45 - Lipidomics and therapeutic potential of nitro-oleic acid acid in a model of familial ALS

Abstract

The lack of current treatments for Amyotrophic Lateral Sclerosis (ALS) highlight the absence of a comprehensive understanding of the biological mechanisms that occur during the process of neurodegeneration. A consistent neuropathological feature of ALS is the extensive inflammation around motor neurons and axonal degeneration, evidenced by the accumulation of reactive astrocytes and activated microglia. Final products of inflammatory processes may be detected in blood and may act as a screening tool to identify treatment response. Herein, we focus on a) detecting products derived from arachidonic acid (AA) metabolization by the lipoxygenase (LOX) or prostaglandin endoperoxide H synthase pathways in blood from G93ASOD mice and b) evaluate the pharmacological modulation of the progress of the disease by electrophilic nitro-fatty acids (NFA), in particular nitro oleic acid (OA-NO2), because its well-documented unique anti-inflammatory properties. Results showed a different behavior of LOX-derived products in G93ASOD mice: an increase in 12-HETE levels was observed when clinical symptoms appeared whereas no changes were detected in age-matched wt mice. In addition, 5-HETE levels decreased faster in G93ASOD mice than in controls. This is in agreement with reports of 12/15-LOX formation in the central nervous system, suggesting that 12-HETE may be involved in brain oxidative damage. No changes in prostaglandins levels were observed in the plasma of transgenic mice while wt levels were greater at day 120. In addition, analysis of plasma samples from both wt and G93ASOD mice showed quantitative differences in lipid-derived products, which correlated with disease onset and progression. Administration of OA-NO2 16 mg/kg, s/c three times a week, to G93ASOD female mice, significantly improved grip strength and reduced weight loss compared to vehicle treated animals. Improved grip strength data were associated to increased heme oxygenase 1 (HO-1) expression. In fact, HO-1 co-localized with reactive astrocytes in the spinal cord of symptomatic mice. Furthermore, significant levels of OA-NO2 were detected in brain and spinal cord from OA-NO2-treated mice. We conclude that LOX-derived oxidation products correlate with disease progression and demonstrate that NFA can cross the brain barrier and be effective to reach the central nervous system to induce neuroprotective mechanisms. In this way, changes in the levels of AA-derived products were observed as well as different expression and activity of LOX in both brain and spinal cord from G93ASOD animals treated with OA-NO2. Overall, we are proposing key mediators of AA-derived pathways as novel footprints of ALS onset and progression with the aim to determine molecules associated with ALS and their underlying biology.