Skip to main content
SpringerLink
Log in

A possible role of transthyretin in the biological mechanism of regulatory peptide neuroprotection

  • Reviews
  • Published:
Molecular Genetics, Microbiology and Virology Aims and scope Submit manuscript

Abstract

The peptide preparation semax has been effectively used for therapy of ischemic stroke. However, the mechanisms of its action are insufficiently understood and actively studied. The full-genome analysis of the transcriptome carried out in our recent work demonstrated that under conditions of focal ischemia of rat brain the semax modified the profile of the transcription activity of many genes. In this case, the difference in the transcription levels of the gene encoding the protein transthyretin (Ttr) expression in rats under the pathological conditions of ischemia and in the presence of semax was very high. A high similarity between the effects of Ttr and coupled molecular systems with the semax effects in ischemic stroke allowed us to suggest that the neuroprotection mechanisms of semax (and, possibly, of other neuroprotection mechanisms of semax) may be mediated by Ttr. In this review, we discuss the role of Ttr in the central nervous system and its possible role in the neuroprotection mechanism of semax.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Silachev, D.N., Shram, S.I., Shakova, F.M., Romanova, G.A., and Myasoedov, N.F., Formation of spatial memory in rats with ischemic lesions to the prefron-tal cortex; effects of a synthetic analog of ACTH (4-7), Neurosci. Behav. Physiol., 2009, vol. 39, pp. 749–756.

    Article  CAS  PubMed  Google Scholar 

  2. Romanova, G.A., Silachev, D.N., Shakova, F.M., Kvashennikova, Y.N., Viktorov, I.V., Shram, S.I., et al., Neuroprotective and antiamnesic effects of Semax during experimental ischemic infarction of the cerebral cortex, Bull. Exp. Biol. Med., 2006, vol. 142, pp. 663–666.

    Article  CAS  PubMed  Google Scholar 

  3. Kaplan, A.Ya., Koshelev, V.B., Nezavibat’ko, V.N., and Ashmarin, I.P., The way to increase an organism resistance against hypoxia with the help of neuropeptide drug semax, Fiziol. Chel., 1992, vol. 18, no. 9, pp. 104–107.

    CAS  Google Scholar 

  4. Gusev, E.I., Skvortsova, V.I., Miasoedov, N.F., Nezavibat’ko, V.N., Zhuravleva, E.I., and Vanichkin, A.V., Semax efficiency in acute period of hemispheric ischemic stroke, Zh. Nevrol. Psikhiatr. im. S.S. Korsakova, 1997, vol. 97, pp. 26–34.

    CAS  PubMed  Google Scholar 

  5. Miasoedov, N.F., Skvortsova, V.I., Nasonov, E.L., Zhuravleva, E.I., Grivennikov, I.A., and Arsen’eva, E.L., et al., Semax neuroprotective effect in acute period of ischemic stroke, Zh. Nevrol. Psikhiatr. im. S.S. Korsakova, 1999, vol. 5, pp. 15–19.

    Google Scholar 

  6. Alekseeva, G.V., Bottaeva, N.A., and Gorshkova, V.V., Semax application in patients with post-hypoxic brain pathology for long-term period, Anesteziol. Reanimatol., 1999, vol. 1, pp. 40–43.

    Google Scholar 

  7. Medvedeva, E.V., Dmitrieva, V.G., Povarova, O.V., Limborska, S.A., Skvortsova, V.I., Myasoedov, N.F., et al., The peptide semax affects the expression of genes related to the immune and vascular systems in rat brain focal ischemia: Genome-wide transcriptional analysis, BMC Genomics, 2014, vol. 15, p. 228.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Medvedeva, E.V., Limborskaya, S.A., Myasoedov, N.F., and Dergunova, L.V., Semax positive effect onto TTR gene expression in the model of rats’ brain focal ischemia, Materialy 7-go Rossiiskogo simpoziuma “Belki i peptidy” (Proc. 7th Russian Symposium “Proteins and Peptides”), Novosibirsk, 2015, p. 367.

    Google Scholar 

  9. Nomenclature Committee of IUB (NC-IUB) IUBIUPAC Joint Commission on Biochemical Nomenclature (JCBN). Newsletter. 1981, J. Biol. Chem., 1981, vol. 256, pp. 12–14.

  10. Ando, Y., Transthyretin: It’s miracle function and pathogenesis, Rinsho Byori Jpn. J. Clin. Pathol., 2009, vol. 57, pp. 228–235.

    CAS  Google Scholar 

  11. Richardson, S.J., Evolutionary changes to transthyretin: Evolution of transthyretin biosynthesis, FEBS J., 2009, vol. 276, pp. 5342–5356.

    Article  CAS  PubMed  Google Scholar 

  12. Alshehri, B., D’Souza, D.G., Lee, J.Y., Petratos, S., and Richardson, S.J., The diversity of mechanisms influenced by transthyretin in neurobiology: Development, disease and endocrine disruption, J. Neuroendocrinol., 2015, vol. 27, pp. 303–323.

    Article  CAS  PubMed  Google Scholar 

  13. Herbert, J., Wilcox, J.N., Pham, K.T., Fremeau, R.T., Zeviani, M., Dwork, A., et al., Transthyretin: A choroid plexus-specific transport protein in human brain. The 1986 S. Weir Mitchell award, Neurology, 1986, vol. 36, pp. 900–911.

    Article  CAS  PubMed  Google Scholar 

  14. Fleming, C.E., Nunes, A.F., and Sousa, M.M., Transthyretin: More than meets the eye, Prog. Neurobiol., 2009, vol. 89, pp. 266–276.

    Article  CAS  PubMed  Google Scholar 

  15. Brouillette, J. and Quirion, R., Transthyretin: A key gene involved in the maintenance of memory capacities during aging, Neurobiol. Aging, 2008, vol. 29, pp. 1721–1732.

    Article  CAS  PubMed  Google Scholar 

  16. Fleming, C.E., Saraiva, M.J., and Sousa, M.M., Transthyretin enhances nerve regeneration, J. Neurochem., 2007, vol. 103, pp. 831–839.

    Article  CAS  PubMed  Google Scholar 

  17. Sousa, J.C., Grandela, C., Fernández-Ruiz, J., de Miguel, R., de Sousa, L., Magalhães, A.I., et al., Transthyretin is involved in depression-like behavior and exploratory activity, J. Neurochem., 2004, vol. 88, pp. 1052–1058.

    Article  CAS  PubMed  Google Scholar 

  18. Gao, C., Zhang, B., Zhang, W., Pu, S., Yin, J., and Gao, Q., Serum prealbumin (transthyretin) predict good outcome in young patients with cerebral infarction, Clin. Exp. Med., 2011, vol. 11, pp. 49–54.

    Article  CAS  PubMed  Google Scholar 

  19. Santos, S.D., Lambertsen, K.L., Clausen, B.H., Akinc, A., Alvarez, R., Finsen, B., et al., CSF transthyretin neuroprotection in a mouse model of brain ischemia, J. Neurochem., 2010, vol. 115, pp. 1434–1444.

    Article  CAS  PubMed  Google Scholar 

  20. Richardson, S.J., Wijayagunaratne, R.C., D’Souza, D.G., Darras, V.M., and Van Herck S.L.J., Transport of thyroid hormones via the choroid plexus into the brain: The roles of transthyretin and thyroid hormone transmembrane transporters, Front. Neurosci., 2015, vol. 9, p. 66.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Schroeder, A.C. and Privalsky, M.L., Thyroid hormones, T3 and T4, in the brain, Front. Endocrinol. (Rome, Italy), 2014, vol. 5, p. 40.

    Google Scholar 

  22. Bauer, M., Goetz, T., Glenn, T., and Whybrow, P.C., The thyroid–brain interaction in thyroid disorders and mood disorders, J. Neuroendocrinol., 2008, vol. 20, pp. 1101–1114.

    Article  CAS  PubMed  Google Scholar 

  23. Ahmed, O.M., El-Gareib, A.W., El-Bakry, A.M., Abd El-Tawab, S.M., Ahmed, R.G., Thyroid hormones states and brain development interactions, Int. J. Dev. Neurosci., 2008, vol. 26, pp. 147–209.

    Article  CAS  PubMed  Google Scholar 

  24. Remaud, S., Gothié, J.-D., Morvan-Dubois, G., and Demeneix, B.A., Thyroid hormone signaling and adult neurogenesis in mammals, Front. Endocrinol. (Rome, Italy), 2014, vol. 5, p. 62.

    Google Scholar 

  25. Naylor, H.M. and Newcomer, M.E., The structure of human retinol-binding protein (RBP) with its carrier protein transthyretin reveals an interaction with the carboxy terminus of RBP, Biochemistry, 1999, vol. 38, pp. 2647–2653.

    Article  CAS  PubMed  Google Scholar 

  26. Goodman, A.B. and Pardee, A.B., Evidence for defective retinoid transport and function in late onset Alzheimer’s disease, Proc. Natl. Acad. Sci. U.S.A., 2003, vol. 100, pp. 2901–2905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. LaMantia, A.S., Forebrain induction,retinoic acid,and vulnerability to schizophrenia: Insights from molecular and genetic analysis in developing mice, Biol. Psychiatry, 1999, vol. 46, pp. 19–30.

    Article  CAS  PubMed  Google Scholar 

  28. Lane, M.A. and Bailey, S.J., Role of retinoid signaling in the adult brain, Prog. Neurobiol., 2005, vol. 75, pp. 275–293.

    Article  CAS  PubMed  Google Scholar 

  29. Etchamendy, N., Enderlin, V., Marighetto, A., Pallet, V., Higueret, P., and Jaffard, R., Vitamin A deficiency and relational memory deficit in adult mice: Relationships with changes in brain retinoid signaling, Behav. Brain Res., 2003, vol. 145, pp. 37–49.

    Article  CAS  PubMed  Google Scholar 

  30. Olson, C.R. and Mello, C.V., Significance of vitamin A to brain function, behavior and learning, Mol. Nutr. Food Res., 2010, vol. 54, pp. 489–495.

    Article  CAS  PubMed  Google Scholar 

  31. Chakrabarti, M., McDonald, A.J., Will Reed, J., Moss, M.A., Das, B.C., and Ray, S.K., Molecular signaling mechanisms of natural and synthetic retinoids for inhibition of pathogenesis in Alzheimer’s disease, J. Alzheimer’s Dis., 2015, vol. 50, pp. 335–352.

    Article  Google Scholar 

  32. Maden, M. and Hind, M., Retinoic acid, a regeneration-inducing molecule, Dev. Dyn., 2003, vol. 226, pp. 237–244.

    CAS  PubMed  Google Scholar 

  33. Sato, Y., Meller, R., Yang, T., Taki, W., and Simon, R.P., Stereo-selective neuroprotection against stroke with vitamin A derivatives, Brain Res., 2008, vol. 1241, pp. 188–192.

    Article  CAS  PubMed  Google Scholar 

  34. Harvey, B.K., Shen, H., Chen, G.-J., Yoshida, Y., and Wang, Y., Midkine and retinoic acid reduce cerebral infarction induced by middle cerebral artery ligation in rats, Neurosci. Lett., 2004, vol. 369, pp. 138–141.

    Article  CAS  PubMed  Google Scholar 

  35. Shen, H., Luo, Y., Kuo, C.-C., Deng, X., Chang, C.-F., Harvey, B.K., et al., 9-Cis-retinoic acid reduces ischemic brain injury in rodents via bone morphogenetic protein, J. Neurosci. Res., 2009, vol. 87, pp. 545–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kitamura, M., Ishikawa, Y., Moreno-Manzano, V., Xu, Q., Konta, T., Lucio-Cazana, J., et al., Intervention by retinoic acid in oxidative stress-induced apoptosis, Nephrol., Dial., Transplant., 2002, vol. 17, no. 9, pp. 84–87.

    Article  CAS  Google Scholar 

  37. Costa, R.H., Van Dyke, T.A., Yan, C., Kuo, F., and Darnell, J.E., Similarities in transthyretin gene expression and differences in transcription factors: Liver and yolk sac compared to choroid plexus, Proc. Natl. Acad. Sci. U.S.A., 1990, vol. 87, pp. 6589–6593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jaeger, A.M., Makley, L.N., Gestwicki, J.E., and Thiele, D.J., Genomic heat shock element sequences drive cooperative human heat shock factor 1 DNA binding and selectivity, J. Biol. Chem., 2014, vol. 289, pp. 30459–30469.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, X., Cattaneo, F., Ryno, L., Hulleman, J., Reixach, N., and Buxbaum, J.N., The systemic amyloid precursor transthyretin (TTR) behaves as a neuronal stress protein regulated by HSF1 in SH-SY5Y human neuroblastoma cells and APP23 Alzheimer’s disease model mice, J. Neurosci., 2014, vol. 34, pp. 7253–7265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ivanova, N.E., The results of the semax application under cognitive impairments in acute ischemic stroke and chronic cerebral ischemia, Eff. Farmakoter., 2012, no. 2, pp. 8–13.

    Google Scholar 

  41. Genovese, T., Impellizzeri, D., Ahmad, A., Cornelius, C., Campolo, M., Cuzzocrea, S., et al., Post-ischemic thyroid hormone treatment in a rat model of acute stroke, Brain Res., 2013, vol. 1513, pp. 92–102.

    Article  CAS  PubMed  Google Scholar 

  42. Storozhevykh, T.P., Tukhbatova, G.R., Senilova, Ya.E., Pinelis, V.G., Andreeva, L.A., and Myasoyedov, N.F., Effects of semax and its Pro-Gly-Pro fragment on calcium homeostasis of neurons and their survival under conditions of glutamate toxicity, Bull. Exp. Biol. Med., 2007, vol. 143, no. 5, pp. 601–604.

    Article  CAS  PubMed  Google Scholar 

  43. Lee, E.J., Bhat, A.R., Kamli, M.R., Pokharel, S., Chun, T., Lee, Y.-H., et al., Transthyretin is a key regulator of myoblast differentiation, PLoS One, 2013, vol. 8, no. 5, p. e63627.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. de Vito, P., Balducci, V., Leone, S., Percario, Z., Mangino, G., Davis, P.J., et al., Nongenomic effects of thyroid hormones on the immune system cells: New targets, old players, Steroids, 2012, vol. 77, pp. 988–995.

    Article  PubMed  Google Scholar 

  45. Inouye, S., Izu, H., Takaki, E., Suzuki, H., Shirai, M., Yokota, Y., et al., Impaired IgG production in mice deficient for heat shock transcription factor 1, J. Biol. Chem., 2004, vol. 279, pp. 38701–38709.

    Article  CAS  PubMed  Google Scholar 

  46. Stavchansky, V.V., Yuzhakov, V.V., Botsina, A.Y., Skvortsova, V.I., Bondurko, L.N., Tsyganova, M.G., et al., The effect of Semax and its C-end peptide PGP on the morphology and proliferative activity of rat brain cells during experimental ischemia: A pilot study, J. Mol. Neurosci., 2011, vol. 45, pp. 177–185.

    Article  CAS  PubMed  Google Scholar 

  47. Richardson, S.J., Lemkine, G.F., Alfama, G., Hassani, Z., and Demeneix, B.A., Cell division and apoptosis in the adult neural stem cell niche are differentially affected in transthyretin null mice, Neurosci. Lett., 2007, vol. 421, pp. 234–238.

    Article  CAS  PubMed  Google Scholar 

  48. Lemkine, G.F., Raj, A., Alfama, G., Turque, N., Hassani, Z., Alegria-Prévot, O., et al., Adult neural stem cell cycling in vivo requires thyroid hormone and its alpha receptor, FASEB J., 2005, vol. 19, no. 7, pp. 863–865.

    CAS  PubMed  Google Scholar 

  49. Fernandez, M., Pirondi, S., Manservigi, M., Giardino, L., and Calzà, L., Thyroid hormone participates in the regulation of neural stem cells and oligodendrocyte precursor cells in the central nervous system of adult rat, Eur. J. Neurosci., 2004, vol. 20, pp. 2059–2070.

    Article  CAS  PubMed  Google Scholar 

  50. Dirks, P., Tieding, S., Schneider, I., Mey, J., and Weiler, R., Characterization of retinoic acid neuromodulation in the carp retina, J. Neurosci. Res., 2004, vol. 78, no. 2, pp. 177–185.

    Article  CAS  PubMed  Google Scholar 

  51. Zhang, D.Q. and McMahon, D.G., Direct gating by retinoic acid of retinal electrical synapses, Proc. Natl. Acad. Sci. U.S.A., 2000, vol. 97, no. 26, pp. 14754–14759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Alekseev, I.B., Lomakina, O.E., Shinalieva, O.N., and Alekseeva, G.N., The efficiency of Semax 0.1% as a neuroprotective therapy in patients with glaucoma, Glaukoma, 2012, no. 1, pp. 48–52.

    Google Scholar 

  53. Eremin, K.O., Kudrin, V.S., Saransaari, P., Oja, S.S., Grivennikov, I.A., Myasoedov, N.F., et al., Semax,an ACTH (4-10) analogue with nootropic properties, activates dopaminergic and serotoninergic brain systems in rodents, Neurochem. Res., 2005, vol. 30, no. 12, pp. 1493–1500.

    CAS  PubMed  Google Scholar 

  54. Tatum, M.C., Ooi, F.K., Chikka, M.R., Chauve, L., Martinez-Velazquez, L.A., Steinbusch, H.W.M., et al., Neuronal serotonin release triggers the heat shock response in C. elegans in the absence of temperature increase, Curr. Biol., 2015, vol. 25, no. 2, pp. 163–174.

    Article  CAS  PubMed  Google Scholar 

  55. Chiang, M.-C., Chen, H.-M., Lai, H.-L., Chen, H.-W., Chou, S.-Y., Chen, C.-M., et al., The A2A adenosine receptor rescues the urea cycle deficiency of Huntington’s disease by enhancing the activity of the ubiquitinproteasome system, Hum. Mol. Genet., 2009, vol. 18, no. 16, pp. 2929–2942.

    Article  CAS  PubMed  Google Scholar 

  56. Doepner, R.F.G., Geigerseder, C., Frungieri, M.B., Gonzalez-Calvar, S.I., Calandra, R.S., Raemsch, R., et al., Insights into GABA receptor signaling in TM3 Leydig cells, Neuroendocrinology, 2005, vol. 81, no. 6, pp. 381–390.

    Article  CAS  PubMed  Google Scholar 

  57. Bromberg, Z., Goloubinoff, P., Saidi, Y., and Weiss, Y.G., The membrane-associated transient receptor potential vanilloid channel is the central heat shock receptor controlling the cellular heat shock response in epithelial cells, PLoS One, 2013, vol. 8, no. 2, p. e57149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Bezuglov, V.V., Akimov, M.G., Gretskaya, N.M., Surin, A.M., Pinelis, V.G., Shram, S.I., et al., The study of the neurotropic peptides role in cell responses regulation, in Horizons in Neuroscience Research, Costa, A. and Villalba, E., Eds., New York: Nova Sci. Publ., 2015, chap. 10, pp. 151–170.

    Google Scholar 

  59. V’yunova, T.V. and Andreeva, L.A., Peptide interaction with receptor systems of cells, Materialy 6-oi mezhdunarodnoi konferentsii “Biologicheskie osnovy individual’noi chuvstvitel’nosti k psikhotropnym sredstvam (Proc. 6th Int. Conference “Biological Foundations of Individual Sensitivity to Psychotropic Drugs”), Moscow, Nov. 9–13, 2015; Eksp. Klin. Farmakol., 2015, vol. 78, no. 999, p. 17.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, 123182, Russia

    T. V. Vyunova, E. V. Medvedeva, L. A. Andreeva, L. V. Dergunova, S. A. Limborska & N. F. Myasoedov

Authors
  1. T. V. Vyunova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. V. Medvedeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L. A. Andreeva
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L. V. Dergunova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. A. Limborska
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N. F. Myasoedov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. V. Vyunova.

Additional information

Original Russian Text © T.V. Vyunova, E.V. Medvedeva, L.A. Andreeva, L.V. Dergunova, S.A. Limborska, N.F. Myasoedov, 2016, published in Molekulyarnaya Genetika, Mikrobiologiya i Virusologiya, 2016, No. 3, pp. 104–109.

Genes, human and animal proteins in the review are used in accordance with the international nomenclature in NCBI databases. Transthyretin protein of humans and animals is given as TTR and Ttr, respectively. Genes are given in italics for humans and animals as TTR and Ttr.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vyunova, T.V., Medvedeva, E.V., Andreeva, L.A. et al. A possible role of transthyretin in the biological mechanism of regulatory peptide neuroprotection. Mol. Genet. Microbiol. Virol. 31, 143–148 (2016). https://doi.org/10.3103/S0891416816030101

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3103/S0891416816030101

Keywords

Search

Navigation