Pioglitazone Increases Blood–Brain Barrier Expression of Fatty Acid-Binding Protein 5 and Docosahexaenoic Acid Trafficking into the Brain

Abstract

Brain levels of docosahexaenoic acid (DHA), an essential cognitively beneficial fatty acid, are reduced in Alzheimer's disease (AD). We have demonstrated in an AD mouse model that this is associated with reduced blood−brain barrier (BBB) transport of DHA and lower expression of the key DHA-trafficking protein, fatty acid-binding protein 5 (FABP5). This study focused on assessing the impact of activating peroxisome proliferator-activated receptor (PPAR) isoforms on FABP5 expression and function at the BBB. Using immortalized human brain endothelial (hCMEC/D3) cells, a 72 h treatment with the PPARα agonist clofibrate (100 μM), and PPARβ/δ agonists GW0742 (1 μM) and GW501506 (0.5 μM), did not affect FABP5 protein expression. In contrast, the PPARγ agonists rosiglitazone (5 μM), pioglitazone (25 μM), and troglitazone (1 μM) increased FABP5 protein expression by 1.15-, 1.18-, and 1.24-fold in hCMEC/D3 cells, respectively, with rosiglitazone and pioglitazone also increasing mRNA expression of FABP5. In line with an increase in FABP5 expression, pioglitazone increased 14 C-DHA uptake into hCMEC/D3 cells 1.20-to 1.33-fold over a 2 min period, and this was not associated with increased expression of membrane transporters involved in DHA uptake. Furthermore, treating male C57BL/6J mice with pioglitazone (40 mg/kg/day for 7 days) led to a 1.79-fold increase in BBB transport of 14 C-DHA over 1 min, using an in situ transcardiac perfusion technique, which was associated with a 1.82-fold increase in brain microvascular FABP5 protein expression. Overall, this study demonstrated that PPARγ can regulate FABP5 at the BBB and facilitate DHA transport across the BBB, important in restoring brain levels of DHA in AD.

Clinically relevant mitochondrial-targeted therapy improves chronic outcomes after traumatic brain injury

“…Recent research shows that pioglitazone plays a role in facilitating docosahexaenoic acid transport across the blood–brain barrier, which may in part contribute to better cognitive performance. 81 …”

Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

“…In addition, concerning the usability and principal applications for such in vitro models, the toxicity evaluation of the drugs/compounds is one of the main research points in early drug discovery, where many conditions related to a wide range of concentrations and incubation times must be deeply evaluated. In our study, the impact towards the BBB of different compounds, non-neurotoxic [ 35 , 36 , 37 ] and neurotoxic [ 38 , 39 ], through a wide range of concentrations was assessed. The permeability coefficient of our integrity marker NaF for the endothelium (Pe NaF ) ( Figure 7 ) showed an effect after exposure to high concentrations of neurotoxic compounds such as tamoxifen and rotenone, which were known to disrupt the BBB [ 38 , 39 ].…”

The Biological Functions and Regulatory Mechanisms of Fatty Acid Binding Protein 5 in Various Diseases

“…Docosahexaenoic acid (DHA) is an omega-3 PUFA, which serves as a beneficial factor in cognitive function and memory. DHA is sufficiently essential in brain function and its levels are reduced in neurodegenerative diseases such as Alzheimer’s disease ( Low et al, 2020 ). An intracellular carrier protein is required to facilitate the cytosolic trafficking of DHA across the brain endothelial cell to maintain the brain levels of DHA since DHA is not produced by the brain.…”

“…In addition, it is also involved in autocrine or paracrine signaling outside the cell, thereby enhancing the effects on systematic glucose, lipid homeostasis, energy metabolism, cell proliferation, and the immunological system. Several studies have reported that FABP5 plays a pivotal role in various diseases including metabolism disorders (e.g., obesity, insulin resistance, and T2DM) ( Yeung et al, 2008 ), skin diseases (e.g., psoriasis) ( Dallaglio et al, 2013 ), neurological diseases (e.g., Alzheimer’s disease) ( Low et al, 2020 ), and carcinoma (e.g., prostate cancer, breast cancer, and cervical cancer) ( Guaita-Esteruelas et al, 2018 ), due to its aberrant expression under pathological conditions. This indicates that FABP5 has tremendous potential in clinical applications.…”