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Quantitative imaging of natural products in fine brain regions using desorption electrospray ionization mass spectrometry imaging (DESI-MSI): Uncaria alkaloids as a case study

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Abstract

Uncaria species (Rubiaceae) are used as traditional Chinese medicines (TCMs) to treat central nervous system (CNS) diseases, and monoterpene indole alkaloids are the main bioactive constituents. Localization and quantification of CNS drugs in fine brain regions are important to provide insights into their pharmacodynamics, for which quantitative mass spectrometry imaging (MSI) has emerged as a powerful technique. A systematic study of the quantitative imaging of seven Uncaria alkaloids in rat brains using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) was presented. The distribution of the alkaloids in thirteen brain regions was quantified successfully using the calibration curves generated by a modified on-tissue approach. The distribution trend of different Uncaria alkaloids in the rat brain was listed as monoterpene indole alkaloids > monoterpene oxindole alkaloids, R-configuration epimers > S-configuration epimers. Particularly, Uncaria alkaloids were detected directly in the pineal gland for the first time and their enrichment phenomenon in this region had an instructive significance in future pharmacodynamic studies.

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References

  1. Hsieh CL, Chen MF, Li TC, Li SC, Tang NY, Hsieh CT, et al. Anticonvulsant effect of Uncaria rhynchophylla (Miq) Jack. in rats with kainic acid-induced epileptic seizure. Am J Chin Med. 1999;27(2):257–64.

    Article  CAS  PubMed  Google Scholar 

  2. Huang H, Zhong R, Xia Z, Song J, Feng L. Neuroprotective effects of rhynchophylline against ischemic brain injury via regulation of the Akt/mTOR and TLRs signaling pathways. Molecules. 2014;19(8):11196–210.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Watanabe H, Zhao Q, Matsumoto K, Tohda M, Murakami Y, Zhang SH, et al. Pharmacological evidence for antidementia effect of Choto-san (Gouteng-san), a traditional Kampo medicine. Pharmacol Biochem Behav. 2003;75(3):635–43.

    Article  CAS  PubMed  Google Scholar 

  4. Niu Y, Li F, Inada C, Tanaka K, Watanabe S, Fujiwara H, et al. Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia. J Pharm Biomed Anal. 2015;104:21–30.

    Article  CAS  PubMed  Google Scholar 

  5. Shao H, Yang Y, Mi Z, Zhu GX, Qi AP, Ji WG, et al. Anticonvulsant effect of rhynchophylline involved in the inhibition of persistent sodium current and NMDA receptor current in the pilocarpine rat model of temporal lobe epilepsy. Neuroscience. 2016;337:355–69.

    Article  CAS  PubMed  Google Scholar 

  6. Ho TY, Tang NY, Hsiang CY, Hsieh CL. Uncaria rhynchophylla and rhynchophylline improved kainic acid-induced epileptic seizures via IL-1β and brain-derived neurotrophic factor. Phytomedicine. 2014;21(6):893–900.

    Article  CAS  PubMed  Google Scholar 

  7. Zhu W, Zhang Y, Huang Y, Lu L. Chinese herbal medicine for the treatment of drug addiction. Int Rev Neurobiol. 2017;135:279–95.

    Article  PubMed  Google Scholar 

  8. Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, et al. Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer’s beta-amyloid proteins. J Neurosci Res. 2006;84(2):427–33.

    Article  CAS  PubMed  Google Scholar 

  9. Li HQ, Ip SP, Yuan QJ, Zheng GQ, Tsim KKW, Dong TTX, et al. Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: studies in a transgenic mouse model of Alzheimer’s disease. Brain Behav Immun. 2019;82:264–78.

    Article  CAS  PubMed  Google Scholar 

  10. Xian YF, Mao QQ, Wu JC, Su ZR, Chen JN, Lai XP, et al. Isorhynchophylline treatment improves the amyloid-β-induced cognitive impairment in rats via inhibition of neuronal apoptosis and tau protein hyperphosphorylation. Journal of Alzheimer’s disease: JAD. 2014;39(2):331–46.

    Article  CAS  PubMed  Google Scholar 

  11. Qiao YL, Zhou JJ, Liang JH, Deng XP, Zhang ZJ, Huang HL, et al. Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT(1A) receptor: insights from transcriptomics. Phytomedicine: international journal of phytotherapy and phytopharmacology. 2021;81: 153436.

    Article  CAS  Google Scholar 

  12. Ikarashi Y, Sekiguchi K, Mizoguchi K. Serotonin receptor binding characteristics of geissoschizine methyl ether, an indole alkaloid in Uncaria hook. Curr Med Chem. 2018;25(9):1036–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Orlando G, Chiavaroli A, Leone S, Brunetti L, Politi M, Menghini L, et al. Inhibitory effects induced by Vicia faba, Uncaria rhyncophylla, and Glycyrrhiza glabra water extracts on oxidative stress biomarkers and dopamine turnover in HypoE22 cells and isolated rat striatum challenged with 6-hydroxydopamine. Antioxidants (Basel). 2019;8(12):602.

  14. Zheng M, Chen M, Liu C, Fan Y, Shi D. Alkaloids extracted from Uncaria rhynchophylla demonstrate neuroprotective effects in MPTP-induced experimental parkinsonism by regulating the PI3K/Akt/mTOR signaling pathway. J Ethnopharmacol. 2021;266: 113451.

    Article  CAS  PubMed  Google Scholar 

  15. Gao L, Zhang Z, Feng Z, Wei W, Wu W, Zhi H, et al. Fast determination of 16 circulating neurotransmitters and their metabolites in plasma samples of spontaneously hypertensive rats intervened with five different Uncaria. J Chromatogr B Analyt Technol Biomed Life Sci. 2021;1179: 122856.

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Q, Zhao JJ, Xu J, Feng F, Qu W. Medicinal uses, phytochemistry and pharmacology of the genus Uncaria. J Ethnopharmacol. 2015;173:48–80.

    Article  CAS  PubMed  Google Scholar 

  17. Yang W, Ip SP, Liu L, Xian YF, Lin ZX. Uncaria rhynchophylla and its major constituents on central nervous system: a review on their pharmacological actions. Curr Vasc Pharmacol. 2020;18(4):346–57.

    Article  CAS  PubMed  Google Scholar 

  18. Hou J, Feng R, Zhang Y, Pan H, Yao S, Han S, et al. Characteristic chromatogram: a method of discriminate and quantitative analysis for quality evaluation of Uncaria stem with hooks. Planta Med. 2018;84(6–07):449–56.

    CAS  PubMed  Google Scholar 

  19. Zhang YN, Yang YF, Xu W, Yang XW. The blood-brain barrier permeability of six indole alkaloids from Uncariae Ramulus Cum Uncis in the MDCK-pHaMDR cell monolayer model. Molecules. 2017;22(11):1944.

    Article  PubMed Central  CAS  Google Scholar 

  20. Kushida H, Fukutake M, Tabuchi M, Katsuhara T, Nishimura H, Ikarashi Y, et al. Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria hook in rat plasma and brain after oral administration of the traditional Japanese medicine Yokukansan using high-performance liquid chromatography with tandem mass spectrometry. Biomed Chromatogr. 2013;27(12):1647–56.

    Article  CAS  PubMed  Google Scholar 

  21. Zhou Q, Ma J, Chen L. Tissue distribution of hirsutine and hirsuteine in mice by ultrahigh-performance liquid chromatography-mass spectrometry. J Anal Methods Chem. 2020;2020:7204315.

    PubMed  PubMed Central  Google Scholar 

  22. Wang W, Ma CM, Hattori M. Metabolism and pharmacokinetics of rhynchophylline in rats. Biol Pharm Bull. 2010;33(4):669–76.

    Article  CAS  PubMed  Google Scholar 

  23. Zhang C, Wu X, Xian Y, Zhu L, Lin G, Lin ZX. Evidence on integrating pharmacokinetics to find truly therapeutic agent for Alzheimer’s disease: comparative pharmacokinetics and disposition kinetics profiles of stereoisomers isorhynchophylline and rhynchophylline in rats. Evid Based Complement Alternat Med. 2019;2019:4016323.

    PubMed  PubMed Central  Google Scholar 

  24. Wang W, Luo S, Chen Y, Li B, Hattori M. Effective separation and simultaneous determination of corynoxeine and its metabolites in rats by high-performance liquid chromatography with tandem mass spectrometry and application to pharmacokinetics and in vivo distribution in main organs. Anal Sci. 2016;32(6):705–7.

    Article  CAS  PubMed  Google Scholar 

  25. Wang J, Qi P, Hou J, Shen Y, Yang M, Bi Q, et al. The profiling of the metabolites of hirsutine in rat by ultra-high performance liquid chromatography coupled with linear ion trap Orbitrap mass spectrometry: an improved strategy for the systematic screening and identification of metabolites in multi-samples in vivo. J Pharm Biomed Anal. 2017;134:149–57.

    Article  CAS  PubMed  Google Scholar 

  26. Tian X, Xu Z, Chen M, Hu P, Liu F, Sun Z, et al. Simultaneous determination of eight bioactive compounds by LC-MS/MS and its application to the pharmacokinetics, liver first-pass effect, liver and brain distribution of orally administrated Gouteng-Baitouweng (GB) in rats. J Chromatogr B Analyt Technol Biomed Life Sci. 2018;1084:122–31.

    Article  CAS  PubMed  Google Scholar 

  27. Bourasset F, Auvity S, Thorne RG, Scherrmann JM. Brain distribution of drugs: brain morphology, delivery routes, and species differences. In: Handbook of experimental pharmacology. Berlin, Heidelberg: Springer; 2021. pp. 1–24.

  28. Ntshangase S, Mdanda S, Naicker T, Kruger HG, Baijnath S, Govender T. Spatial distribution of elvitegravir and tenofovir in rat brain tissue: application of matrix-assisted laser desorption/ionization mass spectrometry imaging and liquid chromatography/tandem mass spectrometry. Rapid communications in mass spectrometry : RCM. 2019;33(21):1643–51.

    Article  CAS  PubMed  Google Scholar 

  29. Buchberger AR, DeLaney K, Johnson J, Li L. Mass spectrometry imaging: a review of emerging advancements and future insights. Anal Chem. 2018;90(1):240–65.

    Article  CAS  PubMed  Google Scholar 

  30. Trim PJ, Snel MF. Small molecule MALDI MS imaging: current technologies and future challenges. Methods (San Diego, Calif). 2016;104:127–41.

    Article  CAS  Google Scholar 

  31. Lietz CB, Gemperline E, Li L. Qualitative and quantitative mass spectrometry imaging of drugs and metabolites. Adv Drug Deliv Rev. 2013;65(8):1074–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Prideaux B, Stoeckli M. Mass spectrometry imaging for drug distribution studies. J Proteomics. 2012;75(16):4999–5013.

    Article  CAS  PubMed  Google Scholar 

  33. Shariatgorji M, Strittmatter N, Nilsson A, Källback P, Alvarsson A, Zhang X, et al. Simultaneous imaging of multiple neurotransmitters and neuroactive substances in the brain by desorption electrospray ionization mass spectrometry. Neuroimage. 2016;136:129–38.

    Article  CAS  PubMed  Google Scholar 

  34. Matsumoto T, Ikarashi Y, Takiyama M, Watanabe J, Setou M. Brain distribution of geissoschizine methyl ether in rats using mass spectrometry imaging analysis. Sci Rep. 2020;10(1):7293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tobias F, Hummon AB. Considerations for MALDI-based quantitative mass spectrometry imaging studies. J Proteome Res. 2020;19(9):3620–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Unsihuay D, Mesa Sanchez D, Laskin J. Quantitative mass spectrometry imaging of biological systems. Annu Rev Phys Chem. 2021;72:307–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bo M. Rhynchophylline in rat blood by high-performance liquid chromatography-coupled microdialysis. J Med Plants Res. 2012;6(15):2977–84.

    Google Scholar 

  38. Wang W, Ma CM, Hattori M. Metabolism of isorhynchophylline in rats detected by LC-MS. J Pharm Pharm Sci: a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques. 2010;13(1):27–37.

    Article  CAS  Google Scholar 

  39. Imamura S, Tabuchi M, Kushida H, Nishi A, Kanno H, Yamaguchi T, et al. The blood-brain barrier permeability of geissoschizine methyl ether in Uncaria hook, a galenical constituent of the traditional Japanese medicine yokukansan. Cell Mol Neurobiol. 2011;31(5):787–93.

    Article  CAS  PubMed  Google Scholar 

  40. O’Brien JS, Fillerup DL, Mead JF. Brain lipids: I. Quantification and fatty acid composition of cerebroside sulfate in human cerebral gray and white matter. J Lipid Res. 1964;5:109–16.

    Article  PubMed  Google Scholar 

  41. O’Brien JS, Sampson EL. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J Lipid Res. 1965;6(4):537–44.

    Article  PubMed  Google Scholar 

  42. Rzagalinski I, Kovačević B, Hainz N, Meier C, Tschernig T, Volmer DA. Toward higher sensitivity in quantitative MALDI imaging mass spectrometry of CNS drugs using a nonpolar matrix. Anal Chem. 2018;90(21):12592–600.

    Article  CAS  PubMed  Google Scholar 

  43. Ali T, Rahman SU, Hao Q, Li W, Liu Z, Ali Shah F, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res. 2020;69(2): e12667.

    Article  CAS  PubMed  Google Scholar 

  44. Song J. Pineal gland dysfunction in Alzheimer’s disease: relationship with the immune-pineal axis, sleep disturbance, and neurogenesis. Mol Neurodegener. 2019;14(1):28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Yoo JH, Ha T-W, Hong JT, Oh K-W. Rhynchophylline, one of major constituents of Uncariae Ramulus et Uncus enhances pentobarbital-induced sleep behaviors and rapid eye movement sleep in rodents. Nps. 2016;22(4):263–9.

    CAS  Google Scholar 

  46. Shi JS, Huang B, Wu Q, Ren RX, Xie XL. Effects of rhynchophylline on motor activity of mice and serotonin and dopamine in rat brain. Zhongguo yao li xue bao = Acta pharmacologica Sinica. 1993;14(2):114–7.

    CAS  PubMed  Google Scholar 

  47. Sakakibara I, Terabayashi S, Kubo M, Higuchi M, Komatsu Y, Okada M, et al. Effect on locomotion of indole alkaloids from the hooks of uncaria plants. Phytomedicine : international journal of phytotherapy and phytopharmacology. 1999;6(3):163–8.

    Article  CAS  Google Scholar 

  48. Quílez AM, Saenz MT, García MD. Uncaria tomentosa (Willd. ex. Roem. & Schult.) DC. and Eucalyptus globulus Labill. interactions when administered with diazepam. Phytotherapy research: PTR. 2012;26(3):458–61.

    PubMed  Google Scholar 

  49. Sun Y-z, Liu R. Therapeutic evaluation on needling method of regulating the conception vessel and calming the mind for perimenopausal sleep disorder. J Acupunct Tuina Sci. 2013;11(3):142–6.

    Article  Google Scholar 

  50. Pan W, Kwak S, Li G, Chen Y, Cai D. Therapeutic effect of Yang-Xue-Qing-Nao granules on sleep dysfunction in Parkinson’s disease. Chin Med. 2013;8:14.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Aizawa R, Kanbayashi T, Saito Y, Ogawa Y, Sugiyama T, Kitajima T, et al. Effects of Yoku-kan-san-ka-chimpi-hange on the sleep of normal healthy adult subjects. Psychiatry Clin Neurosci. 2002;56(3):303–4.

    Article  PubMed  Google Scholar 

  52. Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids and barriers of the CNS. 2011;8(1):7.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Shimada Y, Goto H, Itoh T, Sakakibara I, Kubo M, Sasaki H, et al. Evaluation of the protective effects of alkaloids isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death in cultured cerebellar granule cells from rats. J Pharm Pharmacol. 1999;51(6):715–22.

    Article  CAS  PubMed  Google Scholar 

  54. Wu W, Zhang Z, Li F, Deng Y, Lei M, Long H, et al. A network-based approach to explore the mechanisms of Uncaria alkaloids in treating hypertension and alleviating Alzheimer’s disease. Int J Mol Sci. 2020;21(5):1766.

    Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

We thank Ms. Jing Huang in Waters Corporation for cooperation support. We thank Wei Rao, Emmanuelle Claude, Jonathan P. Willams, Mark Towers, Philippa Hart, and Yanchao Shi in Waters Corporation for the technical support. We also thank Professor Emeritus Geoffrey A. Cordell for editorial contributions in reviewing the manuscript.

Funding

This research was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82003915 and 82003939).

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Author notes

  1. Lei Gao and Zijia Zhang contributed equally to this work

Authors and Affiliations

  1. Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Laboratory for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Lei Gao, Zijia Zhang, Wenyong Wu, Yanping Deng, Haijuan Zhi, Huali Long, Min Lei, Jinjun Hou, Wanying Wu & De-an Guo

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Lei Gao, Wanying Wu & De-an Guo

  3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China

    Wenyong Wu

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  1. Lei Gao
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Contributions

Lei Gao: conceptualization, methodology, software, writing—original draft, data curation, validation, formal analysis, investigation, visualization. Zijia Zhang: conceptualization, methodology, visualization, resources, writing—review and editing, funding acquisition. Wenyong Wu: methodology, software, validation. Yanping Deng: resources. Haijuan Zhi: resources, funding acquisition. Huali Long: resources. Min Lei: resources, validation. Jinjun Hou: conceptualization, methodology, software, validation, writing—review and editing, project administration, funding acquisition. Wanying Wu: resources, supervision, writing—review and editing, project administration, funding acquisition. De-an Guo: resources, supervision, writing—review and editing.

Corresponding authors

Correspondence to Jinjun Hou or Wanying Wu.

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Ethics approval

The use of laboratory animals and all study protocols were approved by the Institutional Animal Care and Use Committee at the Chinese Academy of Sciences Shanghai Institute of Materia Medica.

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Male Wistar rats (200 ± 20 g) were purchased from the SLAC Lab Animal Center (Shanghai, China).

Statement on animal welfare

The management and use of animals during the experiment comply with the relevant regulations of “Guide for the Care and Use of Laboratory Animals issued by the National Research Council of the United States (2010),” “Regulations for the administration of affairs concerning laboratory animals (2017)” issued by the Science and Technology Commission of China, and the relevant regulations provided by the Institutional Animal Care and Use Committee at the Chinese Academy of Sciences Shanghai Institute of Materia Medica.

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Gao, L., Zhang, Z., Wu, W. et al. Quantitative imaging of natural products in fine brain regions using desorption electrospray ionization mass spectrometry imaging (DESI-MSI): Uncaria alkaloids as a case study. Anal Bioanal Chem 414, 4999–5007 (2022). https://doi.org/10.1007/s00216-022-04130-3

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