Pharmacokinetics of oxygenated DHA, 4(RS)-4-F4t-Neuroprostane in rodent brain

Abstract

Docosahexaenoic acid (DHA) are predominantly abundant in cellular membranes of the central nervous system (CNS). The exact molecular mechanisms of how DHA exert its beneficial roles to the CNS remains largely unexplored, but is associated to the generation of anti-inflammatory enzymatic-derived lipid mediators, such as Resolvins (Rv) D1-6, Neuro-protectin D1 (NPD1/PD1), and Protectin DX (PDX), upon receptor-mediated signal transduction. Imbalance of reactive species in tissues spontaneously triggers non-enzymatic lipid peroxidation, especially the highly unsaturated fatty acid, DHA. Neuroprostanes (NeuroPs) are nonenzymatically derived lipid mediators from DHA oxygenation and are believed to be the gold standard for oxidative damage in the brain. These NeuroPs have a vital role to play in the pathogenesis of neurodegenerative diseases like the Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, as the levels of NeuroPs were elevated in the brains of these patients. Not until recently, a 4-series NeuroP (4(RS)-4-F4t-NeuroP), among the eight possible regioisomeric groups has demonstrated to possess anti-arrhythmic property in cellulo and in vivo. This study, for the first time, has further emphasized that not all isoprostanoids are unfavourable. Also, we identified that 4(RS)-4-F4t-NeuroP was the predominant isoprostanoids in normal pig and rat brain. To further probe on its functionality in the brain and its pharmacokinetics, we infused 4(RS)-4-F4t-NeuroP intravenously in male Sprague Dawley rats. The rats were sacrificed at eight different time points after injections: 0 (control), 5 s, 30 s, 1 h, 2 h, 4 h, 6 h and 24 h. Plasma was separated from the whole blood and organs were harvested immediately. The plasma concentration of 4(RS)-4-F4t-NeuroP was quantified throughout the time-course using the LCMS/MS. Our preliminary data suggest that the administration of 4(RS)-4-F4t-NeuroP is rapid with a fast rate of elimination, similar to those administrated with F2-Isoprostanes as previously reported by others.