Unraveling the dual role of bilirubin in neurological Diseases: A Comprehensive exploration of its neuroprotective and neurotoxic effects

Neurodegenerative disorders are characterized by a progressive loss of neurons, causing substantial deficits in motor and cognitive functioning. Bilirubin is a yellow by-product of heme, existing in two primary isoforms namely unconjugated and conjugated, while initially produced unconjugated isomer is lipophilic and cytotoxic in nature. At physiological levels, bilirubin has an important role in brain function by acting as a powerful antioxidant, preventing brain tissues from oxidative damage by eliminating reactive oxygen species (ROS). Additionally, it contributes to immune regulation through microglial activation, cytokine release, complement system interception, fragment crystallization (Fc) receptor modulation, and major histocompatibility complex (MHC II) expression modification, which lower the risk of inflammatory and autoimmune reactions in the central nervous system (CNS). As per the literature, serum bilirubin concentrations are associated with CNS diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), multiple sclerosis (MS), epilepsy, schizophrenia and kernicterus spectrum disorder (KSD), which causes neuronal damage, especially in regions like the basal ganglia and cerebellum, which causes movement abnormalities and cognitive deficits. The aim of this article is to explore the dual role of bilirubin as neuroprotective and neurotoxic, essential for establishing effective therapeutic outcomes for neurodegenerative diseases by looking at its cellular mechanisms and discussing how bilirubin’s antioxidant properties can shield neurons and, in some situations, may induce oxidative stress and apoptosis.