Essential omega-3 fatty acids tune microglial phagocytosis of synaptic elements in the mouse developing brain.

Omega-3 fatty acids (n-3 PUFAs) are essential for the functional maturation of the brain. Westernization of dietary habits in both developed and developing countries is accompanied by a progressive reduction in dietary intake of n-3 PUFAs. Low maternal intake of n-3 PUFAs has been linked to neurodevelopmental diseases in Humans. However, the n-3 PUFAs deficiency-mediated mechanisms affecting the development of the central nervous system are poorly understood. Active microglial engulfment of synapses regulates brain development. Impaired synaptic pruning is associated with several neurodevelopmental disorders. Here, we identify a molecular mechanism for detrimental effects of low maternal n-3 PUFA intake on hippocampal development in mice. Our results show that maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-HETE signaling, altering neuronal morphology and affecting cognitive performance of the offspring. These findings provide a mechanistic insight into neurodevelopmental defects caused by maternal n-3 PUFAs dietary deficiency.

Salba-chia (Salvia hispanica L.) in the treatment of overweight and obese patients with type 2 diabetes: A double-blind randomized controlled trial.

BACKGROUND AND AIM: Preliminary findings indicate that consumption of Salba-chia (Salvia hispanica L.), an ancient seed, improves management of type 2 diabetes and suppresses appetite. The aim of this study was to assesse the effect of Salba-chia on body weight, visceral obesity and obesity-related risk factors in overweight and obese adults with type 2 diabetes. METHODS: A double-blind, randomized, controlled trial with two parallel groups involved 77 overweight or obese patients with type 2 diabetes (HbA1c: 6.5-8.0%; BMI: 25-40 kg/m2). Both groups followed a 6-month calorie-restricted diet; one group received 30 g/1000 kcal/day of Salba-chia, the other 36 g/1000 kcal/day of an oat bran-based control. Primary endpoint was change in body weight over 6-months. Secondary endpoints included changes in waist circumference, body composition, glycemic control, C-reactive protein, and obesity-related satiety hormones. RESULTS: At 6-months, participants on Salba-chia had lost more weight than those on control (1.9 ± 0.5 kg and 0.3 ± 0.4 kg, respectively; P = 0.020), accompanied by a greater reduction in waist circumference (3.5 ± 0.7 cm and 1.1 ± 0.7 cm, respectively; P = 0.027). C-reactive protein was reduced by 1.1 ± 0.5 mg/L (39 ± 17%) on Salba-chia, compared to 0.2 ± 0.4 mg/L (7 ± 20%) on control (P = 0.045). Plasma adiponectin on the test intervention increased by 6.5 ± 0.7%, with no change observed on control (P = 0.022). CONCLUSIONS: The results of this study, support the beneficial role of Salba-chia seeds in promoting weight loss and improvements of obesity related risk factors, while maintaining good glycemic control. Supplementation of Salba-chia may be a useful dietary addition to conventional therapy in the management of obesity in diabetes. REGISTRATION: clinicaltrials.gov identifier: NCT01403571.

n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism.

Decreased docosahexaenoic acid (DHA) and brain-derived neurotrophic factor (BDNF) have been implicated in bipolar disorder. It also has been reported that dietary deprivation of n-3 polyunsaturated fatty acids (PUFAs) for 15 weeks in rats, increased their depression and aggression scores. Here, we show that n-3 PUFA deprivation for 15 weeks decreased the frontal cortex DHA level and reduced frontal cortex BDNF expression, cAMP response element binding protein (CREB) transcription factor activity and p38 mitogen-activated protein kinase (MAPK) activity. Activities of other CREB activating protein kinases were not significantly changed. The addition of DHA to rat primary cortical astrocytes in vitro, induced BDNF protein expression and this was blocked by a p38 MAPK inhibitor. DHA's ability to regulate BDNF via a p38 MAPK-dependent mechanism may contribute to its therapeutic efficacy in brain diseases having disordered cell survival and neuroplasticity.

Dietary n-3 PUFA deprivation alters expression of enzymes of the arachidonic and docosahexaenoic acid cascades in rat frontal cortex.

The enzymes that regulate the brain arachidonic acid (AA) cascade have been implicated in bipolar disorder and neuroinflammation. Fifteen weeks of dietary n-3 polyunsaturated fatty acid (PUFA) deprivation in rats decreases the concentration of docosahexaenoic acid (DHA) and increases its half-life within the brain. Based on this, we hypothesized that such dietary deprivation would decrease expression of enzymes responsible for the metabolic loss of DHA while increasing expression of those responsible for the metabolism of AA. Fifteen weeks of n-3 PUFA deprivation significantly decreased the activity, protein and mRNA expression of the DHA regulatory phospholipase A2 (PLA2), calcium-independent iPLA2, in rat frontal cortex. In contrast the activities, protein and mRNA levels of the AA selective calcium-dependent cytosolic phospholipase (cPLA2) and secretory sPLA2 were increased. Cyclooxygenase (COX)-1 protein but not mRNA was decreased in the n-3 PUFA-deprived rats whereas COX-2 protein and mRNA were increased. This study suggests that n-3 PUFA deprivation increases the half-live of brain DHA by downregulating iPLA2. The finding that n-3 PUFA deprivation increases cPLA2, sPLA2 and COX-2 is opposite to what has been reported after chronic administration of anti-manic agents to rats and suggests that n-3 PUFA deprivation may increase susceptibility to bipolar disorder.

Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex.

Chronic lithium and carbamazepine, which are effective against mania in bipolar disorder, decrease the activity of cytosolic phospholipase A(2) (cPLA(2)) and the turnover rate of arachidonic acid in phospholipids in rat brain. Assuming that stages of bipolar disorder are related to brain arachidonic acid metabolism, we hypothesized that drugs effective in depression would increase cPLA(2) activity. To test this hypothesis, adult male CDF-344 rats were administered fluoxetine (10 mg/kg intraperitoneally (i.p.) or saline (control) (i.p.) chronically for 21 days. Frontal cortex cPLA(2) protein, phosphorylated cPLA(2), activity and mRNA levels were increased after chronic fluoxetine. Transcription factors (activator protein-1, activator protein-2, glucocorticoid response element, polyoma enhancer element-3 and nuclear factor-kappa B) that are known to regulate cPLA(2) gene expression were not significantly changed by chronic fluoxetine, but nuclear AU-rich element/poly(U)-binding/degradation factor-1 RNA-stabilizing protein was increased significantly. The results suggest that chronic fluoxetine increases brain cPLA(2) gene expression post-transcriptionally by increasing cPLA(2) mRNA stabilization. Chronic fluoxetine's effect on cPLA(2) expression was opposite to the effect reported with chronic lithium or carbamazepine administration, and may be part of fluoxetine's mode of action.