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Geissoschizine Methyl Ether, an Alkaloid from the Uncaria Hook, Improves Remyelination After Cuprizone-Induced Demyelination in Medial Prefrontal Cortex of Adult Mice

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Abstract

Accumulating evidence indicates that the medial prefrontal cortex (mPFC) is a site of myelin and oligodendrocyte abnormalities that contribute to psychotic symptoms of schizophrenia. The development of therapeutic approaches to enhance remyelination, a regenerative process in which new myelin sheaths are formed on demyelinated axons, may be an attractive remedial strategy. Geissoschizine methyl ether (GM) in the Uncaria hook, a galenical constituent of the traditional Japanese medicine yokukansan (Yi-gan san), is one of the active components responsible for the psychotropic effects of yokukansan, though little is known about the mechanisms underlying the effects of either that medicine or GM itself. In the present study, we employed a cuprizone (CPZ)-induced demyelination model and examined the cellular changes in response to GM administration during the remyelination phase in the mPFC of adult mice. Using the mitotic marker 5-bromo-2′-deoxyuridine (BrdU), we demonstrated that CPZ treatment significantly increased the number of BrdU-positive NG2 cells, as well as microglia and mature oligodendrocytes in the mPFC. Newly formed oligodendrocytes were increased by GM administration after CPZ exposure. In addition, GM attenuated a decrease in myelin basic protein immunoreactivity caused by CPZ administration. Taken together, our findings suggest that GM administration ameliorated the myelin deficit by mature oligodendrocyte formation and remyelination in the mPFC of CPZ-fed mice. The present findings provide experimental evidence supporting the role for GM and its possible use as a remedy for schizophrenia symptoms by promoting the differentiation of progenitor cells to and myelination by oligodendrocytes.

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Abbreviations

BrdU:

5-Bromo-2′-deoxyuridine

CPZ:

Cuprizone

GM:

Geissoschizine methyl ether

GS:

Glutamine synthetase

GSTpi:

Glutathione S-transferase-pi

MBP:

Myelin basic protein

mPFC:

Medial prefrontal cortex

NF:

Neurofilament

PB:

Phosphate buffer

PBS:

Phosphate-buffered saline

PBST:

PBS containing 0.3 % Triton X-100

References

  1. Baumann N, Pham-Dinh D (2001) Biology of oligodendrocyte and myelin in the mammalian central nervous system. Physiol Rev 81:871–927

    CAS  PubMed  Google Scholar 

  2. Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Buxbaum J, Haroutunian V (2003) White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen Psychiatry 60:443–456

    Article  PubMed  Google Scholar 

  3. Hof PR, Haroutunian V, Copland C, Davis KL, Buxbaum JD (2002) Molecular and cellular evidence for an oligodendrocyte abnormality in schizophrenia. Neurochem Res 27:1193–1200

    Article  CAS  PubMed  Google Scholar 

  4. Uranova NA, Vostrikov VM, Orlovskaya DD, Rachmanova VI (2004) Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res 67:269–275

    Article  PubMed  Google Scholar 

  5. Buchanan RW, Vladar K, Barta PE, Pearlson GD (1998) Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 155:1049–1055

    CAS  PubMed  Google Scholar 

  6. Buchsbaum MS, Hazlett EA (1998) Positron emission tomography studies of abnormal glucose metabolism in schizophrenia. Schizophr Bull 24:343–364

    Article  CAS  PubMed  Google Scholar 

  7. Makinodan M, Rosen KM, Ito S, Corfas G (2012) A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science 337:1357–1360

    Article  CAS  PubMed  Google Scholar 

  8. Franklin RJ, Ffrench-Constant C (2008) Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9:839–855

    Article  CAS  PubMed  Google Scholar 

  9. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N Engl J Med 346:165–173

    Article  PubMed  Google Scholar 

  10. Bagnall AM, Jones L, Ginnelly L, Lewis R, Glanville J, Gilbody S, Davies L, Torgerson D, Kleijnen J (2003) A systematic review of atypical antipsychotic drugs in schizophrenia. Health Technol Assess 7:1–193

    PubMed  Google Scholar 

  11. Iizuka S, Kawakami Z, Imamura S, Yamaguchi T, Sekiguchi K, Kanno H, Ueki T, Kase Y, Ikarashi Y (2010) Electron-microscopic examination of effects of yokukansan, a traditional Japanese medicine, on degeneration of cerebral cells in thiamine-deficient rats. Neuropathology 30:524–536

    Google Scholar 

  12. Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M, Tomita N, Tanji H, Fujiwara H, Seki T, Fujii M, Arai H, Sasaki H (2005) A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J Clin Psychiatry 66:248–252

    Article  PubMed  Google Scholar 

  13. Miyaoka T, Furuya M, Yasuda H, Hayashia M, Inagaki T, Horiguchi J (2008) Yi-gan san for the treatment of borderline personality disorder: an open label study. Progress Neuropsychopharmacol Biol Psychiatry 32:150–154

    Article  Google Scholar 

  14. Miyaoka T, Furuya M, Kristian L, Wake R, Kawakami K, Nagahama M, Kawano K, Ieda M, Tsuchie K, Horiguchi J (2008) Yi-Gan San for the treatment of neuroleptic-induced tardive dyskinesia: an open-label study. Progress Neuropsychopharmacol Biol Psychiatry 32:761–764

    Article  CAS  Google Scholar 

  15. Miyaoka T, Furuya M, Yasuda H, Hayashida M, Nishida A, Inagaki T, Horiguchi J (2008) Yi-gan san as adjunctive therapy for treatment-resistant schizophrenia: an open-label study. Clin Neuropharmacol 32:6–9

    Article  Google Scholar 

  16. Ueda T, Ugawa S, Ishida Y, Shimada S (2011) Geissoschizine methyl ether has third-generation antipsychotic-like actions at the dopamine and serotonin receptors. Eur J Pharmacol 671:79–86

    Article  CAS  PubMed  Google Scholar 

  17. Nishi A, Yamaguchi T, Sekiguchi K, Imamura S, Tabuchi M, Kanno H, Nakai Y, Hashimoto K, Ikarashi Y, Kase Y (2012) Geissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin 1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan. Neuroscience 207:124–136

    Article  CAS  PubMed  Google Scholar 

  18. Franco-Pons N, Torrente M, Colomina MT, Vilella E (2007) Behavioral deficits in the cuprizone-induced murine model of demyelination/remyelination. Toxicol Lett 169:205–213

    Article  CAS  PubMed  Google Scholar 

  19. Xu H, Yang HJ, Clough RW, Browning RA, Zhang Y, Li XM (2009) Behavioral and neurobiological changes in C57BL/6 mice exposed to cuprizone. Behav Neurosci 123:418–429

    Article  CAS  PubMed  Google Scholar 

  20. Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118:723–736

    Article  PubMed  Google Scholar 

  21. Makinodan M, Yamauchi T, Tatsumi K, Okuda H, Takeda T, Kiuchi K, Sadamatsu M, Wanaka A, Kishimoto T (2009) Demyelination in the juvenile period, but not in adulthood, leads to long-lasting cognitive impairment and deficient social interaction in mice. Prog Neuropsychopharmacol Biol Psychiatry 33:978–985

    Article  CAS  PubMed  Google Scholar 

  22. Matsushima GK, Morell P (2001) The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol 11:107–116

    Article  CAS  PubMed  Google Scholar 

  23. Buffo A, Vosko MR, Ertürk D, Hamann GF, Jucker M, Rowitch D, Götz M (2005) Expression pattern of the transcription factor Olig2 in response to brain injuries: implications for neuronal repair. Proc Natl Acad Sci USA 102:18183–18188

    Article  CAS  PubMed  Google Scholar 

  24. Morita S, Oohira A, Miyata S (2010) Activity-dependent remodeling of chondroitin sulfate proteoglycans extracellular matrix in the hypothalamo-neurohypophysial system. Neuroscience 166:1068–1082

    Article  CAS  PubMed  Google Scholar 

  25. Morita S, Ukai S, Miyata S (2013) VEGF-dependent continuous angiogenesis in the median eminence of adult mice. Eur J Neurosci 37:508–518

    Article  CAS  PubMed  Google Scholar 

  26. Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic Press, San Diego

    Google Scholar 

  27. Keirstead HS, Blakemore WF (1999) The role of oligodendrocytes and oligodendrocyte progenitors in CNS remyelination. Adv Exp Med Biol 468:183–197

    Article  CAS  PubMed  Google Scholar 

  28. Islam MS, Tatsumi K, Okuda H, Shiosaka S, Wanaka A (2009) Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions. Neurochem Int 54:192–198

    Article  CAS  PubMed  Google Scholar 

  29. Kotter MR, Li WW, Zhao C, Franklin RJ (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332

    Article  CAS  PubMed  Google Scholar 

  30. Madsen TM, Yeh DD, Valentine GW, Duman RS (2005) Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex. Neuropsychopharmacology 30:27–34

    Article  PubMed  Google Scholar 

  31. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP (2001) TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 4:1116–1122

    Article  CAS  PubMed  Google Scholar 

  32. Hiremath MM, Saito Y, Knapp GW, Ting JP, Suzuki K, Matsushima GK (1998) Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice. J Neuroimmunol 92:38–49

    Article  CAS  PubMed  Google Scholar 

  33. Mizukami K, Asada T, Kinoshita T, Tanaka K, Sonohara K, Nakai R, Yamaguchi K, Hanyu H, Kanaya K, Takao T, Okada M, Kudo S, Kotoku H, Iwakiri M, Kurita H, Miyamura T, Kawasaki Y, Omori K, Shiozaki K, Odawara T, Suzuki T, Yamada S, Nakamura Y, Toba K (2009) A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol 12:191–199

    Article  CAS  PubMed  Google Scholar 

  34. Monji A, Takita M, Samejima T, Takaishi T, Hashimoto K, Matsunaga H, Oda M, Sumida Y, Mizoguchi Y, Kato T, Horikawa H, Kanba S (2009) Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 33:308–311

    Article  CAS  PubMed  Google Scholar 

  35. Shinno H, Utani E, Okazaki S, Kawamukai T, Yasuda H, Inagaki T, Inami Y, Horiguchi J (2007) Successful treatment with Yi-Gan San for psychosis and sleep disturbance in a patient with dementia with Lewy bodies. Progress Neuropsychopharmacol Biol Psychiatry 31:1543–1545

    Article  Google Scholar 

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Acknowledgments

Support for this study and the GM was provided by Tsumura Research Laboratory, Tsumura & Co., Ibaraki, Japan. The work was also supported in part by Scientific Research Grants from the Japan Society for the Promotion of Science (No. 23590221 to A. Wanaka and No. 23500416 to K. Tatsumi). The anti-NF and anti-CD31 hybridoma was obtained from the DSHB, developed under the auspices of the National Institute of Child Health, and Human Development and maintained by the University of Iowa.

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Authors and Affiliations

  1. Department of Anatomy and Neuroscience, Faculty of Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Shoko Morita, Kouko Tatsumi, Hiroaki Okuda & Akio Wanaka

  2. Department of Psychiatry, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan

    Manabu Makinodan & Toshifumi Kishimoto

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  1. Shoko Morita
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  2. Kouko Tatsumi
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  3. Manabu Makinodan
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  4. Hiroaki Okuda
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  6. Akio Wanaka
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Correspondence to Shoko Morita.

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Morita, S., Tatsumi, K., Makinodan, M. et al. Geissoschizine Methyl Ether, an Alkaloid from the Uncaria Hook, Improves Remyelination After Cuprizone-Induced Demyelination in Medial Prefrontal Cortex of Adult Mice. Neurochem Res 39, 59–67 (2014). https://doi.org/10.1007/s11064-013-1190-1

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