Molecular mechanisms of neonatal bilirubin neurotoxicity: The Subcellular Cascade

Unbound bilirubin (UB) crosses the blood-brain barrier (BBB) and accumulates in the brain, leading to astrocyte dysfunction, activated microglia-driven inflammatory responses, impaired oligodendrocyte maturation and myelination, and ultimately neurotoxicity. UB-induced molecular cascade starts with intercalation and subsequent structural and functional disruption of the plasma membrane and membrane-bound organelles including mitochondria and endoplasmic reticulum (ER). Mitochondrial membrane damage leads to depolarization, membrane potential collapse, swelling, increased reactive oxygen species (ROS) generation, ATP loss, and ultimately initiation of intrinsic apoptotic pathway through cytochrome c release. An ER insult initiates unfolded protein response (leads to adaptive response or autophagy), and increased Ca²⁺ efflux into the mitochondria. Both processes converge in inducing mitochondrial apoptotic pathway through BAX/Bak translocation. Next, cytosolic release of damaged mitochondrial DNA, ATP, and ROS triggers (primarily in astrocytes and microglia) NRLP3 inflammasome formation, release of pro-inflammatory cytokines, and ultimately pyroptosis. UB can further initiate TNFR-mediated activation of NF-κB, feeding the inflammatory pathway or necroptosis. Disruption of synaptic transmission is through NMDAR-mediated glutamate excitotoxicity, subsequent Ca²⁺ influx, and activation of downstream apoptotic pathways. While, at low concentration bilirubin is cytoprotective, this review deals with the detrimental subcellular consequences of UB that ultimately leads to bilirubin-induced neurologic dysfunction (BIND).