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

Author(s)

Oliveira da Rocha, Gustavo Henrique ; Loiola, Rodrigo Azevedo ; de Paula-Silva, Marina ; Shimizu, Fumitaka ; Kanda, Takashi ; Vieira, Andrea ; Gosselet, Fabien ; Poliselli Farsky, Sandra Helena

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 21, p. 20-pg., 2022-11-01.

Abstract

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. (AU)

• FAPESP's process: 17/05430-4 - Effects of the interaction between annexin A1 and PPAR gamma upon development of experimental colitis
• Grantee: Gustavo Henrique Oliveira da Rocha
• Support Opportunities: Scholarships in Brazil - Doctorate