Alcohol, inflammation, and blood-brain barrier function in health and disease across development

Abstract

Alcohol is the most commonly used drug of abuse in the world and binge drinking is especially harmful to the brain, though the mechanisms by which alcohol compromises overall brain health remain somewhat elusive. A number of brain diseases and pathological states are accompanied by perturbations in Blood-Brain Barrier (BBB) function, ultimately exacerbating disease progression. The BBB is critical for coordinating activity between the peripheral immune system and the brain. Importantly, BBB integrity is responsive to circulating cytokines and other immune-related signaling molecules, which are powerfully modulated by alcohol exposure. This review will highlight key cellular components of the BBB; discuss mechanisms by which permeability is achieved; offer insight into methodological approaches for assessing BBB integrity; and forecast how alcohol-induced changes in the peripheral and central immune systems might influence BBB function in individuals with a history of binge drinking and ultimately Alcohol Use Disorders (AUD).

Keywords: Adolescence; Alcohol; Blood-brain barrier; Cytokines; Inflammation.

Figure 1:. Hypothetical Mechanistic Outline by which AIE Alters BBB Permeability.

This figure illustrates the hypothesized mechanism through which chronic ethanol exposure during the important developmental period of adolescence may produce sex-specific changes in inflammation, ultimately resulting in elevated male BBB permeability.

Figure 2:. Schematic Representation of the Neurovascular Unit.

This schematic highlights the complex array of cell-to-cell interactions that influence the BBB and molecular access into the CNS. The endothelial cells that form tight junctions are surrounded by the basal lamina as well as pericytes that directly communicate with the endothelial cells. Bidirectional communication occurs at each level between astrocytes, neurons, and microglia as well as astrocytic end-feet connections directly modifying pericyte signaling.

Figure 3:. Comparison of Different Methods of Probing BBB Permeability.

Adult male, Sprague-Dawley rats received 500 μg/kg i.p. LPS injection and 15 hours later BBB permeability was assessed with i.v. 1.0 mL/kg, 2.0% Evans Blue Dye. No differences in dye concentration were observed in gross-dissected brain tissue, evidenced by dye levels being comparable to no dye controls, despite evidence that high dose LPS increased BBB permeability (Ghosh et al., 2014; Banks et al., 2015) (A). In a subsequent pilot, rats (n=2–3) with a history of adolescent intermittent ethanol (AIE) under basal conditions, revealed significant differences in 20 kDa dextran permeability in a range of brain regions (B).

Figure 4:. Evidence of Ethanol’s Ability to Disrupt the NVU.

Studies indicate potential mechanisms by which ethanol-evoked changes may disrupt BBB permeability are indicated by exclamation points on relevant NVU components. While many of the papers referenced in this schematic highlight the specific role that inflammation plays, there exists substantial correlational evidence that long-term ethanol exposure could alter BBB permeability directly.