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Page 94 Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14

Figure 2. The yellow players. Heme: Haemoglobin; HO: Heme oxygenase; Fe: Iron; Co: Carbon monoxide; BLV: Biliverdin; BLVR: Biliverdin-
reductase; UCB: Unconjugated bilirubin (indirect bilirubin); CYP: Cytochrome oxygenase. The picture shows the “yellow players” (see
[7]
text) and the tissues able to produce de novo bilirubin, based on the cited literature (Takeda et al. )
a more complex and fascinating scenario has emerged. First, various cells have been demonstrated to
[7,8]
possess the complete enzymatic apparatus necessary for producing UCB themselves [Figure 2] . A more
expanded and intricate view has emerged from the discovery of the interplay of UCB (and the enzymes
involved in its production and recycling, altogether called the “yellow players”) with cellular functions,
signaling pathways, and defense/adaptation mechanisms (not restricted to redox state). Collectively, these
[2,3]
findings suggest a greater role for the yellow players in cellular homeostasis and defense against diseases .
The interplay of the yellow players with neurological and neurodegenerative diseases is still much less
explored. In this article, we review the currently available evidence on the potential roles of bilirubin and
other yellow players in neurological disease, with special emphasis on inflammation. We will also address
the role of enzyme modulation in bilirubin metabolism, with the goal of increasing the systemic level of
bilirubin and the protection it confers.

INFLAMMATION AND NEUROLOGICAL DISEASES: AN OVERVIEW
Chronic neurodegenerative pathologies are currently the most dominant clinical conditions. They comprise
multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease
(AD) and vascular dementia. Consistent data show that the inflammatory process can be triggered by
protein misfolding or protein accumulation, which are the initial events of a given pathology (i.e., amyloid
for AD, tau protein for frontal dementia, alpha synuclein for PD, etc.) .
[9]