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Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14 Page 95

Aging has been associated with a low-grade sterile inflammatory status of the immune system, in which
interleukin-6 (IL6), IL1β and tumor necrosis factor (TNF) are key players, more evident in an unhealthy
state. Neuroinflammation can be considered one of the most important etiological factors in age-related
[10]
neurodegeneration , associated with a reduction in neuron number, a decrease in neuronal arborization,
[11]
and loss of spines . What fits particularly in this theory, is the strong evidence that in the aging brain,
both macrophages and microglia react with a prolonged and overactive response to stimuli . This
[12]
overactivation induces the production of reactive oxygen species and attracts peripheral leukocytes, and
[13]
both these conditions can activate glial cells . The activation of glial cells promotes telomere shortening,
[14]
which can be a contributor in different neurological conditions, such as AD . Resulting impaired
phagocytosis alters the removal of toxic compounds, such as amyloid-beta (Aβ) and alpha-synuclein
[15]
(aSyn) . Microglial activation is believed to be involved in the occurrence of deterioration in various
[15]
neurodegenerative diseases, such as AD, PD, ALS, and MS . Microglia are the main immune cells of
the central nervous system (CNS), and as the first line of defense, microglia play an important role in the
[16]
inflammatory reaction . In AD, microglia are known for their role in cleaning up Aβ. Meanwhile, in PD,
[17]
a pathological aSyn aggregation can induce microglial activation and dysfunction . Microglia are also
directly involved in MS by producing cytokines such as tumor necrosis factor-a (TNF-a) and interferon-γ
2-
(IFN-γ), superoxide (O ) or nitric oxide (NO), and release of proteolytic and lipolytic enzymes, which can
destroy the myelin sheath [15,18] .

Neuroinflammation and mitochondrial dysfunction are common features of chronic neurodegenerative
diseases. Both conditions can lead to increased oxidative stress, which leads to excess reactive oxygen
species and reactive nitrogen species, resulting in a cascade of events, with injury to polarized bilayers, lipid
peroxidation, lysosomal intrinsic activity and autophagy; all these events together, permit self-potentiation
[19]
of an inflammatory cascade .

Inflammation also plays a role in cerebral small-vessel disease (cSVD), which usually manifests as stroke,
[20]
cognitive impairment, dementia, physical disability and depression . Inflammation in cSVD might be
explained by the role of endothelial cells in the blood-brain barrier. Endothelial cells communicate with
pericytes, astrocytes, microglia, and neural stem cells in the neurovascular unit. Damage to CNS tissues
leads to the disruption of tight junctions that link endothelial cells . It is followed by the infiltration of
[21]
neutrophils and monocytes, the activation of microglia and astrocytes and the invasion of T and B cells.
This inflammatory response is mediated by the nuclear factor κ-light-chain-enhancer of activated B cells
(NFκB) pathway and strongly associated with neuroinflammation in the acute phase of various vascular
injuries such as stroke, diabetic retinopathy, and AD [22,23] .

Bilirubin has been reported to act on all the above-mentioned molecular mechanisms. The following
paragraphs review the state-of-the-art of what it is known about bilirubin and the brain.

BILIRUBIN: A MARKER FOR NEUROLOGICAL DISEASES
Cumulative clinical evidence demonstrates the alteration of total serum bilirubin (TSB) level in
neuroinflammatory diseases, including schizophrenia, MS, PD, AD, ALS, stroke, diabetic retinopathy, etc.
(for details, Table 1). For obvious reasons (limited CNS sample availability, especially in the early stages of
diseases), few data on the potential molecular role of the pigment in these pathologies are available, and
cause-effect studies are possible only by using experimental models.

Schizoprenia
Multiple contrasting studies exist on the potential correlation between the serum level of UCB and
schizophrenia. Studies have reported an increase in UCB level, as in Gilbert’s syndrome in schizophrenia
[24]
compared to other psychiatric diseases (affective disorder and neuropsychosis) and healthy controls .