Differential effect of a carotenoid-rich diet on retina function in non-diabetic and diabetic rats.

Objective: This study was designed to examine the supplementation of a carotenoid-rich carrot powder, on retina function and carotenoid metabolism in non-diabetic control and type 1 diabetic animals. Methods: Male Wistar rats (n = 30) were randomly assigned to diets supplemented with (n = 15) or without (n = 15) carrot powder enriched diets (150 g/kg diet). After 3 weeks of diet adaptation, 8 rats in each group were treated with streptozotocin (iv) to induce type 1 diabetes and fed for a further 9 wk. Retinal function was assessed with the electroretinogram (ERG). Hepatic and plasma retinoids and carotenoids were measured by ultra-performance liquid chromatography. Results: Non-diabetic control rats fed the carrot diet had significantly (p < 0.02) higher rod- and cone- driven post-synaptic b-wave amplitudes, respectively, compared to those fed the control diet. These functional changes correlated with higher (p < 0.05) liver levels of carotenoids (α- and ß- carotene) and retinoids. In diabetic rats, carrot diet exacerbated retina dysfunction; the amplitudes for most of rod- and cone-driven ERG components were the lowest amplitudes among all groups (p < 0.02). Diabetic rats fed the carrot diet had lower hepatic retinol and retinyl palmitate, while having higher α- and ß-carotene levels, indicating diminished hepatic conversion of carotenoids into retinoids. Discussion: Dietary supplementation of high dose dietary carotenoids plays a beneficial role on healthy rat retina function, but exerts a detrimental effect in diabetes, which warrants undertaking detailed mechanistic studies.

Parenteral Lipid Dose Restriction With Soy Oil, Not Fish Oil, Preserves Retinal Function in Neonatal Piglets.

BACKGROUND: A dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (AA) is critical for neonatal retinal development. Both are absent/minimal in parenteral nutrition (PN) using soy-oil emulsions ([SO] Intralipid®) traditionally used for neonatal intestinal failure. In contrast, fish-oil emulsions ([FO] Omegaven®) are enriched in DHA/AA. The aim of this study was to compare retinal function and fatty acid content in neonatal piglets fed PN with SO or FO. METHODS: Two-5-day-old piglets were randomly allocated to SO (n = 4) or FO (n = 4), provided at equivalent doses (5g/kg/d). After 14 days of PN, retinal function was assessed by electroretinography and retinas were harvested for fatty acid content analysis. Sow-fed piglets served as a reference (REF). RESULTS: Light flash-elicited stoppage of cone and rod dark-currents (a-waves) and the ensuing postsynaptic activation of cone and rod ON bipolar cells (b-waves) were comparable between SO and REF. Responses recorded from FO were subnormal (P <0.001) when compared with both SO and REF. Retinal DHA content was similar in both groups (FO, 14.59% vs SO, 12.22%; P = 0.32); while AA was lower in FO (FO, 6.01% vs SO, 8.21%; P = .001). CONCLUSION: Paradoxically, FO containing more DHA and AA did not preserve retinal function when compared with the same low dose of SO. This may be due to the reduced AA enrichment in the retina with FO treatment. Further investigation into the ideal amounts of DHA and AA for optimal neonatal retinal function is required.

A Third-Generation Lipid Emulsion that Contains n-3 Long-Chain PUFAs Preserves Retinal Function in Parenterally Fed Neonatal Piglets.

BACKGROUND: Preterm neonates and those with intestinal failure require prolonged parenteral nutrition (PN) during a critical time of early central nervous system maturation. Conventional lipid emulsions fed to preterm neonates lack n-3 (ω-3) long-chain polyunsaturated fatty acids (LC-PUFAs; >20 carbon chain in length). Recently, fish oil lipid emulsions have been developed that provide both n-6 (ω-6) and n-3 LC-PUFAs, precursors of very long-chain PUFAs (VLC-PUFAs; >24 carbon chain in length). OBJECTIVE: Our objective was to determine the effect of fish oil lipid on retinal function in neonatal piglets fed total PN with the use of the lipid emulsions available in clinical practice. We hypothesized that fish oil-containing parenteral lipid would preserve retinal function more than conventional parenteral lipid. METHODS: Male neonatal piglets (2-5 d of age) were fed isonitrogenous (16 g · kg-1 · d-1), isocaloric (1.1 MJ · kg-1 · d-1) PN that varied only in the lipid emulsion: Intralipid or SMOFlipid at 10 g · kg-1 · d-1 (n = 8/group). Retinal function was assessed after 14 d of treatment by recording electroretinograms under various light intensity conditions. Retinas were then harvested for histology and to determine fatty acid composition. RESULTS: Electroretinogram intensity response curves showed greater photoreceptor a-wave amplitude in piglets fed SMOFlipid than in those fed Intralipid (percentage), for postsynaptic depolarizing bipolar cell b-waves (percentage) and for flicker electroretinogram amplitudes (percentage) (P < 0.05). Compared with those fed Intralipid, SMOFlipid-fed piglets had greater retinal total n-3 LC-PUFAs (15.7% compared with 18.4%; P = 0.04) and n-3 VLC-PUFAs (0.9% compared with 1.5%; P = 0.02), whereas Intralipid-fed piglets had greater total n-6 LC-PUFAs (13.1% compared with 10.5%; P < 0.01) and n-6 VLC-PUFAs (0.7% compared with 0.5%; P = 0.01). Histologically, retinas were indistinguishable between groups. CONCLUSIONS: In a neonatal piglet model of PN feeding, the inclusion of fish oil-based n-3 LC-PUFAs in the lipid emulsion leads to their accretion and endogenous elongation to VLC-PUFAs in the retina, which is associated with better retinal function.

DHA supplementation enhances high-frequency, stimulation-induced synaptic transmission in mouse hippocampus.

While some studies on dietary supplementation with docosahexaenoic acid (DHA, 22:6n-3) have reported a beneficial effect on memory as a function of age, others have failed to find any effect. To clarify this issue, we sought to determine whether supplementing mice with a DHA-enriched diet could alter the ability of synapses to undergo activity-dependent changes in the hippocampus, a brain structure involved in forming new spatial memories. We found that DHA was increased by 29% ± 5% (mean ± SE) in the hippocampus for the supplemented (DHA+) versus nonsupplemented (control) group (n = 5 mice per group; p < 0.05). Such DHA elevation was associated with enhanced synaptic transmission (p < 0.05) as assessed by application of a high-frequency electrical stimulation protocol (100 Hz stimulation, which induced transient (<2 h) increases in synaptic strength) to slices from DHA+ (n = 4 mice) hippocampi when compared with controls (n = 4 mice). Increased synaptic responses were evident 60 min poststimulation. These results suggest that dietary DHA supplementation facilitates synaptic plasticity following brief high-frequency stimulation. This increase in synaptic transmission might provide a physiological correlation for the improved spatial learning and memory observed following DHA supplementation.

Dietary docosahexaenoic acid supplementation prevents age-related functional losses and A2E accumulation in the retina.

PURPOSE: With age, retina function progressively declines and A2E, a constituent of the toxin lipofuscin, accumulates in retinal pigment epithelial (RPE) cells. Both events are typically exacerbated in age-related retina diseases. We studied the effect of dietary docosahexaenoic acid (DHA, C22:6n-3) supplementation on these events, using a transgenic mouse model (mutant human ELOVL4; E4) displaying extensive age-related retina dysfunction and massive A2E accumulation. METHODS: Retina function was assessed with the electroretinogram (ERG) and A2E levels were measured in E4 and wildtype (WT) mice. Dietary DHA was manipulated from 1 to 3, 1 to 6, 6 to 12, and 12 to 18 months: 1% DHA over total fatty acids (E4+, WT+) or similar diet without DHA (E4-, WT-). RESULTS: Increased omega-3/6 ratios (DHA/arachidonic acid) in E4+ and WT+ retinas were confirmed for the 1- to 3-month and 1- to 6-month trials. Although 1- to 3-month intervention had no effects, when prolonged to 1 to 6 months, RPE function (ERG c-wave) was preserved in E4+ and WT+. Intervention from 6 to 12 months led to maintained outer and inner retina function (ERG a- and b-wave, respectively) in E4+. At 12 to 18 months, a similar beneficial effect on retina function occurred in WT+; A2E levels were reduced in E4+ and WT+. CONCLUSIONS: DHA supplementation was associated with: preserved retina function at mid-degenerative stages in E4 mice; prevention of age-related functional losses in WT mice; and reduced A2E levels in E4 and WT mice at the oldest age examined. These findings imply that dietary DHA could have broad preventative therapeutic applications (acting on pathologic and normal age-related ocular processes).

Supranormal electroretinogram in fat-1 mice with retinas enriched in docosahexaenoic acid and n-3 very long chain fatty acids (C24-C36).

PURPOSE: Fat-1 mice can convert n-6 to n-3 fatty acids endogenously, resulting in the accumulation of n-3 fatty acids in major tissues. This was a study of how this conversion affects the major fatty acid found in retina, n-3 docosahexaenoic acid (DHA), the very long chain fatty acids (VLCFA, C24-C36), and retinal function. METHODS: Both wild-type (WT) and fat-1 mice were fed a modified AIN-93G diet containing 10% safflower oil, high in 18:2n-6. Fatty acid composition of individual phospholipids was analyzed in total lipid extracts from whole eyes excluding the lens. Retinal function and levels of proteins involved in cellular stress were assessed with full field electroretinogram (ERG) recordings and immunohistochemistry, respectively. RESULTS: Compared with WT mice, DHA levels in fat-1 mice increased two to five times in all phospholipid classes, whereas n-6 fatty acid levels decreased. Levels of C32 and C34 n-3 pentaenoic and hexaenoic VLCFA in phosphatidylcholine increased whereas n-6 VLCFAs were depleted. Scotopic and photopic ERGs showed unusually high amplitudes for both a- and b-waves and lower thresholds in fat-1 mice. Glial fibrillary acidic protein (GFAP) and carboxyethylpyrrole (CEP, protein adducts produced from DHA oxidation) were respectively increased in Müller cells and photoreceptors of fat-1 mice. CONCLUSIONS: Highly enriched DHA and n-3 VLCFA in the retina lead to supernormal scotopic and photopic ERGs and increases in Müller cell reactivity and oxidative stress in photoreceptors. The regulation of n-3 fatty acids levels and of the n-6/n-3 fatty acid ratio are essential in preserving retinal integrity.