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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 101

The potential protective role of HO-1 induction has been demonstrated in several studies. HO-1 increases
early (24 h) after brain trauma [102] , and in intracerebral haemorrhage models, after infiltration of the
brain by blood components activating the inflammatory response [103] . HO-1 activity is observed in both
endothelial cells and microglia surrounding the haematoma site. The protective effects of HO-1 in neurons
was studied by Orozco-Ibarra et al. [104] , who revealed that the upregulation of HO-1 prevented the death
of cerebellar granule neurons due to mitochondrial toxicity. Further investigation found that the HO-1
products, bilirubin and CORM2 (carbon monoxide releasing molecule), were involved in preventing cell
death.

HO-1 has neuroprotective effects by regulating the phosphatidylinositol 3-kinase (PI3K/AKT) signalling
[105]
pathway and by reducing apoptosis in rats with cerebral haemorrhage . Feng et al. [106] showed that the
PI3K/AKT and extracellular signal regulated kinase pathways are involved in oleanolic acid induced HO-1
expression by activating Nrf2 in vascular smooth muscle cells. As one of the signalling pathways for cell
survival, the PI3K/AKT signal transduction pathway plays an important role in cell proliferation and
differentiation and inhibition of neuronal apoptosis [107] . Therefore, HO-1 may protect the nerves of rats with
cerebral haemorrhage by regulating the PI3K/AKT signalling pathway.

A second isoform of HO exists in the brain, called heme oxygenase-2 (HO-2). Considered constitutive, it
looks like HO-2 in the brain plays the vital function of maintaining adequate levels of UCB to guarantee
normal cellular homeostasis, participating in brain protection [108] . The protective activity of HO-2 has
been reported in intracerebral haemorrhage models, where heme oxygenase-2 gene (Hmox2) deletion
led to greater brain injury volumes and neurological deficits than in wild-type mice after intracerebral
haemorrhage [109] . In brain cultures, Doré et al. [108] expanded our knowledge on the role of HO-2 and
bilirubin as neuroprotective factors by showing increased neuronal death in cerebellar granule cultures
of Hmox2 knockout mice (Hmox2-/-). On the contrary, Hmox2 transfection in human embryonic kidney
293 (HEK293) cells rescued cells from apoptotic death. In another study, the induction of HO-2 activity
by phorbol esters enhanced the production of bilirubin, which protected primary hippocampal and
cortical neuronal cultures from the neurotoxicity of H O . Of note, HO-2 was immunolocalised in neurons
2
2
both before and after traumatic brain injury, whereas HO-1 was highly upregulated in glia only after
traumatic brain injury. Cell loss was significantly greater in Hmox2-/- mice in areas including the cortex,
hippocampus and lateral dorsal thalamus [110] .

Biliverdin (BV), another yellow player, also showed neuroprotective effects by ameliorating cerebral
reperfusion injury in rats most probably via its antiinflammatory activity [111] . Two pathways are known to
be involved in the antiinflammatory mechanism of BV: by activating the nitric oxide-dependent biliverdin
reductase, BV reduces the expression of toll-like receptor-4 (TLR-4) in murine macrophages [112] , and BV
regulates the expression of complement C5a receptor [113] . Furthermore, a study by Zou et al. [111] found the
downregulation of miR-204-5p and its target gene, ETS protooncogene 1 (Ets1), in cerebral ischemia-
reperfusion injury rats following BV administration. Ets1 is known to be responsible for inducing
proinflammatory Th1 type response and causing neuronal death [114] . Therefore, BV may play a crucial role
in preventing injury in stroke by interfering in miRNAs levels.

Additional neurological conditions underpinned by reduced TSB levels
ALS
In ALS, the reduction of TSB levels correlates with both the clinical state and disease duration. Patients
with long-lasting ALS (where motor neuron degeneration is noticed) have lower TSB levels than do
patients with a shorter duration [115] .