Lorenzo's oil, adrenoleukodystrophy, and the blood– brain barrier

Abstract

Adrenoleukodystrophy is a rapid, progressive demyelinating disease affecting the CNS that is characterized by large increases in plasma and tissue very long saturated fatty acids (VLCFA). Lorenzo's oil (LO), consisting of erucic (22:1 n‐9) and oleic (18:1 n‐9) acid in a triglyceride form, is a dietary therapy effective in reducing plasma and tissue VLCFA. Despite the decreased VLCFA, clinical studies indicated that LO failed to stop the progressive demyelination, suggesting that erucic acid, the active component of LO, did not cross the BBB. We addressed this question by infusing [14‐14C] 22:1 n‐9 (170 μCi/kg) into male rats using two different infusion paradigms. The radiotracer was infused (i.v.) into awake, adult male rats over a 10‐min period or infused (i.c.v.) into the fourth ventricle over a 7‐day period using an osmotic mini‐pump. Brains were removed from the cranium, frozen in liquid nitrogen, lipids extracted, and separated using standard techniques. [1‐14C] 20:4 n‐6 was infused (i.v.) and used as a positive control. Following i.v. infusion, 0.011% of the erucic acid was extracted by the brain, compared to 0.055% of the arachidonic acid. About 60% of the brain erucic acid was found in the aqueous fraction compared to 30% for arachidonic acid. Further, erucic acid was targeted to cholesteryl ester and triacylglyceride pools, whereas arachidonic acid was targeted to phospholipid pools. In animals infused i.c.v., 0.078% of the dose was taken up and about 60% of the erucic acid was targeted to phospholipid pools. These results clearly demonstrate that erucic acid crosses the BBB, similar to arachidonic acid, and is incorporated into specific lipid pools.Acknowledgements: This work was supported by The Myelin Project.