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Page 102 Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14

Seasonal affective disorder
Nocturnal plasma bilirubin levels were evaluated in individuals with unipolar recurrent winter seasonal
major depressive disorder and age-/gender-matched controls. Lower bilirubin levels were found in patients
with seasonal affective disorder. The reduction in bilirubin level in this study was proposed as a vulnerable
risk for depression, although only an associative and not a causative link was provided [116] .

Dementia
A significant reduction in TSB levels was reported in patients with cognitive impairment compared to those
with normal cognitive function, although no significant correlation between bilirubin and disease duration
was found [117] . In a further study by Baierle et al. [118] , the authors showed that the significant increase in the
proinflammatory cytokines IL1β and TNFa correlated with the increase in oxidative stress and inversely
associated with low cognitive performance in elderly patients.

AD
As in the majority of neurological conditions, TSB levels are also decreased in AD [119] . The lower
concentration of bilirubin is supposed to have a role in the transition from mild cognitive impairment to
clear AD [120] . Similarly, reduced Hmox1 mRNA [121] and protein [122] levels were detected in the serum of full-
blown AD subjects, and proposed to correlate with cognitive decline [120] . Notably, the diagnosis of AD and
cognitive decline is usually a late event and performed after the pathological alteration has already existed
for some time. In the early stages, the brain tries to protect itself from the oxidative and inflammatory
insult of AD by increasing the endogenous production of UCB. Both HO-1 and biliverdin reductase A
(BLVR-A), the two key enzymes in biliverdin and bilirubin production [Figure 2], have been reported
to be upregulated in the brain of AD patients [103,123] . However, the upregulation of HO-1 will also cause
Fe deposition in the brain, which worsens and accelerates disease progression by enhancing the redox
imbalance in ongoing AD lesions [49,124-126] . It should be recalled that the brain possesses very low antioxidant
capacity compared to other organs, being much lower in neonatal life [127,128] and in the elderly [129,130] .
Thus, the enhanced pro-oxidant milieu due to HO-1 hyperactivation leads to an increased oxidative and
nitrosative post-translational modification of cellular enzymes, with their consequent inactivation [131] . One
of the targets of this mechanism is BLVRA, and thus, UCB production will be stopped [123] .

The chains of events described here, leading to the disruption of UCB-mediated protection and
contributing to the progression of neurological damage fits well with what we described in PD.

IS THE BRAIN DIFFERENT FROM THE REST OF THE BODY?
Differently from extra-CNS diseases involving oxidative imbalance and inflammation, where a positive
correlation between higher TSB level (Gilbert syndrome-like) and reduced disease incidence has been
frequently found [2,3,68] , the most readily evident finding in this review is that brain diseases have lower
TSB levels in common. Two major explanation have been given: (1) lower TSB levels in subjects with
neurological disease may reflect the consumption of UCB due to oxidative stress, although it seems unlikely
that the local redox imbalance occurring in the brain may affect the systemic levels of bilirubin; and (2)
individuals with lower TSB, thus a lower systemic antioxidant status, might be more vulnerable to oxidative
stress [118] and related diseases (both in the brain and extra-CNS organs) [Figure 1].

Experimental evidence strongly supports the notion that an increased concentration of bilirubin in
the CNS exerts antiinflammatory and antioxidant effects. On the other hand, it should be recalled that
hyperactivation of HO-1 in the CNS, reported to be a tentative reaction against brain insults, may enhance
the damage [68,104,131-148] . This specificity of the CNS has to be taken into account in the growing research
aimed at modulating the bilirubin players to increase levels of bilirubin and the protection it confers.