Pioglitazone Attenuates the Effects of Peripheral Inflammation in a Human In Vitro Blood-Brain Barrier Model

Biological mediators secreted during peripheral chronic inflammation reach the bloodstream 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 pathways 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 alpha (TNF alpha), a cytokine commonly released in periphery during IBD, and the anti-inflammatory role of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist (PPAR gamma). The BBB model was treated with either 10% plasma from healthy and IBD donors or 5 ng/mL TNF alpha, following treatment with 10 mu M pioglitazone. Patient plasma did not alter BBB parameters, but TNF alpha levels in plasma from all donors were associated with varying expression of claudin-5, claudin-3 and ICAM-1. TNF alpha 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.

Automated summary

This study investigated the effects of plasma from inflammatory bowel disease (IBD) patients and tumor necrosis factor alpha (TNF alpha) on the blood-brain barrier (BBB), as well as the anti-inflammatory role of pioglitazone. The results showed that TNF alpha increased BBB permeability, while pioglitazone attenuated these effects. Plasma from IBD patients also increased BBB permeability, which was reversed by pioglitazone. These findings demonstrate the potential of pioglitazone in controlling peripheral BBB inflammation associated with inflammatory conditions.