Arachidonic acid (ARA) is a major component of lipid bilayers as well as the key substrate for the eicosanoid cascades. ARA is readily oxidized, and its non-enzymatic and enzymatic oxidation products induce inflammatory responses in nearly all tissues, including lung tissues. Deuteration at bis-allylic positions substantially decreases the overall rate of ARA oxidation when hydrogen abstraction is an initiating event. To compare the effects of dosing of arachidonic acid (H-ARA) and its bis-allylic hexadeuterated form (D-ARA) on lungs in conventionally healthy mice and in an acute lung injury model, mice were dosed with H-ARA or D-ARA for six weeks through dietary supplementation and then challenged with intranasal lipopolysaccharide (LPS) for subsequent analysis of bronchoalveolar lavage fluid and lung tissue. Dosing on D-ARA resulted in successful incorporation of D-ARA into various tissues. D-ARA significantly reduced LPS-induced adverse effects on alveolar septal thickness and the bronchoalveolar area. Oral deuterated ARA is taken up efficiently and protects against adverse LPS-induced pathology. This suggests novel therapeutic avenues for reducing lung damage during severe infections and other pathological conditions with inflammation in the pulmonary system and other inflammatory diseases.
The derivatives of fatty acids are considered as promising bases for the development of medicinal and cosmetic agents. In this regard, it is necessary to study their potential toxicity, including chronic. In repeated toxicity experiments on mice of C57BL6 line, the administration of N-palmitoyl-5-aminolevulinic acid (within liposomes) for 62 days was less toxic than N-palmitoylglycine injected in the same regimen, which resulted in lower mortality of animals. The toxic effects of high doses, both PalGly and Pal-5-ALA, are characterized by a gender dependence: males were more sensitive to PalGly, whereas females - to Pal-5-Ala. Chronic administration of liposomes of phosphatidylcholine (without N-acylamino acids) caused the death of several mice, suggesting that the toxic effects of PalGly and Pal-5-ALA in liposomal form are at least partly due to the influence of the liposomes themselves.
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