Skip to main content
SpringerLink
Log in

p53 and clock genes play an important role in memory and learning ability depression due to long-term ultraviolet A eye irradiation

  • Original Papers
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

Background

Long-term ultraviolet A (UVA) eye irradiation decreases memory and learning ability in mice. However, the underlying mechanism is still unclear.

Objectives

In this study, ICR mice were used to study the effects of long-term UVA eye irradiation.

Methods

The eyes of mice were exposed to UVA from an FL20SBLB-A lamp three times a week for 1 year. Then, we analyzed memory and learning ability in the mice using water maze and step-through passive avoidance tests, and measured the levels of p53, Period2 (Per2), Clock, brain and muscle Arnt-like protein-1 (Bmal1), nicotinamide mononucleotide adenylyltransferase (NMNAT) activity, nicotinamide phosphoribosyltransferase (NAMPT) activity, nicotinamide adenine dinucleotide (NAD+), and sirtuin 1 (Sirt1) in the brains of treated and control animals.

Results

The results showed that the p53 level increased significantly following long-term UVA eye irradiation, whereas the levels of Period2, Bmal1, Clock, NMNAT and NAMPT activities, NAD+, and Sirt1 decreased significantly. Furthermore, we found that p53 inhibition ameliorated the UVA eye irradiation-induced depression of memory and learning ability.

Conclusion

These results indicate that long-term UVA eye irradiation stimulates p53, inhibits the clock gene, and reduces Sirt1 production in the NAD+ constructional system, resulting in reduced memory and learning ability.

Graphic abstract

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Reppert, S. M., & Weaver, D. R. (2001). Molecular analysis of mammalian ircadian rhythms. Annual Review of Physiology, 63, 647–676.

    Article  CAS  Google Scholar 

  2. Hardin, P. E. (2000). From biological clock to biological rhythms. Genome Biology, 1, 1023.

    Article  Google Scholar 

  3. Oda, H. (2015). Chrononutrition. Journal of Nutritional Science and Vitaminology (Tokyo), 61, S92-94.

    Article  CAS  Google Scholar 

  4. Sundar, I. K., Yao, H., Sellix, M. T., & Rahman, I. (2015). Circadian molecular clock in lung pathophysiology. American Journal Physiology-Lung Cellular and Molecular Physiology, 309, L1056-1075.

    Article  CAS  Google Scholar 

  5. Tahira, K., Ueno, T., Fukuda, N., Aoyama, T., Tsunemi, A., Matsumoto, S., et al. (2011). Obesity alters the expression profile of clock genes in peripheral blood mononuclear cells. Archives of Medical Science, 7, 933–940.

    Article  CAS  Google Scholar 

  6. Gómez-Abellán, P., Hernández-Morante, J. J., Luján, J. A., Madrid, J. A., & Garaulet, M. (2008). Clock genes are implicated in the human metabolic syndrome. International Journal of Obesity (Lond), 32, 121–128.

    Article  Google Scholar 

  7. Woon, P. Y., Kaisaki, P. J., Bragança, J., Bihoreau, M.-T., Levy, J. C., Farrall, M., & Gauguier, D. (2007). Aryl hydrocarbon receptor nuclear translocator-like (BMAL1) is associated with susceptibility to hypertension and type 2 diabetes. Proceedings of the National Academy of Sciences of the United States of America, 104, 14112–14417.

    Google Scholar 

  8. Lamia, K. A., Papp, S. J., Yu, R. T., Barish, G. D., Uhlenhaut, N. H., Jonker, J. W., et al. (2011). Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature, 480, 552–556.

    Article  CAS  Google Scholar 

  9. Imai, S., & Guarente, L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology, 24, 464–471.

    Article  CAS  Google Scholar 

  10. Imai, S., & Yoshino, J. (2013). The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing. Diabetes, Obesity and Metabolism, 15, 26–33.

    Article  CAS  Google Scholar 

  11. Yoshino, J., & Imai, S. (2013). Accurate measurement of nicotinamide adenine dinucleotide (NAD+) with high-performance liquid chromatography. Methods in Molecular Biology, 1077, 203–215.

    Article  CAS  Google Scholar 

  12. Ramsey, K. M., Yoshino, J., Brace, C. S., Abrassart, D., Kobayashi, Y., Marcheva, B., et al. (2009). Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science, 324, 651–654.

    Article  CAS  Google Scholar 

  13. Bcheva, G., Slominski, R. S., & Alominski, A. T. (2019). Neuroendocrine aspects of skin aging. International Journal of Molecular Sciences, 20, 2798.

    Article  Google Scholar 

  14. Slominski, A. T., Zmijewski, M. A., Plonka, P. M., Szaflarski, J. P., & Paus, R. (2018). How UV light touches the grain and endocrine system through skin, and why. Endocrinology, 159, 1992–2007.

    Article  CAS  Google Scholar 

  15. Hiramoto, K., & Yamate, Y. (2020). Long-term UVA exposure to the eye compromises memory and learning ability in mice via corticotropin-releasing hormone type 2 receptor. International Journal of Biological Sciences, 16, 2170–2179.

    Article  CAS  Google Scholar 

  16. Hiramoto, K., Jikumaru, M., Yamate, Y., Sato, E. F., & Inoue, M. (2009). Ultraviolet A irradiation of the eye induces immunomodulation of skin and intestine in mice via hypothalomo-pituitary-adrenal pathways. Archives Dermatological Research, 301, 239–244.

    Article  CAS  Google Scholar 

  17. Hiramoto, K., & Kasahara, E. (2016). Long-term UVA eye irradiation causes decreased learning ability in mice. Photodermatology, Photoimmunology & Photomedicine, 32, 129–135.

    Article  CAS  Google Scholar 

  18. Hiramoto, K., Yamate, Y., & Yokoyama, S. (2018). Ultraviolet A eye irradiation ameliorates atopic dermatitis via p53 and clock gene proteins in NC/Nga mice. Photochemistry and Photobiology, 94, 378–383.

    Article  CAS  Google Scholar 

  19. Skobowiat, C., Postlethwaite, A. E., & Slominski, A. T. (2017). Skin exposure to ultraviolet B rapidly activates systemic neuroendocrine and immunosuppressive responses. Photochemistry and Photobiology, 93, 1008–1015.

    Article  CAS  Google Scholar 

  20. Hiramoto, K., Yamate, Y., Sugiyama, D., Matsuda, K., Iizuka, Y., & Yamaguchi, T. (2018). Tranexamic acid inhibits the plasma and non-irradiated skin markers of photoaging induced by long-term UVA eye irradiation in female mice. Biomedicine & Pharmacotherapy, 107, 54–58.

    Article  CAS  Google Scholar 

  21. Komarov, P. G., Komarova, E. A., Kondratov, R. V., Christov-Tselkov, K., Coon, J. S., Chernov, M. V., & Gudkov, A. V. (1999). A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science, 285, 1733–1737.

    Article  CAS  Google Scholar 

  22. Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of Neuroscience Methods, 11, 47–60.

    Article  CAS  Google Scholar 

  23. Lee, S.-S., Kim, C.-J., Shin, M.-S., & Lim, B.-V. (2020). Treadmill exercise ameliorates memory impairment through ERK-Akt-CREB-BDNF signaling pathway in cerebral ischemia gerbils. Journal of Exercise Rehabilitation, 16, 49–57.

    Article  Google Scholar 

  24. Hiramoto, K., Sugiyama, D., Takahashi, Y., & Mafune, E. (2016). The amelioration effect of tranexamic acid in wrinkles induced by skin dryness. Biomedicine & Pharmacotherapy, 80, 16–20.

    Article  CAS  Google Scholar 

  25. Imai, S., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 403, 795–800.

    Article  CAS  Google Scholar 

  26. Gao, J., Wang, W.-Y., Mao, Y.-W., Gräff, J., Guan, J.-S., Pan, L., et al. (2019). A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature, 466, 1105–1109.

    Article  Google Scholar 

  27. Kim, D., Nguyen, M. D., Dobbin, M. M., Fischer, A., Sananbenesi, F., Rodgers, J. T., et al. (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis. EMBO Journal, 26, 3168–3179.

    Google Scholar 

  28. Lu, X., & Lane, D. P. (1993). Differential induction of transcriptionally active p53 following UV or ionizing radiation: Defects in chromosome instability syndromes? Cell, 75, 765–778.

    Article  CAS  Google Scholar 

  29. Bond, J., Haughton, M., Blaydes, J., Gire, V., Wynford-Thomas, D., & Wyllie, F. (1996). Evidence that transcriptional activation by p53 plays a direct role in the induction of cellular senescence. Oncogene, 13, 2097–2104.

    CAS  PubMed  Google Scholar 

  30. Miki, T., Matsumoto, T., Zhao, Z., & Lee, C. C. (2013). p53 regulates Period2 expression and the circadian clock. Nature Communications, 4, 2444.

    Article  Google Scholar 

  31. Nakahata, Y., Sahar, S., Astarita, G., Kaluzova, M., & Sassone-Corsi, P. (2009). Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science, 324, 654–657.

    Article  CAS  Google Scholar 

  32. Skobowiat, C., & Slominski, A. T. (2015). UVB activates hypothalamic-pituitary-adrenal axis in C57BL/6 mice. Journal of Investigative Dermatology, 135, 1638–1648.

    Article  CAS  Google Scholar 

  33. Skobowiat, C., & Slominski, A. T. (2016). Ultraviolet B stimulates propiomelanocortin signalling in the arcute nucleus of the hypothalamus in mice. Experimantal Dermatology, 25, 120–123.

    Article  CAS  Google Scholar 

  34. Hiramoto, K., Okada, T., & Ito, M. (1996). Abnormalities in behaveor, learning ability, and the cholinergic system induced by long-term ultraviolet A irradiation of mice. Neuropsychobiology, 33, 182–185.

    Article  CAS  Google Scholar 

  35. Young, A. R. (1997). Chromophores in human skin. Physics in Medicine & Biology, 42, 789–802.

    Article  CAS  Google Scholar 

  36. Slominski, A. T., Zmijewski, M. A., Semak, I., Kim, T.-K., Janjetovic, Z., Slominski, R. M., & Zmijewski, J. W. (2017). Melatonin, mitochondria, and the skin. Cellular and Molecular Life Sciences, 74, 3913–3925.

    Article  CAS  Google Scholar 

  37. Hirayama, J., Miyamura, N., Uchida, Y., Asaoka, Y., Honda, R., Sawanobori, K., et al. (2009). Common light signaling pathways controlling DNA repair and circadian clock entrainment in Zebrafish. Cell Cycle, 8, 2794–2801.

    Article  CAS  Google Scholar 

  38. Balay, S. D., Widen, S. A., & Waskiewicz, A. J. (2020). Analysis of Zebrafish cryptochrome 2 and 4 expression in UV cone photoreceptors. Gene Expression Patterns, 35, 119100.

    Article  CAS  Google Scholar 

  39. de Assis, L. V. M., Mendes, D., Silva, M. M., Kinker, G. S., Pereira-Lima, I., Menck, C. F. M., & Castracci, A. M. L. (2020). Melanopsin mediates UVA-dependent modulation of proliferation, pigmentation, apoptosis, and molecular clock in normal and malignant melanocytes. Biochimica et Biophysica Acta-Molecular Cell Research, 1867, 118789.

    Article  Google Scholar 

Download references

Funding

This study was supported by JSPS KAKENHI (Grant no. 18K11085).

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan

    Keiichi Hiramoto, Y. Yamate & E. F. Sato

Authors
  1. Keiichi Hiramoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Y. Yamate
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. F. Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KH and YY performed experiments and analyzed the data; KH provided new tools and regents; SE conceived and supervised the study; KH and YY designed experiments and wrote the manuscript.

Corresponding author

Correspondence to Keiichi Hiramoto.

Ethics declarations

Conflict of interests

There are no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hiramoto, K., Yamate, Y. & Sato, E.F. p53 and clock genes play an important role in memory and learning ability depression due to long-term ultraviolet A eye irradiation. Photochem Photobiol Sci 20, 677–685 (2021). https://doi.org/10.1007/s43630-021-00055-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43630-021-00055-5

Keywords

Search

Navigation