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Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats

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Summary

Ligustrazine, an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort, has been clinically applied to treat the cerebrovascular diseases. Hyperhomocysteinemia (Hhcy) is an independent risk factor for Alzheimer’s disease (AD). Memory deficits can be caused by Hhcy via pathologies of AD-like tau and amyloid-β (Aβ) in the hippocampus. Here, we investigated whether homocysteine (Hcy) can induce AD-like pathologies and the effects of ligustrazine on these pathologies. The Hcy rat model was constructed by 14-day Hcy injection via vena caudalis, and rats were treated with daily intragastric administration of ligustrazine at the same time. We found that the pathologies of tau and Aβ were induced by Hcy in the hippocampus, while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine treatment. Our data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced AD-like pathologies.

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References

  1. Brookmeyer R, Johnson E, Ziegler-Graham K, et al. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement, 2007,3(3):186–191

    Article  Google Scholar 

  2. Armstrong RA. Plaques and tangles and the pathogenesis of Alzheimer’s disease. Folia Neuropathol, 2006,44(1): 1–11

    CAS  PubMed  Google Scholar 

  3. Portelius E, Zetterberg H, Andreasson U, et al. An Alzheimer’s disease-specific β-amyloid fragment signature in cerebrospinal fluid. Neurosci Lett, 2006,409(3):215–219

    Article  CAS  Google Scholar 

  4. Mendes D, Oliveira MM, Moreira PI, et al. Beneficial effects of white wine polyphenols-enriched diet on Alzheimer’s disease-like pathology. J Nutr Biochem, 2018,55:165–177

    Article  CAS  Google Scholar 

  5. Smith AD. The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull, 2008,29(2 Suppl):S143–S172

    Article  Google Scholar 

  6. Refsum H, Smith AD, Ueland PM, et al. Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem, 2004,50(1):3–32

    Article  CAS  Google Scholar 

  7. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med, 2002,346(7):476–483

    Article  CAS  Google Scholar 

  8. Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol, 1998,55(11):1449–1455

    Article  CAS  Google Scholar 

  9. Hooshmand B, Solomon A, Kareholt I, et al. Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study. Neurology, 2010,75(16): 1408–1414

    Article  CAS  Google Scholar 

  10. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr, 2005,82(3):636–643

    Article  CAS  Google Scholar 

  11. Sun BL, Li WW, Zhu C, et al. Clinical research on Alzheimer’s disease: progress and perspectives. Neurosci Bull, 2018,34(6):1111–1118

    Article  CAS  Google Scholar 

  12. Xu K, Wang PL, Xu X, et al. An overview on structural modifications of ligustrazine and iological evaluation of its synthetic derivatives. Res Chem Intermediat, 2015,41:1385–1411

    Article  CAS  Google Scholar 

  13. Zhang C, Wang SZ, Zuo PP, et al. Protective effect of tetramethylpyrazine on learning and memory function in D-galactose-lesioned mice, Chin Med Sci J, 2004,19(3):180–184

    CAS  PubMed  Google Scholar 

  14. Chen HF, Li GN, Zhan P, et al. Ligustrazine derivatives. Part 5: design, synthesis and biological evaluation of novel ligustrazinyloxy-cinnamic acid derivatives as potent cardiovascular agents. Eur J Med Chem, 2012,46(11): 5609–5615

    Article  Google Scholar 

  15. Zhang T, Gu JB, Wu LM, et al. 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

    Article  CAS  Google Scholar 

  16. Lu C, Zhang J, Shi XP, et al. 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

    Article  Google Scholar 

  17. So EC, Wong KL, Huang TC, et al. Tetramethylpyrazine protects mice against thioacetamide-induced acute hepatotoxicity. J Biomed Sci, 2002,9(5):410–414

    Article  CAS  Google Scholar 

  18. Zhu XL, Xiong LZ, Wang Q, et al. Therapeutic time window and mechanism of tetramethylpyrazine on transient focal cerebral ischemia/reperfusion injury in rats. Neurosci Lett, 2009,449(1):24–27

    Article  CAS  Google Scholar 

  19. Fan LH, Wang KZ, Cheng B, et al. Anti-apoptotic and neuroprotective effects of tetramethylpyrazine following spinal cord ischemia in rabbits. BMC Neurosci, 2006,7:48

    Article  Google Scholar 

  20. Cheng XR, Zhang L, Hu JJ, et al. Neuroprotective effects of tetramethylpyrazine on hydrogen peroxide-induced apoptosis in PC12 cells. Cell Biol Int, 2007,31(5):438–443

    Article  CAS  Google Scholar 

  21. Zhao TF, Fu YX, Sun H, et al. 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

    Article  CAS  Google Scholar 

  22. Singh C, Liu LF, Wang JM, et al. Allopregnanolone restores hippocampal-dependent learning and memory and neural progenitor survival in aging 3xTg AD and nonTg mice. Neurobiol Aging, 2012,33(8):1493–1506

    Article  CAS  Google Scholar 

  23. Brion JP, Couck AM, Conreur JL. Calcineurin (phosphatase 2B) is present in neurons containing neurofibrillary tangles and in a subset of senile plaques in Alzheimer’s disease. Neurodegeneration, 1995,4(1):13–21

    Article  CAS  Google Scholar 

  24. Minthon L, Hesse C, Sjogren M, et al. The apolipoprotein E epsilon4 allele frequency is normal in fronto-temporal dementia, but correlates with age at onset of disease. Neurosci Lett, 1997,226(1):65–67

    Article  CAS  Google Scholar 

  25. Takahashi M, Tsujioka Y, Yamada T, et al. Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain. Acta Neuropathol, 1999,97(6):635–641

    Article  CAS  Google Scholar 

  26. Janus C, Phinney AL, Chishti MA, et al. New developments in animal models of Alzheimer’s disease. Curr Neurol Neurosci Rep, 2001,1(5):451–457

    Article  CAS  Google Scholar 

  27. Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med, 2014,370(4):311–321

    Article  CAS  Google Scholar 

  28. Zhao L, Wei M, He M, et al. The effects of tetramethylpyrazine on learning and memory abilities of mice with Alzheimer disease and its possible mechanism. Chin Pharmacol Bull, 2008,24(8):1088–1092

    CAS  Google Scholar 

  29. Shi J, Wang YM, Luo GA. Ligustrazine phosphate ethosomes for treatment of Alzheimer’s Disease, in vitro and in animal model studies. AAPS PharmSciTech, 2012,13(2):485–492

    Article  CAS  Google Scholar 

  30. Tan F, Fu WJ, Cheng NF, et al. Ligustrazine reduces blood-brain barrier permeability in a rat model of focal cerebral ischemia and reperfusion. Exp Ther Med, 2015,9(5):1757–1762

    Article  Google Scholar 

  31. Qi CF, Liu Y, Zhang JS, et al. Effect of ligustrazine on nNOS expression and neuranagenesis in adult rats after cerebral ischemia-reperfusion injury. Nan Fang Yi Ke Da Xue Xue Bao (Chinese), 2007,27(6):771–774

    CAS  Google Scholar 

  32. Obeid R, Herrmann W. Mechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett, 2006,580(13):2994–3005

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Neurological Diseases, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Qing Zhang & Lin-xiao Wang

  2. Department of Pediatrics, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Jing Wang

  3. Department of Anesthesiology, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Liang Zhu

  4. Department of Orthopedics, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Shi-jie Jiang

  5. Department of Endocrinology, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213003, China

    Juan Liu

  6. Department of General Surgery, the Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, 213000, China

    Xi-hu Qin

Authors
  1. Qing Zhang
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  2. Jing Wang
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  3. Liang Zhu
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  4. Shi-jie Jiang
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  5. Juan Liu
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  6. Lin-xiao Wang
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  7. Xi-hu Qin
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Corresponding authors

Correspondence to Lin-xiao Wang or Xi-hu Qin.

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All authors declare no conflicts of interest.

Additional information

This project was supported by grants from Changzhou Sci & Tech Program (No. CJ20190063, No. CJ20200090), Young Talent Development Plan of Changzhou Health Commission (No. CZQM2020078, and No. CZQM2020063), China Postdoctoral Science Foundation (No. 2020M670012ZX), National Natural Science Foundation of China (No. 81803498), Jiangsu Planned Projects for Postdoctoral Research Funds (No. 2019K157), and “Mass Entrepreneurship and Innovation Plan” of Jiangsu Province (No. QT201919).

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Zhang, Q., Wang, J., Zhu, L. et al. Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats. CURR MED SCI 41, 548–554 (2021). https://doi.org/10.1007/s11596-021-2379-1

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  • DOI: https://doi.org/10.1007/s11596-021-2379-1

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