Generic placeholder image

Letters in Drug Design & Discovery

Author(s): Haiyun Chen*, Chunyan Yan*, Jie Cao, Zheng Liu, Yewei Sun and Yuqiang Wang

DOI: 10.2174/1570180817999201117145311

DownloadDownload PDF Flyer Cite As
Design, Synthesis, and Biological Evaluation of Novel Tetramethylpyrazine- nitrone Derivatives as Antioxidants

Page: [499 - 508] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Background: Thrombolysis and endovascular thrombectomy are the two main therapeutic strategies for ischemic stroke in clinic. However, reperfusion injury causes oxidative stress leading to overproduction of reactive oxygen species, mitochondrial dysfunction and subsequent cell death.

Methods: We designed and synthesized two tetramethylpyrazine-nitrone derivatives (T-003 and T- 005) and investigated their abilities for scavenging free radicals and protective effects as well as neurite outgrowth promotion in vitro.

Results: Both of them showed potent radical-scavenging activity and neuroprotective effects against iodoacetic acid-induced cell injury. Furthermore, T-003 and T-005 significantly promoted neurite outgrowth in PC12 cells.

Conclusion: Our results suggest that compound T-003 and T-005 could be potent antioxidants for the treatment of neurological disease, particularly ischemic stroke.

Keywords: Ischemic stroke, oxidative stress, tetramethypyrazine-nitrone derivatives, radical-scavenging activity, neurite outgrowth, antioxidants.

Graphical Abstract

[1]
Randolph, S.A. Ischemic Stroke. Workplace Health Saf., 2016, 64(9), 444.
[http://dx.doi.org/10.1177/2165079916665400] [PMID: 27621261]
[2]
Jauch, E.C.; Saver, J.L.; Adams, H.P., Jr; Bruno, A.; Connors, J.J.; Demaerschalk, B.M.; Khatri, P.; McMullan, P.W., Jr; Qureshi, A.I.; Rosenfield, K.; Scott, P.A.; Summers, D.R.; Wang, D.Z.; Wintermark, M.; Yonas, H. American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Peripheral Vascular Disease; Council on Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2013, 44(3), 870-947.
[http://dx.doi.org/10.1161/STR.0b013e318284056a] [PMID: 23370205]
[3]
Nogueira, R.G.; Jadhav, A.P.; Haussen, D.C.; Bonafe, A.; Budzik, R.F.; Bhuva, P.; Yavagal, D.R.; Ribo, M.; Cognard, C.; Hanel, R.A.; Sila, C.A.; Hassan, A.E.; Millan, M.; Levy, E.I.; Mitchell, P.; Chen, M.; English, J.D.; Shah, Q.A.; Silver, F.L.; Pereira, V.M.; Mehta, B.P.; Baxter, B.W.; Abraham, M.G.; Cardona, P.; Veznedaroglu, E.; Hellinger, F.R.; Feng, L.; Kirmani, J.F.; Lopes, D.K.; Jankowitz, B.T.; Frankel, M.R.; Costalat, V.; Vora, N.A.; Yoo, A.J.; Malik, A.M.; Furlan, A.J.; Rubiera, M.; Aghaebrahim, A.; Olivot, J.M.; Tekle, W.G.; Shields, R.; Graves, T.; Lewis, R.J.; Smith, W.S.; Liebeskind, D.S.; Saver, J.L.; Jovin, T.G.; Investigators, D.T. DAWN trial investigators. thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N. Engl. J. Med., 2018, 378(1), 11-21.
[http://dx.doi.org/10.1056/NEJMoa1706442] [PMID: 29129157]
[4]
Warach, S.; Latour, L.L. Evidence of reperfusion injury, exacerbated by thrombolytic therapy, in human focal brain ischemia using a novel imaging marker of early blood-brain barrier disruption. Stroke, 2004, 35(11)(Suppl. 1), 2659-2661.
[http://dx.doi.org/10.1161/01.STR.0000144051.32131.09] [PMID: 15472105]
[5]
Jung, J.E.; Kim, G.S.; Chen, H.; Maier, C.M.; Narasimhan, P.; Song, Y.S.; Niizuma, K.; Katsu, M.; Okami, N.; Yoshioka, H.; Sakata, H.; Goeders, C.E.; Chan, P.H. Reperfusion and neurovascular dysfunction in stroke: from basic mechanisms to potential strategies for neuroprotection. Mol. Neurobiol., 2010, 41(2-3), 172-179.
[http://dx.doi.org/10.1007/s12035-010-8102-z] [PMID: 20157789]
[6]
O’Collins, V.E.; Macleod, M.R.; Donnan, G.A.; Horky, L.L.; van der Worp, B.H.; Howells, D.W. 1,026 experimental treatments in acute stroke. Ann. Neurol., 2006, 59(3), 467-477.
[http://dx.doi.org/10.1002/ana.20741] [PMID: 16453316]
[7]
Shi, L.; Rocha, M.; Leak, R.K.; Zhao, J.; Bhatia, T.N.; Mu, H.; Wei, Z.; Yu, F.; Weiner, S.L.; Ma, F.; Jovin, T.G.; Chen, J. A new era for stroke therapy: Integrating neurovascular protection with optimal reperfusion. J. Cereb. Blood Flow Metab., 2018, 38(12), 2073-2091.
[http://dx.doi.org/10.1177/0271678X18798162] [PMID: 30191760]
[8]
Lin, J.B.; Zheng, C.J.; Zhang, X.; Chen, J.; Liao, W.J.; Wan, Q. Effects of tetramethylpyrazine on functional recovery and neuronal dendritic plasticity after experimental stroke. Evid. Based Complement. Alternat. Med., 2015, •••2015394926
[http://dx.doi.org/10.1155/2015/394926] [PMID: 26379744]
[9]
Shi, J.; Wang, Y.; Luo, G. Ligustrazine phosphate ethosomes for treatment of Alzheimer’s disease, in vitro and in animal model studies. AAPS PharmSciTech, 2012, 13(2), 485-492.
[http://dx.doi.org/10.1208/s12249-012-9767-6] [PMID: 22415639]
[10]
Xiao, X.; Liu, Y.; Qi, C.; Qiu, F.; Chen, X.; Zhang, J.; Yang, P. Neuroprotection and enhanced neurogenesis by tetramethylpyrazine in adult rat brain after focal ischemia. Neurol. Res., 2010, 32(5), 547-555.
[http://dx.doi.org/10.1179/174313209X414533] [PMID: 20501058]
[11]
Zhao, H.; Xu, M.L.; Zhang, Q.; Guo, Z.H.; Peng, Y.; Qu, Z.Y.; Li, Y.N. Tetramethylpyrazine alleviated cytokine synthesis and dopamine deficit and improved motor dysfunction in the mice model of Parkinson’s disease. Neurol. Sci., 2014, 35(12), 1963-1967.
[http://dx.doi.org/10.1007/s10072-014-1871-9] [PMID: 25030124]
[12]
Guo, S.K.; Chen, K.J.; Qian, Z.H.; Weng, W.L.; Qian, M.Y. Tetramethylpyrazine in the treatment of cardiovascular and cerebrovascular diseases. Planta Med., 1983, 47(2), 89.
[http://dx.doi.org/10.1055/s-2007-969959] [PMID: 6844454]
[13]
Rosselin, M.; Poeggeler, B.; Durand, G. Nitrone derivatives as therapeutics: from chemical modification to specific-targeting. Curr. Top. Med. Chem., 2017, 17(18), 2006-2022.
[http://dx.doi.org/10.2174/1568026617666170303115324] [PMID: 28260508]
[14]
Sun, Y.; Jiang, J.; Zhang, Z.; Yu, P.; Wang, L.; Xu, C.; Liu, W.; Wang, Y. Antioxidative and thrombolytic TMP nitrone for treatment of ischemic stroke. Bioorg. Med. Chem., 2008, 16(19), 8868-8874.
[http://dx.doi.org/10.1016/j.bmc.2008.08.075] [PMID: 18790647]
[15]
Zhang, G.; Zhang, T.; Li, N.; Wu, L.; Gu, J.; Li, C.; Zhao, C.; Liu, W.; Shan, L.; Yu, P.; Yang, X.; Tang, Y.; Yang, G.Y.; Wang, Y.; Sun, Y.; Zhang, Z. Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. Br. J. Pharmacol., 2018, 175(3), 517-531.
[http://dx.doi.org/10.1111/bph.14102] [PMID: 29161771]
[16]
Gao, L.; She, H.; Li, W.; Zeng, J.; Zhu, J.; Jones, D.P.; Mao, Z.; Gao, G.; Yang, Q. Oxidation of survival factor MEF2D in neuronal death and Parkinson’s disease. Antioxid. Redox Signal., 2014, 20(18), 2936-2948.
[http://dx.doi.org/10.1089/ars.2013.5399] [PMID: 24219011]
[17]
Kumar, N.; Pruthi, V. Potential applications of ferulic acid from natural sources. Biotechnol. Rep. (Amst.), 2014, 4, 86-93.
[http://dx.doi.org/10.1016/j.btre.2014.09.002] [PMID: 28626667]
[18]
Ren, Z.; Zhang, R.; Li, Y.; Li, Y.; Yang, Z.; Yang, H. Ferulic acid exerts neuroprotective effects against cerebral ischemia/reperfusion-induced injury via antioxidant and anti-apoptotic mechanisms in vitro and in vivo. Int. J. Mol. Med., 2017, 40(5), 1444-1456.
[http://dx.doi.org/10.3892/ijmm.2017.3127] [PMID: 28901374]
[19]
Zhipei, S.; Keren, W.; Han, X. Mengxiao, Cao, Zhenghuai, and Tan. Design, synthesis and evaluation of novel ferulic acid derivatives as multi-target-directed ligands for the treatment of Alzheimer’s disease. ACS Chem. Neurosci., 2018, 10, 1008-1024.
[20]
Perluigi, M.; Joshi, G.; Sultana, R.; Calabrese, V.; De Marco, C.; Coccia, R.; Cini, C.; Butterfield, D.A. In vivo protective effects of ferulic acid ethyl ester against amyloid-beta peptide 1-42-induced oxidative stress. J. Neurosci. Res., 2006, 84(2), 418-426.
[http://dx.doi.org/10.1002/jnr.20879] [PMID: 16634068]
[21]
Schumann, H.; Luo, H-K. 2, 5-dimethyl-3, 6-bis [(2, 6-diisopropylphenylimino) methyl]-and 2, 6-bis [(2, 6-diisopropylphenylimino) methyl] pyrazine: Two new chelating ligands for transition metal complexes. Z. Naturforsch, 2005, 2005, 22-24.
[http://dx.doi.org/10.1515/znb-2005-0104]
[22]
Chen, H.; Tan, G.; Cao, J.; Zhang, G.; Yi, P.; Yu, P.; Sun, Y.; Zhang, Z.; Wang, Y. Design, synthesis, and biological evaluation of novel tetramethylpyrazine derivatives as potential neuroprotective agents. Chem. Pharm. Bull. (Tokyo), 2017, 65(1), 56-65.
[http://dx.doi.org/10.1248/cpb.c16-00699] [PMID: 27746410]
[23]
Stuhr-Hansen, N.; Christensen, J.B.; Harrit, N.; Bjørnholm, T. Novel synthesis of protected thiol end-capped stilbenes and oligo(phenylenevinylene)s (OPVs). J. Org. Chem., 2003, 68(4), 1275-1282.
[http://dx.doi.org/10.1021/jo0263770] [PMID: 12585865]
[24]
Sun, Y.; Zhang, G.; Zhang, Z.; Yu, P.; Zhong, H.; Du, J.; Wang, Y. Novel multi-functional nitrones for treatment of ischemic stroke. Bioorg. Med. Chem., 2012, 20(12), 3939-3945.
[http://dx.doi.org/10.1016/j.bmc.2012.04.016] [PMID: 22579617]
[25]
Chen, H.; Cao, J.; Zhu, Z.; Zhang, G.; Shan, L.; Yu, P.; Wang, Y.; Sun, Y.; Zhang, Z. A Novel tetramethylpyrazine derivative protects against glutamate-induced cytotoxicity through pgc1α/nrf2 and pi3k/akt signaling pathways. Front. Neurosci., 2018, 12, 567.
[http://dx.doi.org/10.3389/fnins.2018.00567] [PMID: 30158850]
[26]
Xu, S.L.; Choi, R.C.Y.; Zhu, K.Y.; Leung, K.W.; Guo, A.J.Y.; Bi, D.; Xu, H.; Lau, D.T.W.; Dong, T.T.X.; Tsim, K.W.K. Isorhamnetin, A. Flavonol aglycone from Ginkgo biloba L., induces neuronal differentiation of cultured pc12 cells: Potentiating the effect of nerve growth factor. Evid. Based Complement. Alternat. Med., 2012, •••2012278273
[http://dx.doi.org/10.1155/2012/278273] [PMID: 22761636]
[27]
Li, S.Y.; Jia, Y.H.; Sun, W.G.; Tang, Y.; An, G.S.; Ni, J.H.; Jia, H.T. Stabilization of mitochondrial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampus. Free Radic. Biol. Med., 2010, 48(4), 597-608.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.12.004] [PMID: 20006702]
[28]
Kamila, Z.; Agnieszka, D. Anna, Kolodziejczak, Helena, and Rotsztejn. Antioxidant properties of ferulic acid and its possible application. Skin Pharmacol. Physiol., 2018, 31, 332-336.
[http://dx.doi.org/10.1159/000491755]
[29]
Floyd, R.A.; Castro Faria Neto, H.C.; Zimmerman, G.A.; Hensley, K.; Towner, R.A. Nitrone-based therapeutics for neurodegenerative diseases: their use alone or in combination with lanthionines. Free Radic. Biol. Med., 2013, 62, 145-156.
[http://dx.doi.org/10.1016/j.freeradbiomed.2013.01.033] [PMID: 23419732]
[30]
Chen, H.Y.; Xu, D.P.; Tan, G.L.; Cai, W.; Zhang, G.X.; Cui, W.; Wang, J.Z.; Long, C.; Sun, Y.W.; Yu, P.; Tsim, K.W.; Zhang, Z.J.; Han, Y.F.; Wang, Y.Q. A potent multi-functional neuroprotective derivative of tetramethylpyrazine. J. Mol. Neurosci., 2015, 56(4), 977-987.
[http://dx.doi.org/10.1007/s12031-015-0566-x] [PMID: 25982925]
[31]
Sigalov, E.; Fridkin, M.; Brenneman, D.E.; Gozes, I. VIP-Related protection against lodoacetate toxicity in pheochromocytoma (PC12) cells: A model for ischemic/hypoxic injury. J. Mol. Neurosci., 2000, 15(3), 147-154.
[http://dx.doi.org/10.1385/JMN:15:3:147] [PMID: 11303779]
[32]
Khodanovich, M.; Kisel, A.; Kudabaeva, M.; Chernysheva, G.; Smolyakova, V.; Krutenkova, E.; Wasserlauf, I.; Plotnikov, M.; Yarnykh, V. Effects of fluoxetine on hippocampal neurogenesis and neuroprotection in the model of global cerebral ischemia in rats. Int. J. Mol. Sci., 2018, 19(1), 162.
[http://dx.doi.org/10.3390/ijms19010162] [PMID: 29304004]
[33]
Dillen, Y.; Kemps, H.; Gervois, P.; Wolfs, E.; Bronckaers, A. Adult neurogenesis in the subventricular zone and its regulation after ischemic stroke: Implications for therapeutic approaches. Transl. Stroke Res., 2020, 11(1), 60-79.
[http://dx.doi.org/10.1007/s12975-019-00717-8] [PMID: 31309427]
[34]
Arvidsson, A.; Collin, T.; Kirik, D.; Kokaia, Z.; Lindvall, O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med., 2002, 8(9), 963-970.
[http://dx.doi.org/10.1038/nm747] [PMID: 12161747]
[35]
Vaudry, D.; Stork, P.J.; Lazarovici, P.; Eiden, L.E. Signaling pathways for PC12 cell differentiation: making the right connections. Science, 2002, 296(5573), 1648-1649.
[http://dx.doi.org/10.1126/science.1071552] [PMID: 12040181]
[36]
Jiang, G.H.W. Chinese Academy of Medical Sciences Peking Union Medical College Doctorial. Dissertation, 1994.4
[37]
Cheng, X-C.; Liu, X-Y.; Xu, W-F.; Guo, X-L.; Ou, Y. Design, synthesis, and biological activities of novel Ligustrazine derivatives. Bioorg. Med. Chem., 2007, 15(10), 3315-3320.
[http://dx.doi.org/10.1016/j.bmc.2007.03.033] [PMID: 17383884]
[38]
Liu, F.; Lu, J.; Manaenko, A.; Tang, J.; Hu, Q. Mitochondria in ischemic stroke: New insight and implications. Aging Dis., 2018, 9(5), 924-937.
[http://dx.doi.org/10.14336/AD.2017.1126] [PMID: 30271667]
[39]
Yang, J.; Ahn, H.N.; Chang, M.; Narasimhan, P.; Chan, P.H.; Song, Y.S. Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice. J. Neurochem., 2013, 124(4), 523-535.
[http://dx.doi.org/10.1111/jnc.12111] [PMID: 23199288]
[40]
Wang, C.X.; Shuaib, A. NXY-059: A neuroprotective agent in acute stroke. Int. J. Clin. Pract., 2004, 58(10), 964-969.
[http://dx.doi.org/10.1111/j.1368-5031.2004.00245.x] [PMID: 15587776]
[41]
Guan, D.; Su, Y.; Li, Y.; Wu, C.; Meng, Y.; Peng, X.; Cui, Y. Tetramethylpyrazine inhibits CoCl2 -induced neurotoxicity through enhancement of Nrf2/GCLc/GSH and suppression of HIF1α/NOX2/ROS pathways. J. Neurochem., 2015, 134(3), 551-565.
[http://dx.doi.org/10.1111/jnc.13161] [PMID: 25952107]
[42]
Sperling, O.; Bromberg, Y.; Oelsner, H.; Zoref-Shani, E. Reactive oxygen species play an important role in iodoacetate-induced neurotoxicity in primary rat neuronal cultures and in differentiated PC12 cells. Neurosci. Lett., 2003, 351(3), 137-140.
[http://dx.doi.org/10.1016/S0304-3940(03)00858-9] [PMID: 14623125]
[43]
Dad, A.; Jeong, C.H.; Pals, J.A.; Wagner, E.D.; Plewa, M.J. Pyruvate remediation of cell stress and genotoxicity induced by haloacetic acid drinking water disinfection by-products. Environ. Mol. Mutagen., 2013, 54(8), 629-637.
[http://dx.doi.org/10.1002/em.21795] [PMID: 23893730]
[44]
Reiner, P.B.; Laycock, A.G.; Doll, C.J. A pharmacological model of ischemia in the hippocampal slice. Neurosci. Lett., 1990, 119(2), 175-178.
[http://dx.doi.org/10.1016/0304-3940(90)90827-V] [PMID: 2280893]
[45]
Zhao, Y.; Guan, Y.F.; Zhou, X.M.; Li, G.Q.; Li, Z.Y.; Zhou, C.C.; Wang, P.; Miao, C.Y. Regenerative neurogenesis after ischemic stroke promoted by nicotinamide phosphoribosyltransferase-nicotinamide adenine dinucleotide cascade. Stroke, 2015, 46(7), 1966-1974.
[http://dx.doi.org/10.1161/STROKEAHA.115.009216] [PMID: 26060246]
[46]
Braun, H.; Schäfer, K.; Höllt, V. BetaIII tubulin-expressing neurons reveal enhanced neurogenesis in hippocampal and cortical structures after a contusion trauma in rats. J. Neurotrauma, 2002, 19(8), 975-983.
[http://dx.doi.org/10.1089/089771502320317122] [PMID: 12225657]