Gender-Specific Beneficial Effects of Docosahexaenoic Acid Dietary Supplementation in G93A-SOD1 Amyotrophic Lateral Sclerosis Mice
Docosahexaenoic acid (DHA) is an essential fatty acid modulating key nervous system functions, including neuroinflammation, and regulation of pre- and postsynaptic membrane formation. DHA concentration decreases in the lumbar spinal cord (LSC) of amyotrophic lateral sclerosis (ALS) patients and murine preclinical models. Using a dietary supplementation, we increased DHA levels (2% mean increase, p < 0.01) in the LSC of the familial ALS murine model B6SJL-Tg(SOD1*G93A)1Gur/J. This DHA-enriched diet significantly increases male mouse survival by 7% (average 10 days over 130 days of life expectancy), and delays motor dysfunction (based on stride length) and transgene-associated weight loss (p < 0.01). DHA supplementation led to an increased anti-inflammatory fatty acid profile (ca 30%, p < 0.01) and a lower concentration of circulating proinflammatory cytokine TNF-α (p < 0.001 in males). Furthermore, although DHA-treated mice did not exhibit generally decreased protein oxidative markers (glutamic and aminoadipic semialdehydes, carboxyethyllysine, carboxymethyllysine, and malondialdehydelysine), dietary intake of DHA reduced immunoreactivity towards DNA oxidative damage markers (8-oxo-dG) in the LSC. In vitro we demonstrate that DHA and α-tocopherol addition to a model of motor neuron demise (neonatal rat organotypic spinal cord model under chronic excitotoxicity) also preserves motor neuron number, in comparison with untreated spinal cords. Also, beneficial effects on cell viability were evidenced for the motor neuron cell line NSC-34 in front of H2O2 insult (p < 0.001). Globally we show a sex-specific benefit of dietary DHA supplementation in the G93A ALS mouse model, compared with mice fed an isocaloric control or a n-3-depleted diet. These changes were associated with an increased DHA concentration in the LSC and were compatible with in vitro results showing DHA neuroprotective properties. These results suggest the need for further study on the interaction of gender-influenced biological parameters and DHA in ALS pathogenesis.
Key WordsPolyunsaturated fatty acids protein oxidative modification neuroinflammation estrogens n-3 fatty acids
We thank D. Argilés and M. Martí for their skillful assistance. Grants were received from the Instituto de Salud Carlos III (PI 17-000134) to MPO and from the Generalitat de Catalunya 2017SGR696 to RP. PT is a predoctoral fellow from the Ministerio de Educacion (FPU16/01446). Support was also received in the form of a FUNDELA Grant, RedELA-Plataforma Investigación and the Fundació Miquel Valls (Jack Van den Hoek donation). FEDER funds are acknowledged (“A way to make Europe”).
Compliance with Ethical Standards
All experimental procedures were approved by the Institutional Animal Care Committee of the University of Lleida, according to local laws and to the Directive 2010/63/EU of the European Parliament
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