SummaryEpidemiological data suggest that a poor x3 status favoured by the low x3/x6 polyunsaturated fatty acids ratio in western diets contributes to cognitive decline in the elderly, but mechanistic evidence is lacking. We therefore explored the impact of x3 deficiency on the evolution of glutamatergic transmission in the CA1 of the hippocampus during aging by comparing 4 groups of rats aged 6-22 months fed x3-deficient or x3/x6-balanced diets from conception to sacrifice: Young x3 Balanced (YB) or Deficient (YD), Old x3 Balanced (OB) or Deficient (OD) rats. x3 Deficiency induced a 65% decrease in the amount of docosahexaenoic acid (DHA, the main x3 in cell membranes) in brain phospholipids, but had no impact on glutamatergic transmission and astroglial function in young rats. Aging induced a 10% decrease in brain DHA, a 35% reduction of synaptic efficacy (fEPSP/PFV) due to decreased presynaptic glutamate release and a 30% decrease in the astroglial glutamate uptake associated with a marked astrogliosis (+100% GFAP). The x3 deficiency further decreased these hallmarks of aging (OD vs. OB rats: À35% fEPSP/PFV P < 0.05, À15% astroglial glutamate uptake P < 0.001, +30% GFAP P < 0.01). This cannot be attributed to aggravation of the brain DHA deficit because the brains of OD rats had more DHA than those of YD rats. Thus, x3 deficiency worsens the age-induced degradation of glutamatergic transmission and its associated astroglial regulation in the hippocampus.

Omega-3 fatty acids are important for several neuronal and cognitive functions. Altered omega-3 fatty acid status has been implicated in reduced resistance to stress and mood disorders. We therefore evaluated the effects of repeated restraint stress (6 h/day for 21 days) on adult rats fed omega-3 deficient, control or omega-3 enriched diets from conception. We measured body weight, plasma corticosterone and hippocampus glucocorticoid receptors and correlated these data with emotional and depression-like behaviour assessed by their open-field (OF) activity, anxiety in the elevated-plus maze (EPM), the sucrose preference test and the startle response. We also determined their plasma and brain membrane lipid profiles by gas chromatography. Repeated restraint stress caused rats fed a control diet to lose weight. Their plasma corticosterone increased and they showed moderate behavioural changes, with increases only in grooming (OF test) and entries into the open arms (EPM). Rats fed the omega-3 enriched diet had a lower stress-induced weight loss and plasma corticosterone peak, and reduced grooming. Rats chronically lacking omega-3 fatty acid exhibited an increased startle response, a stress-induced decrease in locomotor activity and exaggerated grooming. The brain omega-3 fatty acids increased as the dietary omega-3 fatty acids increased; diets containing preformed long-chain omega-3 fatty acid were better than diets containing the precursor alpha-linolenic acid. However, the restraint stress reduced the amounts of omega-3 incorporated. These data showed that the response to chronic restraint stress was modulated by the omega-3 fatty acid supply, a dietary deficiency was deleterious while enrichment protecting against stress.

The many functions of astrocytes, such as glutamate recycling and morphological plasticity, enable them to stabilize synapses environment and protect neurons. Little is known about how they adapt to glucocorticoid-induced stress, and even less about the influence of dietary factors. We previously showed that omega-3 polyunsaturated fatty acids (x3PUFA), dietary fats which alleviate stress responses, influence the way astroglia regulate glutamatergic synapses. We have explored the role of docosahexaenoic acid (DHA), the main x3PUFA, in the astroglial responses to corticosterone, the main stress hormone in rodents to determine whether x3PUFA help astrocytes resist stress. Cultured rat astrocytes were enriched in DHA or arachidonic acid (AA, the main x6PUFA) and given 100 nM corticosterone for several days.Corticosterone stimulated astrocyte glutamate recycling by increasing glutamate uptake and glutamine synthetase (GS), and altered the astrocyte cytoskeleton. DHA-enriched astrocytes no longer responded to the action of corticosterone on glutamate uptake, had decreased GS, and the cytoskeletal effect of corticosterone was delayed, while AA-enriched cells were unaffected. The DHA-dependent anti-corticosterone effect was related to fewer glucocorticoid receptors, while corticosterone increased DHA incorporation into astrocyte membranes. Thus, DHA helps astrocytes resist the influence of corticosterone, so perhaps promoting a sustainable response by the stressed brain.

Hyperhomocysteinemia, defined by an increased plasma homocysteine level, is commonly associated with chronic liver diseases. A link between the elevated homocysteine level and oxidative stress has been demonstrated. Indeed the pathogenesis of liver diseases in the case of hyperhomocysteinemia could be due to this production of oxidative stress. Many studies have demonstrated the antioxidative properties of lycopene, a carotenoid. Therefore, the present study was designed to induce hyperhomocysteinemia in male Wistar rats in order to analyze the effect of lycopene supplementation on homocysteine metabolism, on phase I and phase II xenobiotic-metabolizing enzyme activities, and on liver injury by histological examination and analysis of biochemical markers. We found that rats with a high methionine diet showed abnormal histological features, with an increase of serum homocysteine, alanine aminotransferase and aspartate aminotransferase levels, decreased hepatic cystathionine beta synthase and S-adenosyl-homocysteine hydrolase activities and an increased hepatic malondialdehyde level. We demonstrated the reversal effect of lycopene supplementation on hyperhomocysteinemia. Taken together, these findings provide additional clues on the hepatoprotective effects of lycopene.