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Page 98 Jayanti et al. Neuroimmunol Neuroinflammation 2020;7:92-108 I http://dx.doi.org/10.20517/2347-8659.2019.14

methyl-4-phenylpyridinium (MPP+) treated rats (a model for PD) revealed that the overexpression of
Hmox1 protects dopaminergic neurons by reducing the expression of TNF-a and IL1β, and increasing
brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF)
[51]
expression . Both growth factors, BDNF and GDNF, are able to prevent injury to dopaminergic neurons
and improve the behavioural deficits in PD [52-54] . A recent work based on organotypic cultures of substantia
nigra (challenged with rotenone to induce PD) demonstrated that inflammation and redox imbalance
[55]
are early and simultaneous triggers for dopaminergic neuron loss . In this study, Hmox1 upregulation
occurs only at the very first phases of neurodegeneration (3 hours after rotenone challenging, a time which
represents the pre-diagnosis stage in human PD based on dopaminergic neuron loss). Similarly, Bdnf
expression initially increased but then rapidly declined below the control level accompanying dopaminergic
neuron demise. The modulation trend of both markers (Hmox1 and Bdnf) was interpreted as a failed
[55]
tentative reaction to the insult , supporting the hypothesis of the interplay between L-DOPA and bilirubin
[56]
(see above). This interpretation may also agree with a recent finding of Song et al. , who reported that
the expression levels of HO-1 in the saliva of PD patients with early-stage (stage 1) based on the Hoehn
and Yahr scale were significantly higher compared to control subjects or PD patients at stage 3 (advanced
PD). The authors proposed an additional value of HO-1 as a potential biomarker in idiopathic PD patients.
Notably, hyperactivation of HO-1 may exacerbate oxidative stress by the deposition of iron (Fe), one of its
products [Figure 2], a phenomena frequently observed in neurological lesions and known to worsen the
[49]
disease . This aspect is discussed in detail later on in the review.
Contrary to PD and schizophrenia, other neurological conditions have been associated with a reduced TSB
level.

Multiple sclerosis
MS is a chronic inflammatory disease characterized by the destruction of myelin in the brain and spinal
[57]
cord likely due to loss of immune system tolerance to myelin . TSB levels have been reported to be
lower (vs. healthy controls) also in MS subjects with clinically isolated syndrome (predominately by
neuroinflammation) and relapsing-remitting multiple sclerosis (predominately by neurodegenerative
[58]
disorder), where predominate neurodegenerative disorders . Interestingly, bilirubin levels have been
shown to be significantly lower in relapsing-remitting multiple sclerosis compared to clinically isolated
[59]
syndrome patients , suggesting a relationship between increased disease severity and decreased TSB. This
hypothesis seems to be confirmed by the study of Ljubisavljevic et al. who found a significant correlation
[59]
between higher TSB and lower disability status, fewer MRI lesions, and shorter disease duration in both
study groups. In the brain tissue from MS patients, enhanced nitrotyrosine staining, one of the markers of
[60]
oxidative damage , was found in demyelinated regions, specifically in hypertrophic astrocytes and foamy
macrophages on inflammatory lesions . The damaged sites also showed an upregulation of antioxidant
[61]
enzymes, including HO-1, compared to normal-appearing white matter and white matter tissue from
control brains with no neurological disease, and HO-1 immunoreactivity was particularly confined to
[61]
microglia . These findings emphasize the close interaction between oxidative stress and inflammation in
MS.

The effects of bilirubin on MS have also been studied in the animal model for the disease, the so-called
experimental autoimmune encephalomyelitis (EAE) model, where the infiltration of lymphocytes, the
activation of CD4 T cells, and death of oligodendrocytes lead to the destruction of myelin sheaths [62,63] .
+
Figure 3 illustrates the most relevant mechanisms of action of bilirubin in EAE, one of the best-known
models unravelling the interplay between MS and bilirubin. Bilirubin administration in the EAE model
effectively prevented both acute and chronic EAE, even better than did glucocorticoid treatment, the most
commonly used therapy for MS [64,65] .