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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 97

(TGFβ) and microglial activation [32,33] . This inflammatory picture is similar to that observed in kernicterus
[34]
spectrum disorders, the neurological sequel due to severe neonatal hyperbilirubinemia . Dalman and
[35]
Cullberg reported that neonates experiencing severe neonatal hyperbilirubinemia (TSB > 15 mg/dL)
might later have an increased frequency of mental disorders. This clinical hypothesis is supported
[36]
by the finding in the Gunn rat, the animal model for severe neonatal hyperbilirubinemia , showing
severe hyperbilirubinemia in the first weeks of life . The Gunn rat displays a stereotypical behaviour,
[37]
a supposedly typical symptom of schizophrenia, associated with microglia activation (indicative of
inflammation), decreased ribosomal protein synthesis activity in neuronal cells, decreased neurogenesis,
and increased apoptosis [38,39] .

On the other hand, multiple studies have reported lower TSB levels among schizophrenia patients
compared to patients suffering from some other psychiatric disorder and healthy controls [40-42] . To reconcile
[42]
these contradictory findings, Vítek et al. evaluated the correlation of bilirubin level with variability of
the promoter of the gene for UGT1A1 (uridine-diphospho-glucuronosyltransferase 1A1) (responsible for
hepatic conjugation of UCB) between schizophrenia patients and controls. They noticed that an increase in
bilirubin of 1 mM (0.06 mg/dL) could reduce the odds for schizophrenia status up to 19%.

[26]
Notably, UGTs participate in the metabolism of dopamine , a critical neurotransmitter, the loss of which
is responsible for motor PD, and dopaminergic over activity has recently been suspected responsible for
psychosis in schizophrenia . An additional potential link between these two pathologies might be heme
[43]
oxygenase-1 (HO-1). The overexpression of this enzyme in the astrocytes of glial fibrillary acidic protein-
heme oxygenase-1 (GFAP-HMOX1) transgenic mice resulted in increased subcortical oxidative imbalance
with the induction of mitochondrial damage and autophagy, augmented dopamine and serotonin levels
in the basal ganglia, and reduced dopamine 1 receptor (D1) in the nucleus accumbens, and enzyme
[44]
overexpression caused degeneration of axons in the hippocampus and hyperkinetic behavior . However,
there is still no clear evidence of HO-1 alteration in the clinical setting for schizophrenia.

PD
PD is another neurological disease linked to UCB. A study comparing 420 PD patients and 435 healthy
control showed not only a significant increase in bilirubin in PD patients but also a negative correlation
between bilirubin level and progression from a less to more severe staging of the disease . Complementary
[45]
[46]
with this study, Moccia et al. also reported higher TSB concentration in drug-naive PD patients
[47]
compared to controls, and Qin et al. also observed an upregulation of levels of direct bilirubin (conjugated
bilirubin, in clinical terminology), accompanied by reduced UCB (indirect bilirubin) levels in PD patients
compared to the healthy group. Notably, L-DOPA treatment (the most used therapeutic approach to PD,
[48]
able to improve symptomatology temporarily), has been found to increase TSB by about 20% . Because
L-DOPA may increase the oxidative stress causing dopaminergic neuron loss in PD, and since bilirubin is a
well-known antioxidant, an increased bilirubin level has been interpreted as a possible protective response
to the disease .
[48]

As noted in the Introduction, almost every cell in the body possesses the full enzymatic equipment for
[7]
producing UCB itself [Figure 2]. Modulation of the enzymes responsible for UCB production in the
brain of subjects with neurological/neurodegenerative diseases has been reported, including PD patients.
An increased HO-1 signal has been detected in reactive astrocytes and affected dopaminergic neurons
showing Lewy bodies . Although, the authors suggested that the HO-1 induction was uniquely due to
[49]
its antioxidant properties, it is clear now that the elevation of HO-1 levels also represents an attempt to
downregulate inflammation .
[50]
A direct proof of the protective effect of HO-1 induction has been obtained in experimental models. The
injection of adenovirus containing human heme oxygenase-1 gene (Hmox1) into the substantia nigra of