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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Mini-Review Article

An Overview of Tetramethylpyrazine (Ligustrazine) and its Derivatives as Potent Anti-Alzheimer’s Disease Agents

Author(s): Syed Nasir Abbas Bukhari* and Ruchika Yogesh

Volume 19, Issue 7, 2022

Published on: 25 May, 2022

Page: [565 - 578] Pages: 14

DOI: 10.2174/1570180819666220405232333

Price: $65

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Abstract

Tetramethylpyrazine (TMP), or ligustrazine, is an alkaloid isolated from the Chinese herb Ligusticum wallichii. It is known for its broad-spectrum medicinal properties against several diseases, and various studies have shown that it can modulate diverse biological targets and signaling pathways to produce neuroprotective effects, especially against Alzheimer’s disease (AD). This has attracted significant research attention evaluating TMP as a potent multitarget anti-AD agent. This review compiles the results of studies assessing the neuroprotective mechanisms exerted by TMP as well as its derivatives prepared using a multi-target-directed ligand strategy to explore its multitarget modulating properties. The present review also highlights the work done on the design, synthesis, structure-activity relationships, and mechanisms of some potent TMP derivatives that have shown promising anti-AD activities. These derivatives were designed, synthesized, and evaluated to develop anti-AD molecules with enhanced biological and pharmacokinetic activities compared to TMP. This review article paves the way for the exploration and development of TMP and TMP derivatives as an effective treatment for AD.

Keywords: Tetramethylpyrazine, ligustrazine, Alzheimer’s disease, neuroprotection, Multi Target Drug Ligands (MTDLs), pharmacokinetic activities.

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[1]
Ran, X.; Ma, L.; Peng, C.; Zhang, H.; Qin, L-P. Ligusticum chuanxiong Hort: A review of chemistry and pharmacology. Pharm. Biol., 2011, 49(11), 1180-1189.
[http://dx.doi.org/10.3109/13880209.2011.576346] [PMID: 22014266]
[2]
Tsai, C-C.; Lai, T-Y.; Huang, W-C.; Liu, I.M.; Cheng, J-T. Inhibitory effects of potassium channel blockers on tetramethylpyrazine-induced relaxation of rat aortic strip in vitro. Life Sci., 2002, 71(11), 1321-1330.
[http://dx.doi.org/10.1016/S0024-3205(02)01852-0] [PMID: 12106597]
[3]
Li, M.; Handa, S.; Ikeda, Y.; Goto, S. Specific inhibiting characteristics of tetramethylpyrazine, one of the active ingredients of the Chinese herbal medicine ‘Chuanxiong,’ on platelet thrombus formation under high shear rates. Thromb. Res., 2001, 104(1), 15-28.
[http://dx.doi.org/10.1016/S0049-3848(01)00343-7] [PMID: 11583735]
[4]
Shih, Y-H.; Wu, S-L.; Chiou, W-F.; Ku, H-H.; Ko, T-L.; Fu, Y-S. Protective effects of tetramethylpyrazine on kainate-induced excitotoxici-ty in hippocampal culture. Neuroreport, 2002, 13(4), 515-519.
[http://dx.doi.org/10.1097/00001756-200203250-00032] [PMID: 11930173]
[5]
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 pro-tects 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]
[6]
Bie, B-H.; Chen, Y.; Zhao, Z-Q. Ligustrazine inhibits high voltage-gated Ca(2+) and TTX-resistant Na(+) channels of primary sensory neuron and thermal nociception in the rat: A study on peripheral mechanism. Neurosci. Bull., 2006, 22(2), 79-84.
[PMID: 17687402]
[7]
Ju, X.D.; Deng, M.; Ao, Y.F.; Yu, C.L.; Wang, J.Q.; Yu, J.K.; Cui, G.Q.; Hu, Y.L. The protective effect of tetramethylpyrazine on cartilage explants and chondrocytes. J. Ethnopharmacol., 2010, 132(2), 414-420.
[http://dx.doi.org/10.1016/j.jep.2010.08.020] [PMID: 20723588]
[8]
Kwan, C.Y.; Daniel, E.E.; Chen, M.C. Inhibition of vasoconstriction by tetramethylpyrazine: Does it act by blocking the voltage-dependent Ca channel? J. Cardiovasc. Pharmacol., 1990, 15(1), 157-162.
[http://dx.doi.org/10.1097/00005344-199001000-00025] [PMID: 1688974]
[9]
Peng, W.; Hucks, D.; Priest, R.M.; Kan, Y.M.; Ward, J.P. Ligustrazine-induced endothelium-dependent relaxation in pulmonary arteries via an NO-mediated and exogenous L-arginine-dependent mechanism. Br. J. Pharmacol., 1996, 119(5), 1063-1071.
[http://dx.doi.org/10.1111/j.1476-5381.1996.tb15778.x] [PMID: 8922759]
[10]
Lv, L.; Jiang, S-S.; Xu, J.; Gong, J-B.; Cheng, Y. Protective effect of ligustrazine against myocardial ischaemia reperfusion in rats: The role of endothelial nitric oxide synthase. Clin. Exp. Pharmacol. Physiol., 2012, 39(1), 20-27.
[http://dx.doi.org/10.1111/j.1440-1681.2011.05628.x] [PMID: 22004361]
[11]
Qu, Y.J.; Bai, H.B.; Wang, C.Z.; Xu, J.D.; Zhang, T.T.; Han, Z.Y. Inhibition of tetramethylpyrazine on the proliferation of rat airway smooth muscle cells. Zhongguo Yaolixue Tongbao, 2010, 26, 814-818.
[12]
Zhang, L.; Deng, M.; Zhou, S. Tetramethylpyrazine inhibits hypoxia-induced pulmonary vascular leakage in rats via the ROS-HIF-VEGF pathway. Pharmacology, 2011, 87(5-6), 265-273.
[http://dx.doi.org/10.1159/000326082] [PMID: 21494058]
[13]
Li, W-M.; Liu, H-T.; Li, X-Y.; Wu, J-Y.; Xu, G.; Teng, Y-Z.; Ding, S-T.; Yu, C. The effect of tetramethylpyrazine on hydrogen peroxide-induced oxidative damage in human umbilical vein endothelial cells. Basic Clin. Pharmacol. Toxicol., 2010, 106(1), 45-52.
[PMID: 19821832]
[14]
Gao, X.; Zhao, X.L.; Zhu, Y.H.; Li, X.M.; Xu, Q.; Lin, H.D.; Wang, M.W. Tetramethylpyrazine protects palmitate-induced oxidative dam-age and mitochondrial dysfunction in C2C12 myotubes. Life Sci., 2011, 88(17-18), 803-809.
[http://dx.doi.org/10.1016/j.lfs.2011.02.025] [PMID: 21396380]
[15]
Yang, Y.; Li, Z-H.; Liu, H.; Shi, W.D.; Zhang, J. Inhibitory effect of tetramethylpyrazine preconditioning on overload training-induced myocardial apoptosis in rats. Chin. J. Integr. Med., 2015, 21(6), 423-430.
[http://dx.doi.org/10.1007/s11655-014-1752-3] [PMID: 24829152]
[16]
Wan, J-y.; Ye, D-y.; Wu, P.; Zhang, L.; Gong, X.; Huang, Y. Effect of tetramethylpyrazine on lipopolysaccharides induced macrophage cyclo-oxidase-2 expression and apoptosis of cardiac myocytes. Chinese J. Integr. Trad. West. Med., 2004, 24(10), 906-911.
[17]
Lin, K-H.; Kuo, W-W.; Jiang, A-Z.; Pai, P.; Lin, J-Y.; Chen, W-K.; Day, C.H.; Shen, C-Y.; Padma, V.V.; Huang, C.Y. Tetramethylpyra-zine ameliorated hypoxia-induced myocardial cell apoptosis via HIF-1α/JNK/p38 and IGFBP3/BNIP3 inhibition to upregulate PI3K/Akt survival signaling. Cell. Physiol. Biochem., 2015, 36(1), 334-344.
[18]
Li, X-Y.; He, J-L.; Liu, H-T.; Li, W-M.; Yu, C. Tetramethylpyrazine suppresses interleukin-8 expression in LPS-stimulated human umbil-ical vein endothelial cell by blocking ERK, p38 and nulear factor-kappaB signaling pathways. J. Ethnopharmacol., 2009, 125(1), 83-89.
[http://dx.doi.org/10.1016/j.jep.2009.06.008] [PMID: 19540326]
[19]
Sullivan, J.L. Macrophage iron, hepcidin, and atherosclerotic plaque stability. Exp. Biol. Med. (Maywood), 2007, 232(8), 1014-1020.
[http://dx.doi.org/10.3181/0703-MR-54] [PMID: 17720947]
[20]
Zeng, G.Y.; Zhou, Y.P.; Zhang, L.Y.; Zhang, Y. Effects of tetramethylpyrazine on cardiac haemodynamics in dogs (author’s transl). Yao Xue Xue Bao, 1982, 17(3), 182-186.
[PMID: 7102333]
[21]
Liu, S.Y.; Sylvester, D.M. Antithrombotic/antiplatelet activity of tetramethylpyrazine. Thromb. Res., 1990, 58(2), 129-140.
[http://dx.doi.org/10.1016/0049-3848(90)90170-H] [PMID: 2349541]
[22]
Jia, J.; Zhang, X.; Hu, Y-S.; Wu, Y.; Wang, Q-Z.; Li, N-N.; Wu, C-Q.; Yu, H-X.; Guo, Q-C. Protective effect of tetraethyl pyrazine against focal cerebral ischemia/reperfusion injury in rats: Therapeutic time window and its mechanism. Thromb. Res., 2009, 123(5), 727-730.
[http://dx.doi.org/10.1016/j.thromres.2008.11.004] [PMID: 19128823]
[23]
Lin, J-B.; Zheng, C-J.; Zhang, X.; Chen, J.; Liao, W-J.; Wan, Q. Effects of tetramethylpyrazine on functional recovery and neuronal den-dritic plasticity after experimental stroke. Evid. Based Complement. Alternat. Med., 2015, 2015, 394926-394926.
[http://dx.doi.org/10.1155/2015/394926] [PMID: 26379744]
[24]
Xiao, Z.; Hu, J.; Lu, H.; Zhuo, X.; Xu, D.; Wang, S.; Li, J. Effect of tetramethylpyrazine on the expression of macrophage migration inhibi-tory factor in acute spinal cord injury in rats. J. Cent. South Univ. Med. Sci., 2012, 37(10), 1031-1036.
[25]
Shin, J-W.; Moon, J-Y.; Seong, J-W.; Song, S-H.; Cheong, Y-J.; Kang, C.; Sohn, N-W. Effects of tetramethylpyrazine on microglia activa-tion in spinal cord compression injury of mice. Am. J. Chin. Med., 2013, 41(6), 1361-1376.
[http://dx.doi.org/10.1142/S0192415X13500912] [PMID: 24228606]
[26]
Li, N.; Jia, X.H.; Wang, J.Y. Effects of tetramethylpyrazine on apoptosis of human leukemia cells and the expressions of apoptotic-relevant proteins. Tumor, 2014, 34, 919-923.
[27]
Wang, X-J.; Xu, Y-H.; Yang, G-C.; Chen, H-X.; Zhang, P. Tetramethylpyrazine inhibits the proliferation of acute lymphocytic leukemia cell lines via decrease in GSK-3. Oncol. Rep., 2015, 33(5), 2368-2374.
[http://dx.doi.org/10.3892/or.2015.3860] [PMID: 25812605]
[28]
Xu, X.Y.; Yan, P.K.; Chen, G.; Liao, D.F. Inhibition of tetramethylpyrazine on Lewis lung carcinomas, microvessel growth and VEGF expression in mice. Zhongguo Yaolixue Tongbao, 2004, 20, 151-154.
[29]
Yin, J.; Yu, C.; Yang, Z.; He, J-L.; Chen, W-J.; Liu, H-Z.; Li, W-M.; Liu, H-T.; Wang, Y-X. Tetramethylpyrazine inhibits migration of SKOV3 human ovarian carcinoma cells and decreases the expression of interleukin-8 via the ERK1/2, p38 and AP-1 signaling pathways. Oncol. Rep., 2011, 26(3), 671-679.
[PMID: 21637924]
[30]
Cao, J.; Miao, Q.; Miao, S.; Bi, L.; Zhang, S.; Yang, Q.; Zhou, X.; Zhang, M.; Xie, Y.; Zhang, J.; Wang, S. Tetramethylpyrazine (TMP) exerts antitumor effects by inducing apoptosis and autophagy in hepatocellular carcinoma. Int. Immunopharmacol., 2015, 26(1), 212-220.
[http://dx.doi.org/10.1016/j.intimp.2015.03.028] [PMID: 25841319]
[31]
Yang, Q-H.; Liang, Y.; Xu, Q.; Zhang, Y.; Xiao, L.; Si, L-Y. Protective effect of tetramethylpyrazine isolated from Ligusticum chuanxiong on nephropathy in rats with streptozotocin-induced diabetes. Phytomedicine, 2011, 18(13), 1148-1152.
[32]
Lan, Z.; Bi, K.S.; Chen, X.H. Ligustrazine attenuates elevated levels of indoxyl sulfate, kidney injury molecule-1 and clusterin in rats ex-posed to cadmium. Food Chem. Toxicol., 2014, 63, 62-68.
[33]
Lu, C.; Jiang, Y.; Zhang, F.; Shao, J.; Wu, L.; Wu, X.; Lian, N.; Chen, L.; Jin, H.; Chen, Q.; Lu, Y.; Zheng, S. Tetramethylpyrazine prevents ethanol-induced hepatocyte injury via activation of nuclear factor erythroid 2-related factor 2. Life Sci., 2015, 141, 119-127.
[http://dx.doi.org/10.1016/j.lfs.2015.08.018] [PMID: 26341692]
[34]
Qiu, F.; Liu, Y.; Zhang, P-B.; Tian, Y-F.; Zhao, J-J.; Kang, Q-Y.; Qi, C-F.; Chen, X-L. The effect of ligustrazine on cells proliferation in cortex and striatum after focal cerebral ischemia in adult rats. Zhong Yao Cai, 2006, 29(11), 1196-1200.
[PMID: 17228661]
[35]
Zhang, T. Protective effect of ligustrazine on brain. Zhonghua Yixue Yanjiu Zazhi, 2006, 6, 993-994.
[36]
Huang, X.; Yang, J.; Huang, X.; Zhang, Z.; Liu, J.; Zou, L.; Yang, X. Tetramethylpyrazine improves cognitive impairment and modifies the hippocampal proteome in two mouse models of Alzheimer’s Disease. Front. Cell Dev. Biol., 2021, 9(469), 632843.
[http://dx.doi.org/10.3389/fcell.2021.632843] [PMID: 33791294]
[37]
Kao, T-K.; Ou, Y-C.; Kuo, J-S.; Chen, W-Y.; Liao, S-L.; Wu, C-W.; Chen, C-J.; Ling, N-N.; Zhang, Y-H.; Peng, W-H. Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats. Neurochem. Int., 2006, 48(3), 166-176.
[http://dx.doi.org/10.1016/j.neuint.2005.10.008] [PMID: 16316708]
[38]
Zhang, C.; Wang, S-Z.; Zuo, P-P.; Cui, X.; Cai, J. Protective effect of tetramethylpyrazine on learning and memory function in D-galactose-lesioned mice. Chin. Med. Sci. J., 2004, 19(3), 180-184.
[39]
Fan, L-H.; Wang, K-Z.; Cheng, B.; Wang, C-S.; Dang, X-Q. Anti-apoptotic and neuroprotective effects of Tetramethylpyrazine following spinal cord ischemia in rabbits. BMC Neurosci., 2006, 7(1), 48-48.
[http://dx.doi.org/10.1186/1471-2202-7-48] [PMID: 16774675]
[40]
Cheng, X-R.; Zhang, L.; Hu, J-J.; Sun, L.; Du, G-H. Neuroprotective effects of tetramethylpyrazine on hydrogen peroxide-induced apopto-sis in PC12 cells. Cell Biol. Int., 2007, 31(5), 438-443.
[http://dx.doi.org/10.1016/j.cellbi.2006.10.001] [PMID: 17321170]
[41]
Lu, C.; Zhang, J.; Shi, X.; Miao, S.; Bi, L.; Zhang, S.; Yang, Q.; Zhou, X.; Zhang, M.; Xie, Y.; Miao, Q.; Wang, S. Neuroprotective effects of tetramethylpyrazine against dopaminergic neuron injury in a rat model of Parkinson’s disease induced by MPTP. Int. J. Biol. Sci., 2014, 10(4), 350-357.
[http://dx.doi.org/10.7150/ijbs.8366] [PMID: 24719552]
[42]
Weng, G.; Zhou, B.; Liu, T.; Huang, Z.; Huang, S. Tetramethylpyrazine improves cognitive function of Alzheimer’s Disease mice by regu-lating SSTR4 ubiquitination. Drug Des. Devel. Ther., 2021, 15, 2385-2399.
[http://dx.doi.org/10.2147/DDDT.S290030] [PMID: 34103899]
[43]
Zhang, Q.; Wang, J.; Zhu, L.; Jiang, S.J.; Liu, J.; Wang, L.X.; Qin, X.H. Ligustrazine attenuates hyperhomocysteinemia-induced alzheimer-like pathologies in rats. Curr. Med. Sci., 2021, 41(3), 548-554.
[http://dx.doi.org/10.1007/s11596-021-2379-1] [PMID: 34169425]
[44]
Tan, Z. Erratum: Neural protection by naturopathic compounds-an example of tetramethylpyrazine from retina to brain. J. Ocul. Biol. Dis. Infor., 2009, 2(3), 137-144.
[http://dx.doi.org/10.1007/s12177-009-9033-7] [PMID: 20046848]
[45]
Oxford, A.E.; Stewart, E.S.; Rohn, T.T. Clinical trials in Alzheimer’s Disease: A hurdle in the path of remedy. Int. J. Alzheimers Dis., 2020, 2020, 5380346-5380346.
[46]
Weller, J.; Budson, A. Current understanding of Alzheimer’s disease diagnosis and treatment. F1000 Res., 2018, 7, 1161.
[http://dx.doi.org/10.12688/f1000research.14506.1]
[47]
Silva, M.V.F.; Loures, C.M.G.; Alves, L.C.V.; de Souza, L.C.; Borges, K.B.G.; Carvalho, M.D.G. Alzheimer’s disease: Risk factors and potentially protective measures. J. Biomed. Sci., 2019, 26(1), 33-33.
[http://dx.doi.org/10.1186/s12929-019-0524-y] [PMID: 31072403]
[48]
Rajasekhar, K.; Govindaraju, T. Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alz-heimer’s disease. RSC Advances, 2018, 8(42), 23780-23804.
[http://dx.doi.org/10.1039/C8RA03620A]
[49]
Zhang, W.; Bai, Y.; Wang, Y.; Xiao, W. Polypharmacology in drug discovery: A review from systems pharmacology perspective. Curr. Pharm. Des., 2016, 22(21), 3171-3181.
[http://dx.doi.org/10.2174/1381612822666160224142812] [PMID: 26907941]
[50]
Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51(3), 347-372.
[http://dx.doi.org/10.1021/jm7009364] [PMID: 18181565]
[51]
Pal, T.; Bhimaneni, S.; Sharma, A.; Flora, S.J.S. Design, synthesis, biological evaluation and molecular docking study of novel pyridox-ine–triazoles as anti-Alzheimer’s agents. RSC Advances, 2020, 10(44), 26006-26021.
[http://dx.doi.org/10.1039/D0RA04942E]
[52]
Rosini, M.; Simoni, E.; Caporaso, R.; Minarini, A. Multitarget strategies in Alzheimer’s disease: Benefits and challenges on the road to therapeutics. Future Med. Chem., 2016, 8(6), 697-711.
[http://dx.doi.org/10.4155/fmc-2016-0003] [PMID: 27079260]
[53]
Prati, F.; Cavalli, A.; Bolognesi, M.L. Navigating the chemical space of multitarget-directed ligands: From hybrids to fragments in Alz-heimer’s Disease. Molecules, 2016, 21(4), 466.
[http://dx.doi.org/10.3390/molecules21040466] [PMID: 27070562]
[54]
Agatonovic-Kustrin, S.; Kettle, C.; Morton, D.W. A molecular approach in drug development for Alzheimer’s disease. Biomed. Pharmacother., 2018, 106, 553-565.
[55]
Kim, M.; Kim, S-O.; Lee, M.; Lee, J.H.; Jung, W-S.; Moon, S-K.; Kim, Y-S.; Cho, K-H.; Ko, C-N.; Lee, E.H. Tetramethylpyrazine, a natu-ral alkaloid, attenuates pro-inflammatory mediators induced by amyloid β and interferon-γ in rat brain microglia. Eur. J. Pharmacol., 2014, 740, 504-511.
[http://dx.doi.org/10.1016/j.ejphar.2014.06.037] [PMID: 24975095]
[56]
Graeber, M.B.; Streit, W.J. Microglia: Biology and pathology. Acta Neuropathol., 2010, 119(1), 89-105.
[http://dx.doi.org/10.1007/s00401-009-0622-0] [PMID: 20012873]
[57]
Lue, L-F.; Kuo, Y-M.; Beach, T.; Walker, D.G. Microglia activation and anti-inflammatory regulation in Alzheimer’s disease. Mol. Neurobiol., 2010, 41(2-3), 115-128.
[http://dx.doi.org/10.1007/s12035-010-8106-8] [PMID: 20195797]
[58]
Zhao, L.; Wei, M.J.; He, M.; Jin, W.B.; Zhao, H.S.; Yao, W.F. The effects of tetramethylpyrazine on learning and memory abilities of mice with Alzheimer disease and its possible mechanism. Zhongguo Yaolixue Tongbao, 2008, 24, 1088-1092.
[59]
Pluta, R. Alzheimer lesions after ischemia-reperfusion brain injury. Folia Neuropathol., 2004, 42(3), 181-186.
[PMID: 15535038]
[60]
Pluta, R. Ischemia-Reperfusion Pathways in Alzheimer’s Disease; Nova Science Publishers, Inc.: Hauppauge, New York, USA, 2007.
[61]
Pluta, R.; Amek, M.U. Brain ischemia and ischemic blood-brain barrier as etiological factors in sporadic Alzheimer’s disease. Neuropsychiatr. Dis. Treat., 2008, 4(5), 855-864.
[http://dx.doi.org/10.2147/NDT.S3739] [PMID: 19183778]
[62]
Pluta, R. Role of ischemic blood-brain barrier on amyloid plaques development in Alzheimer’s disease brain. Curr. Neurovasc. Res., 2007, 4(2), 121-129.
[http://dx.doi.org/10.2174/156720207780637207] [PMID: 17504210]
[63]
Nakagawa, T.; Hasegawa, Y.; Uekawa, K.; Senju, S.; Nakagata, N.; Matsui, K.; Kim-Mitsuyama, S. Transient mild cerebral ischemia signif-icantly deteriorated cognitive impairment in a mouse model of Alzheimer’s Disease via angiotensin AT1 receptor. Am. J. Hypertens., 2017, 30(2), 141-150.
[http://dx.doi.org/10.1093/ajh/hpw099] [PMID: 27572961]
[64]
Kao, T-K.; Chang, C-Y.; Ou, Y-C.; Chen, W-Y.; Kuan, Y-H.; Pan, H-C.; Liao, S-L.; Li, G-Z.; Chen, C-J. Tetramethylpyrazine reduces cel-lular inflammatory response following permanent focal cerebral ischemia in rats. Exp. Neurol., 2013, 247, 188-201.
[http://dx.doi.org/10.1016/j.expneurol.2013.04.010] [PMID: 23644042]
[65]
Fan, L.; Wang, K.; Shi, Z.; Die, J.; Wang, C.; Dang, X. Tetramethylpyrazine protects spinal cord and reduces inflammation in a rat model of spinal cord ischemia-reperfusion injury. J. Vasc. Surg., 2011, 54(1), 192-200.
[http://dx.doi.org/10.1016/j.jvs.2010.12.030] [PMID: 21458204]
[66]
Qiu, F.; Liu, Y.; Qian, Y.H.; Zhao, J.J.; Tian, Y.F.; Qi, C.F. Effect of ligustrazine on cell proliferation in subventricular zone of lateral cere-bral ventricle after adult rat suffering from focal cerebral ischemia. Sichuan Da Xue Xue Bao Yi Xue Ban, 2006, 37(5), 726-729.
[PMID: 17037737]
[67]
Yeh, T-S.; Ho, Y-C.; Hsu, C-L.; Pan, S-L. Spinal cord injury and Alzheimer’s disease risk: A population-based, retrospective cohort study. Spinal Cord, 2018, 56(2), 151-157.
[http://dx.doi.org/10.1038/s41393-017-0009-3] [PMID: 29057990]
[68]
Hu, J.; Lang, Y.; Cao, Y.; Zhang, T.; Lu, H. The neuroprotective effect of tetramethylpyrazine against contusive spinal cord injury by acti-vating PGC-1α in rats. Neurochem. Res., 2015, 40(7), 1393-1401.
[http://dx.doi.org/10.1007/s11064-015-1606-1] [PMID: 25981953]
[69]
Huang, J.-H.; Cao, Y.; Zeng, L.; Wang, G.; Cao, M.; Lu, H.-B.; Hu, J.-Z. Tetramethylpyrazine enhances functional recovery after contusion spinal cord injury by modulation of MicroRNA-21, FasL, PDCD4 and PTEN expression. Brain Res. 2016, 1648(Pt A), 35-45.
[70]
Wang, C.; Wang, P.; Zeng, W.; Li, W. Tetramethylpyrazine improves the recovery of spinal cord injury via Akt/Nrf2/HO-1 pathway. Bioorg. Med. Chem. Lett., 2016, 26(4), 1287-1291.
[http://dx.doi.org/10.1016/j.bmcl.2016.01.015] [PMID: 26786697]
[71]
Fan, Y.; Wu, Y. Tetramethylpyrazine alleviates neural apoptosis in injured spinal cord via the downregulation of miR-214-3p. Biomed. Pharmacother., 2017, 94, 827-833.
[72]
Koushki, D.; Latifi, S.; Norouzi Javidan, A.; Matin, M. Efficacy of some non-conventional herbal medications (sulforaphane, tanshinone IIA, and tetramethylpyrazine) in inducing neuroprotection in comparison with interleukin-10 after spinal cord injury: A meta-analysis. J. Spinal Cord Med., 2015, 38(1), 13-22.
[http://dx.doi.org/10.1179/2045772314Y.0000000215] [PMID: 24969510]
[73]
Hu, J-Z.; Huang, J-H.; Xiao, Z-M.; Li, J-H.; Li, X-M.; Lu, H-B. Tetramethylpyrazine accelerates the function recovery of traumatic spinal cord in rat model by attenuating inflammation. J. Neurol. Sci., 2013, 324(1-2), 94-99.
[http://dx.doi.org/10.1016/j.jns.2012.10.009] [PMID: 23140983]
[74]
Shimohama, S. Apoptosis in Alzheimer’s disease-an update. Apoptosis, 2000, 5(1), 9-16.
[75]
Zhong, M.; Ma, W.; Zhang, X.; Wang, Y.; Gao, X. Tetramethyl pyrazine protects hippocampal neurons against anoxia/reoxygenation inju-ry through inhibiting apoptosis mediated by JNK/MARK signal pathway. Med. Sci. Monit., 2016, 22, 5082-5090.
[http://dx.doi.org/10.12659/MSM.898921] [PMID: 28009855]
[76]
Gong, G.; Yuan, L.; Cai, L.; Ran, M.; Zhang, Y.; Gong, H.; Dai, X.; Wu, W.; Dong, H. Tetramethylpyrazine suppresses transient oxygen-glucose deprivation-induced connexin32 expression and cell apoptosis via the ERK1/2 and p38 MAPK pathway in cultured hippocampal neurons. PLoS One, 2014, 9(9), e105944.
[http://dx.doi.org/10.1371/journal.pone.0105944] [PMID: 25237906]
[77]
Kale, J.; Osterlund, E.J.; Andrews, D.W. BCL-2 family proteins: Changing partners in the dance towards death. Cell Death Differ., 2018, 25(1), 65-80.
[http://dx.doi.org/10.1038/cdd.2017.186] [PMID: 29149100]
[78]
Shen, Z.X.; Lü, H.B.; Li, X.M.; Xu, D.Q.; Hu, J.Z.; Wang, X.Y. Tetramethylpyrazine accelerated spinal cord repair through regulation of caspase-3 and neurofilament protein expression: An acute spinal cord injury model in rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2008, 33(8), 693-699.
[PMID: 18772508]
[79]
Zhao, T.; Fu, Y.; Sun, H.; Liu, X. Ligustrazine suppresses neuron apoptosis via the Bax/Bcl-2 and caspase-3 pathway in PC12 cells and in rats with vascular dementia. IUBMB Life, 2018, 70(1), 60-70.
[http://dx.doi.org/10.1002/iub.1704] [PMID: 29247598]
[80]
Guan, D.; Su, Y.; Li, Y.; Wu, C.; Meng, Y.; Peng, X.; Cui, Y. Tetramethylpyrazine inhibits CoCl2 -induced neurotoxicity through en-hancement 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]
[81]
Christophe, M.; Nicolas, S. Mitochondria: A target for neuroprotective interventions in cerebral ischemia-reperfusion. Curr. Pharm. Des., 2006, 12, 739-757.
[82]
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]
[83]
Liu, H-T.; Du, Y-G.; He, J-L.; Chen, W-J.; Li, W-M.; Yang, Z.; Wang, Y-X.; Yu, C. Tetramethylpyrazine inhibits production of nitric oxide and inducible nitric oxide synthase in lipopolysaccharide-induced N9 microglial cells through blockade of MAPK and PI3K/Akt signaling pathways, and suppression of intracellular reactive oxygen species. J. Ethnopharmacol., 2010, 129(3), 335-343.
[http://dx.doi.org/10.1016/j.jep.2010.03.037] [PMID: 20371283]
[84]
Wu, W.; Yu, X.; Luo, X-P.; Yang, S-H.; Zheng, D. Tetramethylpyrazine protects against scopolamine-induced memory impairments in rats by reversing the cAMP/PKA/CREB pathway. Behav. Brain Res., 2013, 253, 212-216.
[http://dx.doi.org/10.1016/j.bbr.2013.07.052] [PMID: 23916742]
[85]
Li, G.; Liu, S.; Wang, H.; Pan, R.; Tang, H.; Yan, X.; Wang, Y.; Fu, Y.; Jing, F.; Dong, J. Ligustrazine ameliorates lipopolysaccha-ride induced neurocognitive impairment by activating autophagy via the PI3K/AKT/mTOR pathway. Int. J. Mol. Med., 2020, 45(6), 1711-1720.
[http://dx.doi.org/10.3892/ijmm.2020.4548] [PMID: 32236586]
[86]
Wang, S.; Xia, B.; Qiao, Z.; Duan, L.; Wang, G.; Meng, W.; Liu, Z.; Wang, Y.; Zhang, M. Tetramethylpyrazine attenuated bupivacaine-induced neurotoxicity in SH-SY5Y cells through regulating apoptosis, autophagy and oxidative damage. Drug Des. Devel. Ther., 2019, 13, 1187-1196.
[http://dx.doi.org/10.2147/DDDT.S196172] [PMID: 31114159]
[87]
Qin, W.; Haroutunian, V.; Katsel, P.; Cardozo, C.P.; Ho, L.; Buxbaum, J.D.; Pasinetti, G.M. PGC-1α expression decreases in the Alzheimer disease brain as a function of dementia. Arch. Neurol., 2009, 66(3), 352-361.
[http://dx.doi.org/10.1001/archneurol.2008.588] [PMID: 19273754]
[88]
Benek, O.; Korabecny, J.; Soukup, O. A perspective on multi-target drugs for Alzheimer’s Disease. Trends Pharmacol. Sci., 2020, 41(7), 434-445.
[http://dx.doi.org/10.1016/j.tips.2020.04.008] [PMID: 32448557]
[89]
Jiang, G.H.W. Chinese academy of medical sciences & peking union medical college doctorial dissertation. Nat. Careers, 1994. Available from: https://www.nature.com/naturecareers/employer/79137
[90]
Tsai, T-H.; Liang, C. Pharmacokinetics of tetramethylpyrazine in rat blood and brain using microdialysis. Int. J. Pharm., 2001, 216(1-2), 61-66.
[http://dx.doi.org/10.1016/S0378-5173(01)00572-5] [PMID: 11274807]
[91]
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]
[92]
Sun, Y.; Yu, P.; Zhang, G.; Wang, L.; Zhong, H.; Zhai, Z.; Wang, L.; Wang, Y. Therapeutic effects of tetramethylpyrazine nitrone in rat ischemic stroke models. J. Neurosci. Res., 2012, 90(8), 1662-1669.
[http://dx.doi.org/10.1002/jnr.23034] [PMID: 22431378]
[93]
Zhang, Z.; Zhang, G.; Sun, Y.; Szeto, S.S.W.; Law, H.C.H.; Quan, Q.; Li, G.; Yu, P.; Sho, E.; Siu, M.K.W.; Lee, S.M.Y.; Chu, I.K.; Wang, Y. Tetramethylpyrazine nitrone, a multifunctional neuroprotective agent for ischemic stroke therapy. Sci. Rep., 2016, 6(1), 37148-37148.
[http://dx.doi.org/10.1038/srep37148] [PMID: 27841332]
[94]
Zhang, G.; Zhang, T.; Wu, L.; Zhou, X.; Gu, J.; Li, C.; Liu, W.; Long, C.; Yang, X.; Shan, L.; Xu, L.; Wang, Y.; Sun, Y.; Zhang, Z. Neuro-protective effect and mechanism of action of tetramethylpyrazine nitrone for ischemic stroke therapy. Neuromolecular Med., 2018, 20(1), 97-111.
[http://dx.doi.org/10.1007/s12017-018-8478-x] [PMID: 29411248]
[95]
Zhang, T.; Gu, J.; Wu, L.; Li, N.; Sun, Y.; Yu, P.; Wang, Y.; Zhang, G.; Zhang, Z. Neuroprotective and axonal outgrowth-promoting effects of tetramethylpyrazine nitrone in chronic cerebral hypoperfusion rats and primary hippocampal neurons exposed to hypoxia. Neuropharmacology, 2017, 118, 137-147.
[http://dx.doi.org/10.1016/j.neuropharm.2017.03.022] [PMID: 28342896]
[96]
Zhang, G.; Zhang, F.; Zhang, T.; Gu, J.; Li, C.; Sun, Y.; Yu, P.; Zhang, Z.; Wang, Y. Tetramethylpyrazine nitrone improves neurobehavior-al functions and confers neuroprotection on rats with traumatic brain injury. Neurochem. Res., 2016, 41(11), 2948-2957.
[http://dx.doi.org/10.1007/s11064-016-2013-y] [PMID: 27452038]
[97]
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]
[98]
Floyd, R.A. Nitrones as therapeutics in age-related diseases. Aging Cell, 2006, 5(1), 51-57.
[http://dx.doi.org/10.1111/j.1474-9726.2006.00189.x] [PMID: 16441843]
[99]
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]
[100]
Kim, J.H.; Wang, Q.; Choi, J.M.; Lee, S.; Cho, E.J. Protective role of caffeic acid in an Aβ25-35-induced Alzheimer’s disease model. Nutr. Res. Pract., 2015, 9(5), 480-488.
[http://dx.doi.org/10.4162/nrp.2015.9.5.480] [PMID: 26425277]
[101]
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]
[102]
Xu, D.; Chen, H.; Mak, S.; Hu, S.; Tsim, K.W.K.; Hu, Y.; Sun, Y.; Zhang, G.; Wang, Y.; Zhang, Z.; Han, Y. Neuroprotection against gluta-mate-induced excitotoxicity and induction of neurite outgrowth by T-006, a novel multifunctional derivative of tetramethylpyrazine in neuronal cell models. Neurochem. Int., 2016, 99, 194-205.
[http://dx.doi.org/10.1016/j.neuint.2016.07.006] [PMID: 27445088]
[103]
Zhang, G.; Wu, J.; Huang, C.; Cheng, J.; Su, Z.; Zhu, Z.; Yang, X.; Guo, B.; Wu, L.; Zhang, Z.; Zhang, G.; Chen, H.; Sun, Y.; Wang, Y. The tetramethylpyrazine analogue T-006 alleviates cognitive deficits by inhibition of tau expression and phosphorylation in transgenic mice modeling Alzheimer’s Disease. J. Mol. Neurosci., 2021, 71(7), 1456-1466.
[http://dx.doi.org/10.1007/s12031-020-01762-x] [PMID: 33403592]
[104]
Xu, D.; Duan, H.; Zhang, Z.; Cui, W.; Wang, L.; Sun, Y.; Lang, M.; Hoi, P.M.; Han, Y.; Wang, Y.; Lee, S.M. The novel tetramethylpyrazine bis-nitrone (TN-2) protects against MPTP/MPP+-induced neurotoxicity via inhibition of mitochondrial-dependent apoptosis. J. Neuroimmune Pharmacol., 2014, 9(2), 245-258.
[http://dx.doi.org/10.1007/s11481-013-9514-0] [PMID: 24233519]
[105]
Xu, D-P.; Zhang, K.; Zhang, Z-J.; Sun, Y-W.; Guo, B-J.; Wang, Y-Q.; Hoi, P-M.; Han, Y-F.; Lee, S.M-Y. A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-κB and the PKCα/PI3-K/Akt path-ways. Neurochem. Int., 2014, 78, 76-85.
[http://dx.doi.org/10.1016/j.neuint.2014.09.001] [PMID: 25217805]
[106]
Guo, B.; Xu, D.; Duan, H.; Du, J.; Zhang, Z.; Lee, S.M.; Wang, Y. Therapeutic effects of multifunctional tetramethylpyrazine nitrone on models of Parkinson’s disease in vitro and in vivo. Biol. Pharm. Bull., 2014, 37(2), 274-285.
[http://dx.doi.org/10.1248/bpb.b13-00743] [PMID: 24305623]
[107]
Hu, S.; Hu, H.; Mak, S.; Cui, G.; Lee, M.; Shan, L.; Wang, Y.; Lin, H.; Zhang, Z.; Han, Y. On-chip integrated photonic circuits based on two-dimensional materials and hexagonal boron nitride as the optical confinement layer. J. Appl. Phys., 2018, 9, 73-73.
[108]
Wang, P.; Zhang, H.; Chu, F.; Xu, X.; Lin, J.; Chen, C.; Li, G.; Cheng, Y.; Wang, L.; Li, Q.; Zhang, Y.; Lei, H. Synthesis and protective effect of new ligustrazine-benzoic acid derivatives against CoCl2-induced neurotoxicity in differentiated PC12 cells. Molecules, 2013, 18(10), 13027-13042.
[http://dx.doi.org/10.3390/molecules181013027] [PMID: 24145795]
[109]
Zhang, H-N.; An, C-N.; Zhang, H-N.; Pu, X-P. Protocatechuic acid inhibits neurotoxicity induced by MPTP in vivo. Neurosci. Lett., 2010, 474(2), 99-103.
[http://dx.doi.org/10.1016/j.neulet.2010.03.016] [PMID: 20227465]
[110]
Gepdiremen, A.; Hacimüftüoglu, A.; Düzenli, S. Oztaş, S.; Süleyman, H. Effects of salicylic acid in glutamate- and kainic acid-induced neurotoxicity in cerebellar granular cell culture of rats. Pharmacol. Res., 2000, 42(6), 547-551.
[http://dx.doi.org/10.1006/phrs.2000.0717] [PMID: 11058407]
[111]
Singh, J.C.H.; Kakalij, R.M.; Kshirsagar, R.P.; Kumar, B.H.; Komakula, S.S.B.; Diwan, P.V. Cognitive effects of vanillic acid against strep-tozotocin-induced neurodegeneration in mice. Pharm. Biol., 2015, 53(5), 630-636.
[http://dx.doi.org/10.3109/13880209.2014.935866] [PMID: 25472801]
[112]
Li, G.; Li, G.; Tian, Y.; Zhang, Y.; Hong, Y.; Hao, Y.; Chen, C.; Wang, P.; Lei, H. A novel ligustrazine derivative T-VA prevents neurotox-icity in differentiated PC12 cells and protects the brain against ischemia injury in MCAO rats. Int. J. Mol. Sci., 2015, 16(9), 21759-21774.
[http://dx.doi.org/10.3390/ijms160921759] [PMID: 26370988]
[113]
Zhang, H.; Zhang, Y. Proliferative activity and neuroprotective effect of ligustrazine derivative by irritation of vascular endothelial growth factor expression in middle cerebral artery occlusion rats. Trop. J. Pharm. Res., 2016, 15(2), 275-283.
[http://dx.doi.org/10.4314/tjpr.v15i2.8]
[114]
Szwajgier, D.; Borowiec, K.; Pustelniak, K. The neuroprotective effects of phenolic acids: Molecular mechanism of action. Nutrients, 2017, 9(5), E477.
[http://dx.doi.org/10.3390/nu9050477] [PMID: 28489058]
[115]
Zhang, C.; Yan, W.; Zhao, R.; Xu, B.; Fang, X.; Yan, M.; Zhang, Y.; Wang, P.; Lei, H. Design, synthesis and evaluation of new ligustrazine derivatives as potential plasma-stable neuroprotective agents. MedChemComm, 2017, 8(3), 652-656.
[http://dx.doi.org/10.1039/C7MD00003K] [PMID: 30108782]
[116]
Li, G.; Xu, X.; Xu, K.; Chu, F.; Song, J.; Zhou, S.; Xu, B.; Gong, Y.; Zhang, H.; Zhang, Y.; Wang, P.; Lei, H. Ligustrazinyl amides: A novel class of ligustrazine-phenolic acid derivatives with neuroprotective effects. Chem. Cent. J., 2015, 9(1), 9-9.
[http://dx.doi.org/10.1186/s13065-015-0084-5] [PMID: 25810760]
[117]
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]
[118]
Chen, L.; Wei, X.; Hou, Y.; Liu, X.; Li, S.; Sun, B.; Liu, X.; Liu, H. Tetramethylpyrazine analogue CXC195 protects against cerebral is-chemia/reperfusion-induced apoptosis through PI3K/Akt/GSK3β pathway in rats. Neurochem. Int., 2014, 66, 27-32.
[http://dx.doi.org/10.1016/j.neuint.2014.01.006] [PMID: 24462584]
[119]
Wu, W.; Liang, X.; Xie, G.; Chen, L.; Liu, W.; Luo, G.; Zhang, P.; Yu, L.; Zheng, X.; Ji, H.; Zhang, C.; Yi, W. Synthesis and evaluation of novel ligustrazine derivatives as multi-targeted inhibitors for the treatment of Alzheimer’s Disease. Molecules, 2018, 23(10), E2540.
[http://dx.doi.org/10.3390/molecules23102540] [PMID: 30301153]
[120]
Chen, X.; Cui, L.; Duan, X.; Ma, B.; Zhong, D. Pharmacokinetics and metabolism of the flavonoid scutellarin in humans after a single oral administration. Drug Metab. Dispos., 2006, 34(8), 1345-1352.
[http://dx.doi.org/10.1124/dmd.106.009779] [PMID: 16714374]
[121]
Dong, Y.; Zhang, X.; Liu, M.; Yang, Y.; Guo, T.; Mao, Y.; Zhang, J.; Fu, X.; Zhao, Y.; Chen, J.; Dong, L.; Qiao, C. Hybrid molecules of scutellarein and tertramethylpyrazine’s active metabolites for ischemic stroke. Bioorg. Med. Chem. Lett., 2019, 29(19), 126608-126608.
[http://dx.doi.org/10.1016/j.bmcl.2019.08.012] [PMID: 31444086]

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