Diffusion of docosahexaenoic and eicosapentaenoic acids through the blood-brain barrier: An in situ cerebral perfusion study

Docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids are n-3 polyunsaturated fatty acids with a therapeutic potential for CNS diseases. Here, using an in situ brain perfusion technique in mice, we show that [¹⁴C]-DHA and [¹⁴C]-EPA readily cross the mouse blood-brain barrier (BBB) with brain transport coefficients (Clup) of 48 ± 3 μl g^-1 s^-1 and 52 ± 4 μl g^-1 s^-1, respectively. Mechanical capillary depletion of brain homogenates showed that less than 10% of [¹⁴C]-DHA or [¹⁴C]-EPA remained in endothelial cells of the brain vasculature, demonstrating that both molecules fully crossed the BBB. Addition of bovine serum albumin decreased the Clup of [¹⁴C]-DHA to 0.6 ± 0.3 μl g^-1 s^-1, indicating that binding to albumin reduced importantly, but not totally, the passage of DHA through the BBB. The Clup of [¹⁴C]-DHA or [¹⁴C]-EPA was not saturable at concentration up to 100 μM, suggesting that these compounds crossed the BBB by simple diffusion. However, long-term high-DHA dietary consumption reduced the Clup of [¹⁴C]-DHA to 33 ± 6 μl g^-1 s^-1 (-20%, p < 0.01). These results confirm that the brain uptake of DHA or EPA perfused with a physiological buffer is comparable to highly diffusible drugs like diazepam, and can be modulated by albumin binding and chronic dietary DHA intake.