Page 35 - Read Online

Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14 Page 103

CONCLUSION
Studies assessing clearly the molecular events correlating bilirubin and neurological damage are still
lacking, and many conclusions are based on clinical series. Understanding the role of bilirubin and all the
other yellow players in the development and progression of the different neurological disorders may help
in deciphering the efficacy of the modulation of bilirubin level to prevent CNS diseases. However, due to
the side effects of the drugs inducing HO-1 activity, caution must be taken before their recommendation.
More intriguing and promising is the in situ CNS elevation of UCB level achievable by the development
of molecules modulating BLVR. The future will hopefully provide the much-needed answer due to the
medical and social burden of neurological disorders.

DECLARATIONS
Authors’ contributions
Made substantial contributions to the search of the literature, the writing of the manuscript, and the
revision and discussion of the contents of the paper: Jayanti S, Moretti R, Tiribelli C, Gazzin S

Availability of data and materials
Not applicable.

Financial support and sponsorship
Jayanti S was supported in part by a fellowship from the Lembaga Pengelola Dana Pendidikan of Ministry
of Finance of Indonesia and an internal grant from the Italian Liver Foundation. The funders had no role in
data analysis and interpretation and also writing of the manuscript.

Conflicts of interest
All authors declare that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2020.

REFERENCES
1. Gazzin S, Masutti F, Vitek L, Tiribelli C. The molecular basis of jaundice: an old symptom revisited. Liver Int 2017;37:1094-102.
2. Gazzin S, Vitek L, Watchko J, Shapiro SM, Tiribelli C. A novel perspective on the biology of bilirubin in health and disease. Trends Mol
Med 2016;22:758-68.
3. Wagner KH, Wallner M, Mölzer C, Gazzin S, Bulmer AC, et al. Looking to the horizon: the role of bilirubin in the development and
prevention of age-related chronic diseases. Clin Sci (Lond) 2015;129:1-25.
4. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A
2002;99:16093-8.
5. Sedlak TW, Snyder SH. Bilirubin benefits: cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004;113:1776-82.
6. Sedlak TW, Saleh M, Higginson DS, Paul BD, Juluri KR, et al. Bilirubin and glutathione have complementary antioxidant and
cytoprotective roles. Proc Natl Acad Sci U S A 2009;106:5171-6.
7. Takeda TA, Mu A, Tai TT, Kitajima S, Taketani S. Continuous de novo biosynthesis of haem and its rapid turnover to bilirubin are
necessary for cytoprotection against cell damage. Sci Rep 2015;5:10488.
8. Yuan X, Rietzschel N, Kwon H, Walter Nuno AB, Hanna DA, et al. Regulation of intracellular heme trafficking revealed by subcellular
reporters. Proc Natl Acad Sci U S A 2016;113:E5144-52.
9. Chitnis T, Weiner HL. CNS inflammation and neurodegeneration. J Clin Invest 2017;127:3577-87.