Exploring lipophilic compounds that induce BDNF secretion in astrocytes beyond the BBB using a new multi-cultured human in vitro BBB model

Brain-derived neurotrophic factor (BDNF) cannot cross the blood-brain barrier (BBB) when administered peripherally, which hinders its therapeutic potential. We utilized an in vitro BBB model—a tri-culture of a human endothelial cell line, a pericyte cell line, and an astrocyte cell line—to study the effect of twenty candidate lipophilic compounds on stimulating BDNF secretion in pericytes and astrocytes. The prostaglandin E2 receptor 4 agonist and sphingosine-1-phosphate receptor 5 agonist facilitated secretion of BDNF in the astrocyte, but did not decrease the transendothelial electrical resistance. These compounds may be promising agents for neurodegenerative and neuroinflammatory diseases. [Display omitted] •We examined the effects of lipophilic compounds on the secretion of BDNF at the BBB.•We used a new in vitro BBB model, which was a triple culture of human BBB cells.•The S1P5 agonist and EP4 agonist facilitated secretion of BDNF from astrocytes.