Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood–Brain Barrier Model
Résumé
Biological mediators secreted during peripheral chronic inflammation reach the blood-
stream and may damage the blood–brain barrier (BBB), triggering central nervous system (CNS)
disorders. Full-fledged human BBB models are efficient tools to investigate pharmacological path-
ways and mechanisms of injury at the BBB. We here employed a human in vitro BBB model to
investigate the effects of either plasma from inflammatory bowel disease (IBD) patients or tumor
necrosis factor α (TNFα), a cytokine commonly released in periphery during IBD, and the anti-
inflammatory role of pioglitazone, a peroxisome proliferator-activated receptor γ agonist (PPARγ).
The BBB model was treated with either 10% plasma from healthy and IBD donors or 5 ng/mL
TNFα, following treatment with 10 µM pioglitazone. Patient plasma did not alter BBB parameters,
but TNFα levels in plasma from all donors were associated with varying expression of claudin-5,
claudin-3 and ICAM-1. TNFα treatment increased BBB permeability, claudin-5 disarrangement,
VCAM-1 and ICAM-1 expression, MCP1 secretion and monocyte transmigration. These effects were
attenuated by pioglitazone. Plasma from IBD patients, which evoked higher BBB permeability, also
increased ICAM-1 expression, this effect being reversed by pioglitazone. Our findings evidence
how pioglitazone controls periphery-elicited BBB inflammation and supports its repurposing for
prevention/treating of such inflammatory conditions.
Origine : Publication financée par une institution