Neuropathological Responses to Chronic NMDA in Rats Are Worsened by Dietary n-3 PUFA Deprivation but Are Not Ameliorated by Fish Oil Supplementation

Abstract

BackgroundDietary long-chain n-3 polyunsaturated fatty acid (PUFA) supplementation may be beneficial for chronic brain illnesses, but the issue is not agreed on. We examined effects of dietary n-3 PUFA deprivation or supplementation, compared with an n-3 PUFA adequate diet (containing alpha-linolenic acid [18:3 n-3] but not docosahexaenoic acid [DHA, 22:6n-3]), on brain markers of lipid metabolism and excitotoxicity, in rats treated chronically with NMDA or saline.MethodsMale rats after weaning were maintained on one of three diets for 15 weeks. After 12 weeks, each diet group was injected i.p. daily with saline (1 ml/kg) or a subconvulsive dose of NMDA (25 mg/kg) for 3 additional weeks. Then, brain fatty acid concentrations and various markers of excitotoxicity and fatty acid metabolism were measured.ResultsCompared to the diet-adequate group, brain DHA concentration was reduced, while n-6 docosapentaenoic acid (DPA, 22:5n-6) concentration was increased in the n-3 deficient group; arachidonic acid (AA, 20:4n-6) concentration was unchanged. These concentrations were unaffected by fish oil supplementation. Chronic NMDA increased brain cPLA2 activity in each of the three groups, but n-3 PUFA deprivation or fish oil did not change cPLA2 activity or protein compared with the adequate group. sPLA2 expression was unchanged in the three conditions, whereas iPLA2 expression was reduced by deprivation but not changed by supplementation. BDNF protein was reduced by NMDA in N-3 PUFA deficient rats, but protein levels of IL-1β, NGF, and GFAP did not differ between groups.ConclusionsN-3 PUFA deprivation significantly worsened several pathological NMDA-induced changes produced in diet adequate rats, whereas n-3 PUFA supplementation did not affect NMDA induced changes. Supplementation may not be critical for this measured neuropathology once the diet has an adequate n-3 PUFA content.

Threshold changes in rat brain docosahexaenoic acid incorporation and concentration following graded reductions in dietary alpha-linolenic acid

“…This is consistent with evidence of decreased mRNA, protein or activity of DHA-metabolizing enzymes, including DHA-releasing calcium-independent phospholipase A 2 VIA (iPLA 2 ), cyclooxygenase (COX)-1 and 12-lipoxygenase (LOX) [21, 22]. The decrease in brain DHA metabolism is accompanied by a reciprocal increase in AA-metabolizing group IVA calcium-dependent phospholipase A 2 (cPLA 2 ) and COX-2 [21, 22]. While brain AA turnover or half-life did not change [23, 24], n-6 DPA concentration and turnover increased [25], suggesting that n-6 DPA replaces DHA and may act as a substrate for AA-metabolizing enzymes during chronic n-3 deficiency.…”

“…turnover) within membrane phospholipids [19] and increased elimination half-life from 33 to 90 days [20]. This is consistent with evidence of decreased mRNA, protein or activity of DHA-metabolizing enzymes, including DHA-releasing calcium-independent phospholipase A 2 VIA (iPLA 2 ), cyclooxygenase (COX)-1 and 12-lipoxygenase (LOX) [21, 22]. The decrease in brain DHA metabolism is accompanied by a reciprocal increase in AA-metabolizing group IVA calcium-dependent phospholipase A 2 (cPLA 2 ) and COX-2 [21, 22].…”

“…Many rodent studies reported deleterious effects of n-3 PUFA deficient diets (0.2% α-LNA) on brain neuropathology and behavior [15–18], particularly when challenged with trauma or a neurotoxin [3, 22, 45]. While these studies demonstrate the essentiality of dietary α-LNA for maintaining brain DHA levels and function, they are not likely to be clinically relevant because extreme n-3 PUFA deficiency may not be common in humans.…”

N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update

“…Fish oil supplemented and n-3 PUFA adequate diets appeared to decrease NMDA induced cPLA 2 activity compared to diets deficient in n-3 PUFA, despite not changing cPLA 2 protein level. Fish oil and n-3 PUFA adequate diets also did not modify NMDA induced GFAP, IL-1 and sPLA 2 increases in protein levels (Keleshian et al, 2014).…”

Omega-3 polyunsaturated fatty acids and brain aging

“…Dietary v-3 PUFA seems to be crucial for plasma membrane function, interneuron signaling, synaptic transmission and cognition, in both aging brains and those damaged by traumatic brain injury [30], and excitotoxic damage [31,32]. The long-term deficits in hippocampal synaptic plasticity caused by prenatal exposure to ethanol can be reversed by v-3 PUFA [33]; v-3 PUFA can also selectively reduce the excitatory sharp waves (that model the interictal 'spikes' occurring in temporal lobe epilepsy) in hippocampal slices [34].…”