triolein and Inflammation

X-linked adrenoleukodystrophy is a rare inherited demyelinating disorder characterized by an abnormal accumulation of very long chain fatty acids, mainly hexacosanoic acid (26:0), due to a mutation of the gene encoding for a peroxisomal membrane protein. The only available, and partially effective, therapeutic treatment consists of dietary intake of a 4:1 mixture of triolein and trierucin, called Lorenzo's oil (LO), targeted to inhibit the elongation of docosanoic acid (22:0) to 26:0. In this study we tested whether, besides inhibiting elongation, an enhancement of peroxisomal beta oxidation induced by conjugated linoleic acid (CLA), will improve somatosensory evoked potentials and modify inflammatory markers in adrenoleukodystrophy females carriers. We enrolled five heterozygous women. They received a mixture of LO (40 g/day) with CLA (5 g/day) for 2 months. The therapeutic efficacy was evaluated by the means of plasma levels of 26:0, 26:0/22:0 ratio, modification of cerebrospinal fluid (CSF) inflammatory markers and somatosensory evoked potentials. Changes of fatty acid profile, and in particular CLA incorporation, were also evaluated in CSF and plasma. The results showed that CLA promptly passes the blood brain barrier and the mixture was able to lower both 26:0 and 26:0/22:0 ratio in plasma. The mixture improved somatosensory evoked potentials, which were previously found unchanged or worsened with dietary LO alone, and reduced IL-6 levels in CSF in three out of five patients. Our data suggest that the synergic activity of CLA and LO, by enhancing peroxisomal beta-oxidation and preventing 26:0 formation, improves the somatosensory evoked potentials and reduces neuroinflammation.

Topics: Adrenoleukodystrophy; Biomarkers; Blood-Brain Barrier; Drug Combinations; Erucic Acids; Evoked Potentials, Somatosensory; Fatty Acids; Female; Heterozygote; Humans; Inflammation; Inflammation Mediators; Interleukin-6; Linoleic Acids, Conjugated; Lipid Metabolism; Middle Aged; Oleic Acid; Oxidation-Reduction; Triolein

Alzheimer's disease (AD) brains are characterized by accumulation of amyloid beta protein (Abeta) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Abeta accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Abeta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Abeta, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Abeta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Abeta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Abeta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Abeta. Thus, inflammation potentially increases brain levels of Abeta by three mechanisms: increased influx, decreased efflux, and increased neuronal production.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Blood-Brain Barrier; Blotting, Western; Brain; Cyclooxygenase Inhibitors; Cytokines; Disease Progression; Dose-Response Relationship, Drug; Indomethacin; Inflammation; Lipopolysaccharides; Low Density Lipoprotein Receptor-Related Protein-1; Male; Mice; Oxidative Stress; Protein Transport; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Receptors, LDL; Triolein; Tumor Suppressor Proteins

We have developed methods for coating with fibrinogen both liposomes and microscopic droplets of olive oil. Because the fibrinogen bound to them is functional in the classic sense of fibrin gelation, the coated microparticles may have potential as vehicles for the targeted delivery of various molecules to sites of fibrin(ogen) deposition in vivo. So that we could assess directly this potential, we first established a method for eliciting reproducibly a focal, fibrin(ogen)-rich, inflammatory lesion in a hind footpad of mice. We then monitored the tissue distribution of fibrinogen-coated microparticles following their injection into the tail vein of mice bearing this well-defined lesion. As happens with most microparticles following their intravenous administration, liposomes and oil droplets, whether coated with fibrinogen or not, accumulate rapidly in the liver and spleen of treated animals. Indeed, in the case of oil droplets, accumulation of fibrinogen-coated microparticles in those organs and in the lungs is even greater than that of fibrinogen-free microparticles. However, as distinct from fibrinogen-free liposomes and oil droplets, fibrinogen-coated microparticles also accumulate in the inflamed hind footpad. We conclude that fibrinogen-coated liposomes and oil droplets do have potential as vehicles for delivering molecules to sites of fibrin(ogen) deposition in vivo.

Topics: Adjuvants, Immunologic; Animals; Carbon Radioisotopes; Chromatography, Gel; Drug Compounding; Fibrin; Fibrinogen; Hindlimb; Inflammation; Inulin; Iodine Radioisotopes; Liposomes; Mice; Microspheres; Olive Oil; Particle Size; Plant Oils; Poloxamer; Triolein

The intravenous injection of triolein in the rabbit, besides general consequences in some viscera (functional ischemic necrosis of the right ventricle, systemic cerebral and kidney embolisms), induces in the lung non specific reactions similar to those observed after other pulmonary agressions. Yet, some peculiarities are observed only in this experimental model: severe and persistent septal oedema due to early endothelial changes; intensive inflammatory response with numerous macrophages. On the other hand, except in zones with epithelio-conjonctive repair process of necrotic foci, the epithelial reaction reduced to a temporary predominance of type 2-pneumonocytes, remains of low intensity.

Topics: Animals; Disease Models, Animal; Edema; Embolism, Fat; Inflammation; Kidney Glomerulus; Lung; Rabbits; Time Factors; Triolein