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The role of bilirubin and heme metabolism in neuronal stress signaling

Bilirubin is amongst the most frequently measured peripheral metabolites, yet its roles in vivo are not totally understood. Believed to be a marker for liver function, it is now increasingly evident that bilirubin plays vital roles in the brain. Bilirubin is synthesized by Biliverdin reductase (BVR) from biliverdin, which in turn is derived from heme. BVR exists as two isoforms, BVR‐A and BVR‐B, of which BVR‐A is enriched in the brain. In addition to its role in bilirubin generation, BVR‐A is a kinase and transcription factor, and participates in several signaling pathways. Besides, these activities, the BVR pathway plays significant roles in maintenance of redox homeostasis in cells. Cell culture studies have shown that depletion of BlvrA, the gene encoding BVRA causes elevated oxidative stress and associated cellular damage. Using BlvrA−/− mice, we show that BVRA is the major enzyme responsible for bilirubin production. The gall bladders of these mice are green due to accumulation of biliverdin and inability to produce bilirubin. We analyzed the effects of bilirubin depletion in the brain using these mice. Paucity of bilirubin leads to elevated superoxide production in the brain and altered cytoprotective response to stress stimuli. These mice are defective in several antioxidant defense pathways. BlvrA mice also display a variety of behavioral abnormalities including cognitive deficits. We further show that bilirubin is a potent and direct superoxide scavenger in vivo, which accounts for its role in maintenance of redox balance. Treatment of mice with N‐methyl D‐aspartate (NMDA), an excitotoxin, results in increased neuronal death and larger lesions in BlvrA−/− mice. NMDA receptor activation is known to elevate superoxide production via the NADPH oxidases, enzymes which are known to be inhibited by the BVR‐bilirubin pathway. Taken together, our findings uncover important roles for BVR in neuroprotective processes. Modulating the BVR/bilirubin pathway may offer therapeutic benefits in neurodegenerative diseases involving redox imbalance.