Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

Abstract

The blood-brain barrier (BBB) regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS) in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer's disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD), here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species) substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

Figure 1

Proposed model of blood-brain barrier (BBB) disruption in bipolar disorder. Increased BBB permeability through the endothelial cells (pink) and basal membrane (dark pink) may facilitate increased migration of inflammatory molecules into the brain. Activation of microglial cells (light orange) and an increase in reactive oxygen species (ROS) would amplify neuroinflammatory processes and ultimately induce damage in the myelin sheath, either directly via lipid/protein oxidation or indirectly via oligodendrocyte dysfunction (dark orange).