell induced by oxyhemoglobin after subarachnoid hemorrhage. Acta Neurochirurgica Supplement, 110, 167–171.PubMed

Macdonald, R. L. (2014). Delayed neurological deterioration after subarachnoid haemorrhage. Nature Reviews Neurology, 10, 44–58.CrossRefPubMed

Macdonald, R. L., Cusimano, M. D., Etminan, N., Hanggi, D., Hasan, D., Ilodigwe, D., et al. (2013). Subarachnoid Hemorrhage International Trialists data repository (SAHIT). World Neurosurgery, 79, 418–422.CrossRefPubMed

Macdonald, R. L., & Weir, B. K. (1994). Cerebral vasospasm and free radicals. Free Radical Biology and Medicine, 16, 633–643.CrossRefPubMed

O’Neill, A. H., Chandra, R. V., & Lai, L. T. (2017). Safety and effectiveness of microsurgical clipping, endovascular coiling, and stent assisted coiling for unruptured anterior communicating artery aneurysms: a systematic analysis of observational studies. Journal of NeuroInterventional Surgery, 9, 761–765.CrossRefPubMed

Osburn, W. O., Wakabayashi, N., Misra, V., Nilles, T., Biswal, S., Trush, M. A., et al. (2006). Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of superoxide anion. Archives of Biochemistry and Biophysics, 454, 7–15.CrossRefPubMedPubMedCentral

Park, S., Yamaguchi, M., Zhou, C., Calvert, J. W., Tang, J., & Zhang, J. H. (2004). Neurovascular protection reduces early brain injury after subarachnoid hemorrhage. Stroke, 35, 2412–2417.CrossRefPubMed

Reed, J. C. (2002). Apoptosis-based therapies. Nature Reviews Drug Discovery, 1, 111–121.CrossRefPubMed

Santiago, E., Contreras, C., Garcia-Sacristan, A., Sanchez, A., Rivera, L., Climent, B., et al. (2013). Signaling pathways involved in the H₂O₂-induced vasoconstriction of rat coronary arteries. Free Radical Biology and Medicine, 60, 136–146.CrossRefPubMed

Shao, Z., Wu, P., Wang, X., Jin, M., Liu, S., Ma, X., et al. (2018). Tetramethylpyrazine protects against early brain injury and inhibits the PERK/Akt pathway in a rat model of subarachnoid hemorrhage. Neurochemical Research, 43, 1650–1659.CrossRefPubMed

Suen, D. F., Norris, K. L., & Youle, R. J. (2008). Mitochondrial dynamics and apoptosis. Genes & Development, 22, 1577–1590.CrossRef

Sugawara, T., Ayer, R., Jadhav, V., & Zhang, J. H. (2008). A new grading system evaluating bleeding scale in filament perforation subarachnoid hemorrhage rat model. Journal of Neuroscience Methods, 167, 327–334.CrossRefPubMed

Sugawara, T., Noshita, N., Lewen, A., Gasche, Y., Ferrand-Drake, M., Fujimura, M., et al. (2002). Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. Journal of Neuroscience, 22, 209–217.CrossRefPubMed

Sun, Y., Jiang, J., Zhang, Z., Yu, P., Wang, L., Xu, C., et al. (2008). Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke. Bioorganic & Medicinal Chemistry, 16, 8868–8874.CrossRef

Sun, Y., Yu, P., Zhang, G., Wang, L., Zhong, H., Zhai, Z., et al. (2012). Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. Journal of Neuroscience Research, 90, 1662–1669.CrossRefPubMed

Sun, J., Zhang, Y., Lu, J., Zhang, W., Yan, J., Yang, L., et al. (2018). Salvinorin A ameliorates cerebral vasospasm through activation of endothelial nitric oxide synthase in a rat model of subarachnoid hemorrhage. Microcirculation, 25, e12442.CrossRefPubMed

Willis, S., Day, C. L., Hinds, M. G., & Huang, D. C. (2003). The Bcl-2-regulated apoptotic pathway. Journal of Cell Science, 116, 4053–4056.CrossRefPubMed

Wu, Q., Zhang, X. S., Wang, H. D., Zhang, X., Yu, Q., Li, W., et al. (2014). Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Marine Drugs, 12, 6125–6141.CrossRefPubMedPubMedCentral

Yang, Y., Chen, S., & Zhang, J. M. (2017). The updated role of oxidative stress in subarachnoid hemorrhage. Current Drug Delivery, 14, 832–842.PubMed

Zhang, T., Gu, J., Wu, L., Li, N., Sun, Y., Yu, P., et al. (2017a). Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia. Neuropharmacology, 118, 137–147.CrossRefPubMed

Zhang, X., Wu, Q., Zhang, Q., Lu, Y., Liu, J., Li, W., et al. (2017b). Resveratrol attenuates early brain injury after experimental subarachnoid hemorrhage via inhibition of NLRP3 inflammasome activation. Frontiers in Neuroscience, 11, 611.CrossRefPubMedPubMedCentral

Zhang, Z. Y., Yang, M. F., Wang, T., Li, D. W., Liu, Y. L., Zhang, J. H., et al. (2015). Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. Cellular and Molecular Neurobiology, 35, 543–553.CrossRefPubMed

Zhang, Z., Zhang, G., Sun, Y., Szeto, S. S., Law, H. C., Quan, Q., et al. (2016a). Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy. Scientific Reports, 6, 37148.CrossRefPubMedPubMedCentral

Zhang, G., Zhang, T., Wu, L., Zhou, X., Gu, J., Li, C., et al. (2018). Neuroprotective effect and mechanism of action of tetramethylpyrazine nitrone for ischemic stroke therapy. Neuromolecular Medicine, 20, 97–111.CrossRefPubMed

Zhang, G., Zhang, F., Zhang, T., Gu, J., Li, C., Sun, Y., et al. (2016b). Tetramethylpyrazine nitrone improves neurobehavioral functions and confers neuroprotection on rats with traumatic brain injury. Neurochemical Research, 41, 2948–2957.CrossRefPubMed

Zhang, J., Zhu, Y., Zhou, D., Wang, Z., & Chen, G. (2010). Recombinant human erythropoietin (rhEPO) alleviates early brain injury following subarachnoid hemorrhage in rats: possible involvement of Nrf2-ARE pathway. Cytokine, 52, 252–257.CrossRefPubMed

Zheng, J. S., Zhan, R. Y., Zheng, S. S., Zhou, Y. Q., Tong, Y., & Wan, S. (2005). Inhibition of NADPH oxidase attenuates vasospasm after experimental subarachnoid hemorrhage in rats. Stroke, 36, 1059–1064.CrossRefPubMed

Title: Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models
Authors: Liangmiao Wu
Zhiyang Su
Ling Zha
Zeyu Zhu
Wei Liu
Yewei Sun
Pei Yu
Yuqiang Wang
Gaoxiao Zhang
Zaijun Zhang
Publication date: 01-09-2019
Publisher: Springer US
Keywords: Subarachnoid Hemorrhage
Subarachnoid Hemorrhage
Published in: NeuroMolecular Medicine / Issue 3/2019
Print ISSN: 1535-1084
Electronic ISSN: 1559-1174
DOI: https://doi.org/10.1007/s12017-019-08543-9

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Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models

Abstract

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Abstract

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