4.2.1. Neuroinflammation Mediated by LPS

A neuroinflammation model could be obtained by injection of LPS intraperitoneally (i.p. injection) or directly in the brain of C57BL/6J mice; i.p. injection of LPS works to increase the levels of TNF-α, IL-1β, IL-6, iNOS, and CCL2 in the brain. Expression of these mRNA and the number of Iba-1 positive cells significantly decrease when synaptamide is administered (5 mg/kg). These effects are not observed when synaptamide is injected in Gprotein-coupled receptor 110 (GPR110) knock-out mice after LPS induction, suggesting that anti-inflammatory effects in vivo depend on GPR110 [32]. In another study, fish hydrolysate supplementation, containing low amounts of DHA (143 μg in 150 μL of fish hydrolysate supplement/day), reduced expression of TLR4, cytokines (IL-6, TNF-α, IL-1β,), CCL2, and the inhibitor of the nuclear factor κB (IκB) in mice with LPS induction. DHA alone reduced only IL-6 expression. Furthermore, the authors observed lower expressions of CD86, CD68, and CD11b M1-markers in DHA groups compared to LPS groups fed with fish hydrolysate, but no effect on CD206, CD36, and Arg1-M2 markers were observed in the hippocampus. The authors suggest that the DHA effect is potentialized in fish oil by other low molecular weight peptides [34]. As well as in in vitro experiment, RvD2 could inhibit microglia activation in PD model LPS-treated animals (RvD2 per 25, 50, and 100 ng/kg, 27 days post LPS-treatment). The activation of microglia is significantly lower after treating animals with RvD2 (25, 50, and 100 ng/kg, 27 days post LPS-treatment) than in the vehicle group (more ramified microglia and less CD11b content of the substantia nigra pars compacta in the treated group). Furthermore, IL-18, IL-6, NO, TNF-α, and IL-1β production induced

by LPS were significantly inhibited by RvD2 in a dose dependent manner (2,5 μM to 20 μM), in vivo (serum) and in vitro, probably through inhibition of the TLR4/NF-kB pathway [44]. In their study, Fourrier et al. showed that 1-palmitoyl,2-docosahexaenoyl-PC (PC-DHA, 4.33 μg/g of mouse) attenuates the effect of LPS in mice brains when injected 24 h prior to LPS induction. Particularly, IL-6 production induced by LPS significantly decreased in the hippocampus. The in vitro results on BV-2 microglial cells suggest that these effects could be mediated by GP130 receptors [23]. Some authors did not observe significant effects of DHA dietary supplementation in vivo, even with a DHA increase in the brain. In [35], even though supplementing piglets with herring oil (DHA: 32.30% W/W total fatty acid), starting at postnatal day 2, led to a concentration increase of 27% at 14 postnatal days compared to piglets without supplementation, no attenuation of the LPS induced inflammation was observed. In a different model of LPS-induced inflammation (intracerebroventricular LPS injections in C57Bl/6 male mice), similar results were obtained. Indeed, DHA (fish oil, 1.4% of total fatty acids) increased more than 90% in fat-1 mice compared to their wildtype littermates, and a similar increase was observed in the brains of fish oil-fed mice compared to wildtype animals fed with a safflower diet. Despite this increase, no change in the expression of pro-inflammatory genes was found [36]. These contradictory results could be explained by the different modalities of LPS injection, the different animal models used, and the variations in analysis time.
