Bilirubin is a yellow endogenous derivate of the heme catabolism. Since the 1980s, it has been recognized as one of the most potent antioxidants in nature, able to counteract 10,000× higher intracellular concentrations of H2O2. In the recent years, not only bilirubin, but also its precursor biliverdin, and the enzymes involved in their productions (namely heme oxygenase and biliverdin reductase; altogether the “yellow players”—YPs) have been recognized playing a protective role in diseases characterized by a chronic prooxidant status. Based on that, there is an ongoing effort in inducing their activity as a therapeutic option. Nevertheless, the understanding of their specific contributions to pathological conditions of the central nervous system (CNS) and their role in these diseases are limited. In this review, we will focus on the most recent evidence linking the role of the YPs specifically to neurodegenerative and neurological conditions. Both the protective, as well as potentially worsening effects of the YP’s activity will be discussed.

Inflammation links neurodegenerative, neuropsychiatric and other neurological diseases (NDs) with acute brain events. It is responsible for the alteration of neurotransmission and circuity, brain architecture, and cell fate, affecting mood and personality (anxiety, depression and schizophrenia) and behavior (decline in cognitive, motor and speech abilities, altered sleep, fatigue, pain sensitivity and dementia). Inflammation is also a key component in systemic chronic diseases (cardiovascular disease, cancer, diabetes, and metabolic syndrome), in which bilirubin has been demonstrated to improve the diseases by acting as a multi-target antiinflammatory molecule, and where the evaluation of pharmacological modulation of the pigment level as a therapeutic approach has already started. While altered serum bilirubin levels have been reported in ND patients, the potential activity of bilirubin in the brain is vague. This review summarizes the available fragmentary information on the interplay of bilirubin with neuroinflammation, aiming to elucidate the pigment's role in the central nervous system environment.