Dihomo-gamma-linolenic Acid Research Articles

Effects of the incubation of long-chain polyunsaturated fatty acids on platelet lipids and thromboxane release

Alterations of dietary lipids have been advocated to manipulate platelet release of thromboxane A 2. We studied the effects of incubating platelets with several different polyunsaturated fatty acids on platelet-lipid profile and release of thromboxane A 2 in response to platelet stimulation. Porcine platelets were isolated by centrifugation, washed three times in Tyrode's solution, and incubated with fatty acids (500 μM) in Tyrode's solution with albumin. Seven polyunsaturated fatty acids of varying lengths (18-, 20-, and 22-carbon chain) of the ω3 and ω6 families were incubated for 60 min at concentrations of 0, 10, 30, and 100 μM with saturated fatty acids comprising the remainder of the 500 μM fatty acids. The platelets were then stimulated for 5 min with A 23187 (30 μM). Indomethacin was added, and the platelets were pelleted. Platelet lipids were extracted in hexane, transesterified and quantified by gas chromatography. Using radioimmunoassay, we measured thromboxane B 2, the stable metabolite of thromboxane A 2, in the platelets' supernatant. A 1-h incubation in each of the seven polyunsaturated fatty acids had no significant effect on platelet-lipid composition. We found a significant increase in thromboxane B 2 production in arachidonic acid (100 μM) incubated platelets (324.0 ± 63.8% of baseline) that was inhibited by eicosapentaenoic acid (81.0 ± 26.8%, P < 0.01) and to a lesser extent by dihomogammalinolenic acid (189.8 ± 28.3%, P < 0.03). We conclude that in altering diets to affect platelet release of thromboxane, the two fatty acids of interest are the 20-carbon chain fatty acids, dihomogammalinolenic acid and eicosapentaenoic acid. The ideal amount of each of these fatty acids to be incorporated entails supraphysiologic but pharmacologically achievable levels of fatty acids in plasma.

Cytotoxic action of alpha-linolenic and eicosapentaenoic acids on myeloma cells in vitro

Both alpha-linolenic (ALA) and eicosapentaenoic acids (EPA) were toxic to SP 2/0 mouse myeloma cells in vitro. On the other hand, linoleic acid (LA), gamma-linolenic acid (GLA), di-homo-gamma linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA) and oleic acid (OA) were much less effective in their growth suppressive actions. Both nordihydroguaiaretic acid (NDGA) and Indomethacin (IM) could block the action of the fatty acids indicating a role for prostaglandins (PGs) and leukotrienes (LTs) in the growth suppressive action of ALA and EPA. Superoxide dismutase (SOD) completely blocked, while vitamin E and reduced glutathione (GSH) could prevent to a limited extent the anti-proliferative effects of ALA and EPA. Catalase, mannitol, chlorpromazine (CPZ) and trifluoperazine (TFP) did not block the cytotoxic actions of ALA and EPA. N G-mono-methyl l-arginine (N GMMA), an analogue of l-arginine, which inhibits nitric oxide synthase, was ineffective in preventing the cytotoxicity induced by ALA and EPA. Fatty acid analysis of the various lipid fractions of SP 2/0 cells treated with ALA and EPA showed significant incorporation of these fatty acids in the cell membrane lipid pools. These results suggest that ALA and EPA induced suppression of SP 2/0 cell proliferation is cyclo-oxygenase (CO), lipoxygenase (LO) and superoxide dependent. Lipid peroxidation has only a limited role in this process. Both calmodulin dependent process and l-arginine derived nitric oxide do not seem to have a role in the cytotoxic action of ALA and EPA in these cells.

The incorporation of dietary n-3 polyunsaturated fatty acids into porcine platelet phospholipids and their effects on platelet thromboxane A 2 release

We investigated the dynamic changes in fatty acid (FA) composition in platelet phospholipid (PL) and in the release of thromboxane from stimulated platelets in pigs prefed a diet enriched with polyunsaturated fatty acids (PUFA) of the n-3 and n-6 families of FAs. For 20 days, we fed pigs diets supplemented with either corn oil, fish oil, or fish and borage oil. Platelets were separated from blood drawn at baseline and then on day 4, 8, 12, 16 and 20 of the dietary regimen. Analysis of the FA contained in platelet PL demonstrated that significant changes in PUFA composition occurred during dietary supplementation with fish oil and fish and borage oil. Eicosapentaenoic acid (EPA) from fish oil was rapidly incorporated into PL of platelets and reached a steady-state plateau by day 12. An increase in the content of docosahexaenoic acid (DHA) in the platelets' PL was observed in both groups receiving fish oil. This increase in n-3 PUFA in platelet PL occurred with a concomitant decrease in the content of n-6 FA, primarily of arachidonic acid (AA) in the PL of platelets in both fish oil groups. Dietary supplementation with borage oil, which contains gammalinolenic acid (GLA), increased dihomogammalinolenic acid (DGLA) content in platelet PL. Following A 23187 stimulation of platelets, levels of thromboxane B 2 (TxB 2), the stable metabolite of thromboxane A 2 (TxA 2), were significantly suppressed in both fish oil groups compared to the corn oil-supplemented group. Dietary supplementation of EPA and EPA plus GLA increased platelet PL content of EPA, and EPA and DGLA, respectively. Following platelet stimulation, TxA 2 production was significantly increased, an increase that was attenuated in the platelets from pigs prefed fish oil, and even more so in the fish and borage-oil-prefed pigs.

Long-Term Ovariectomy Effect on Plasma Glucose,Lipids,Antioxidant Vitamins, and Lipid Peroxides: Relationship with Aortic Cholesterol and Fatty Acid Distribution in Rats.

This study was performed to determine plasma lipid changes and antioxidant status in relation to cholesterol content and fatty acid distribution in the aorta of rats after long-term ovariectomy (OV). After 12 months, OV induced in rat plasma a significant increase in glucose, total cholesterol, and triglycerides compared with the corresponding values for the control rats (C) of the same age (p<0.0005, p<0.005, p<0.000S, respectively). These changes were associated with a significant increase in lipid peroxide level (p<0.05) and a significant decrease in vitamin E in the plasma from group OV compared with the group C level (p<0.0001). Conversely, OV after 7 and 12 months induced a significant increase in vitamin C (p<0.001, p<0.0001, respectively). Concerning plasma fatty acid distribution, after 12 months, OV caused a significant increase in gamma and dihomo gamma linolenic acid (p<0.0005, p<0.05, respectively). These changes were associated with a significant increase in aortic cholesterol in group OV (p<0.0005), and a significant decrease in the percentage of arachidonic acid (p<0.005) and of the total amount of fatty acids of the n-3 series (p<0.0001) and plasmalogen fatty acids (C16:0, p<0.005; C 18:0, p<0.05) compared with the corresponding values for group C. These results show that OV induced, independently of any effects of aging, plasma-specific lipid alterations with dysregulation of oxidative status, which could be crucial in the development of atherothrombotic disease.

The serum cholesterol ester fatty acid composition but not the serum concentration of alpha tocopherol predicts the development of myocardial infarction in 50-year-old men: 19 years follow-up

A low serum tocopherol concentration and a low proportion of linoleic acid in plasma cholesterol esters have been reported to be associated with coronary heart disease. This study was undertaken to evaluate the predictive importance of the serum cholesterol ester fatty acid composition and serum tocopherol concentration in addition to established risk factors for myocardial infarction. The study comprised 2322 fifty-year-old men who participated in a health survey in 1970–1973 regarding risk factors for coronary heart disease. The proportions of myristic, palmitic, palmitoleic, and dihomogammalinolenic acid were significantly higher in 1970–1973 in subjects who suffered myocardial infarction during the following 19 years, while the proportion of linoleic acid was lower, than in those who remained healthy. Serum tocopherol did not differ significantly between the groups. LDL HDL ratio, systolic blood pressure, and arachidonic acid/dihomogammalinolenic acid ratio were significant independent discriminators between cases and controls in a stepwise logistic regression analysis. This study suggests that middle-aged men who later develop a myocardial infarction are characterized not only by conventional risk factors but also by an altered fatty acid composition of serum cholesterol esters, with a low arachidonic to dihomogammalinolenic acid ratio, indicating reduced Δ 5 desaturase activity. This may imply that changes in the quality of dietary fat intake, or an altered capacity to metabolize fatty acids in the body, could precede the development of coronary heart disease.

Oleic Acid and Linoleic Acid Are the Major Determinants of Changes in Keratinocyte Plasma Membrane Viscosity

Keratinocytes were grown in medium with no essential fatty acids as well as in media with specially selected fatty acid augmentations. Gas chromatographic determinations of 21 fatty acids in the phospholipids were correlated with plasma membrane viscosity obtained by electron paramagnetic resonance studies (n = 24). Using standard procedures from multivariate analysis, we derived an expression that modeled the viscosity data as a function of four key fatty acid levels: [formula see text] where the fatty acids are given in mole percent of total lipids and are identified as two number sequences: number of carbons followed by number of double bonds. No other fatty acid made a significant contribution to the regression equation. The range of viscosity was very large, varying from 60 to 120 cP over the sample population. The results are interpreted to indicate that polyunsaturated fatty acids are replaced with monounsaturated fatty acids by the keratinocytes and that dihomogamma-linolenic acid (20:3, n-6) plays an important role in membrane viscosity when essential fatty acids are available in the growth medium of these adult human cultured keratinocytes.

Relation of Smoking and Alcohol Consumption to Serum Fatty Acids

To examine the relation of cigarette smoking and alcohol consumption to serum fatty acid levels, the authors conducted a cross-sectional study of 190 men who were enrolled in the Multiple Risk Factor Intervention Trial between 1973 and 1976. After controlling for dietary fat, cholesterol, energy intake, and other potential confounders, the authors found that smoking and alcohol intake were associated with the serum cholesterol ester and phospholipid levels of several fatty acids. As the number of cigarettes smoked per day increased, the levels of cholesterol ester and phospholipid palmitoleic acid (16:1) and oleic acid (18:1) and the levels of phospholipid dihomogammalinolenic acid (20:3) and omega-9 eicosatrienoic acid (20:3) increased (all p's < or = 0.01). Serum levels of phospholipid omega-3 docosahexaenoic acid (22:6) and cholesterol ester and phospholipid arachidonic acid (20:4) were inversely associated with smoking (all p's < or = 0.01). As the number of alcoholic drinks per week increased, levels of cholesterol ester and phospholipid palmitic acid (16:0) and oleic acid (18:1), cholesterol ester myristic acid (14:0), and phospholipid palmitoleic acid (16:1), adrenic acid (22:4), and omega-9 eicosatrienoic acid (20:3) increased (all p's < 0.05), whereas levels of cholesterol ester and phospholipid linoleic acid (18:2) and phospholipid stearic acid (18:0) and the serum polyunsaturated fat: saturated fat ratio decreased (all p's < or = 0.01). These results suggest that smoking and alcohol consumption may influence the absorption, synthesis, or metabolism of serum fatty acids. Studies that use serum fatty acid levels as indicators of dietary fat intake should control for the effects of cigarette smoking and alcohol consumption.

γ-Linolenic Acid Supplementation Can Affect Cancer Cell Proliferation via Modification of Fatty Acid Composition

We examined the effect of gamma-linolenic acid (GLA) supplementation on the growth and fatty acid composition of three human tumor cell lines (the neuroblastoma CHP-212, the tubal carcinoma TG, and the colon carcinoma SW-620), in order to evaluate the relationship between GLA-induced tumor cell death and the distribution of fatty acids in tumor cells. At the highest GLA concentrations (10 and 20 μg/ml), the DNA synthesis was completely abolished; at 5 μg/ml GLA only SW-620 cells did not proliferate, while CHP-212 and TG cells showed a residual [3H]-thymidine incorporation. GLA levels were very low in cells grown in control medium; GLA supplementation caused a significant incorporation of GLA itself in all the cell lines at each concentration. In TG and CHP-212 cells, GLA was metabolized, although to a different extent, to dihomo-gamma linolenic acid and arachidonic acid. SW-620 cells neither elongated nor desaturated the incorporated GLA. The highest cytostatic effect was reached when GLA was not transformed into its metabolites, suggesting that the GLA toxicity to tumor cells is not dependent on metabolites but is due to GLA itself.

Schizophrenia, tardive dyskinesia and essential fatty acids

Several reports have indicated that people suffering from schizophrenia show an associated abnormality in levels of certain essential fatty acids (EFAs) in blood cells. Similar abnormalities have also been noted in association with the presence of tardive dyskinesia (TD). In order to study this further, 72 patients with the diagnosis of schizophrenia or schizoaffective disorder were examined to assess the relationship between psychiatric status, movement disorder (TD) and relative levels of the n-3 and n-6 essential fatty acids in red blood cell membranes and plasma. Patients were followed up over the next 4.5 years to determine whether or not changes in clinical state showed any systematic relationship to changes in essential fatty acid levels. We hypothesised that patients with schizophrenia would show persistently lowered levels of n-6 and n-3 series essential fatty acids, compared with normal controls. We further hypothesised that this abnormality would be greater in the presence versus absence of TD and the dominance of negative rather than positive symptoms. The only consistent findings were that lower levels of linoleic acid and higher levels of dihomogamma-linolenic acid characterised the patient population compared with control subjects but there was considerable variability in patients' EFA profile.

Metabolism of gammalinolenic acid in human neutrophils.

Gammalinolenic acid (GLA), when provided as a dietary supplement, has been reported to improve clinical symptoms of several inflammatory disorders. The goal of the current study was to examine the metabolism of GLA and its relationship to arachidonic acid (AA) in the human neutrophil. Initial studies indicated that neutrophils provided GLA in vitro rapidly elongate it (by two carbons) to dihomogammalinolenic acid (DGLA). The bulk of this newly formed DGLA is incorporated into neutral lipids and specifically triacylglycerides. Neutrophils from volunteers supplemented with GLA as borage oil also had elevated quantities of DGLA but not GLA, when compared with neutrophils from volunteers not consuming the GLA supplement. To determine whether DGLA could be mobilized from cellular glycerolipids, neutrophils were stimulated with ionophore A23187 and fatty acid levels were determined. DGLA and AA were both released during stimulation, and the quantities of DGLA mobilized increased threefold after in vitro GLA supplementation. Exogenously provided DGLA was converted to one major metabolite during cell stimulation; this product migrated on reverse-phase HPLC with the 15-lipoxygenase product, 15-hydroxy-eicosa-trienoic acid (15-HETre). Both 15-HETre and DGLA (provided exogenously) inhibited the formation of leukotriene B4, (LTB4) and 20-hydroxy-leukotriene B4 (20-OH-LTB4). The IC50 for 15-HETre inhibition of both LTR, and 20-OH-LTB4 in A23187-stimulated neutrophils was 5 microM. This inhibition could be reversed by removing the compounds from the cells. Taken together, these data reveal that there are enzymes within the human neutrophil that metabolize GLA or its elongation product DGLA, and that the metabolism of GLA and AA may interact at a number of critical junctures.

Rapid modulation of lung and liver macrophage phospholipid fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic fatty acids

Dienoic eicosanoids derived from phospholipid arachidonic acid (AA) in lung and liver macrophages promote leukosequestration, thrombosis, and tissue injury. Current enteral diets (diet A) are enriched with linoleic acid (LA), a precursor of AA. Novel diets low in LA and containing eicosapentaenoic acid (EPA) and gamma-linolenic acid (GLA) foster formation of less inflammatory eicosanoids. The study objective was to assess the rapidity and extent of LA and AA displacement in vivo from alveolar macrophage (AM phi), lung, and liver Kupffer and endothelial (KE) cell phospholipids in rats fed enterally with diets enriched with 5.3% (by wt) EPA and either 1.2% or 4.6% GLA (diets B and C, respectively). After surgical placement of catheters, the rats were fed enterally and co-infused intravenously with either endotoxin or vehicle continuously for 3 or 6 d. Rats given either diet B or C had significantly lower (P < 0.01) relative percentages of AA and LA within the AM phi, lung, and KE cell phospholipids, and concomitantly higher percentages of EPA compared with rats infused with diet A after 3 d of enteral feeding irrespective of endotoxin co-infusion. Incorporation of dihomo-gamma-linolenic acid (DHGLA), the metabolite of GLA, into lung and KE phospholipids was significant in rats given diet C. Most of the changes in fatty acid composition occurred by day 3. The polyunsaturated fatty acid composition of AM phi, lung, and KE cell phospholipids can be rapidly modified by continuous short-term enteral feeding with EPA- and GLA-enriched diets irrespective of concurrent endotoxemia.

Changes of the mucosal n3 and n6 fatty acid status occur early in the colorectal adenoma-carcinoma sequence.

Despite data favouring a role of dietary fat in colonic carcinogenesis, no study has focused on tissue n3 and n6 fatty acid (FA) status in human colon adenoma-carcinoma sequence. Thus, FA profile was measured in plasma phospholipids of patients with colorectal cancer (n = 22), sporadic adenoma (n = 27), and normal colon (n = 12) (control group). Additionally, mucosal FAs were assessed in both diseased and normal mucosa of cancer (n = 15) and adenoma (n = 21) patients, and from normal mucosa of controls (n = 8). There were no differences in FA profile of both plasma phospholipids and normal mucosa, between adenoma and control patients. There were considerable differences, however, in FAs between diseased and paired normal mucosa of adenoma patients, with increases of linoleic (p = 0.02), dihomogammalinolenic (p = 0.014), and eicosapentaenoic (p = 0.012) acids, and decreases of alpha linolenic (p = 0.001) and arachidonic (p = 0.02) acids in diseased mucosa. A stepwise reduction of eicosapentaenoic acid concentrations in diseased mucosa from benign adenoma to the most advanced colon cancer was seen (p = 0.009). Cancer patients showed lower alpha linolenate (p = 0.002) and higher dihomogammalinolenate (p = 0.003) in diseased than in paired normal mucosa. In conclusion changes in tissue n3 and n6 FA status might participate in the early phases of the human colorectal carcinogenesis.

Effects of unsaturated fatty acids on expression of early response genes in human T lymphocytes.

Administration of gamma-linolenic acid, which is converted rapidly to dihomo-gamma-linolenic acid (DGLA), reduces joint swelling and tenderness in patients with rheumatoid arthritis. Joint tissue inflammation in patients with rheumatoid arthritis is due in part to activation of T lymphocytes. DGLA suppresses T cell activation and production of interleukin-2 (IL-2). The protooncogenes c-myc and c-fos are early response genes which are critical to regulation of T cell proliferation. We therefore examined the effects of gamma-linolenic acid and other unsaturated fatty acids on c-myc and c-fos expression by means of the polymerase chain reaction and Northern blotting. IL-2 production by the human T cell line Jurkat is dependent on a fall in mRNA for c-myc and a rise in mRNA for c-fos. The data presented here indicate that reduction of steady-state levels of mRNA for c-myc and rises in steady-state levels of mRNA for c-fos are both reduced markedly in cells incubated with DGLA. Cells incubated with arachidonic acid, eicosapentaenoic acid or oleic acid exhibit more modest changes in expression of these early response genes.

The significance of polyunsaturated fatty acids in cutaneous biology.

The skin epidermis displays a highly active metabolism of polyunsaturated fatty acids (PUFA). Dietary deficiency of linoleic acid (LA) and 18-carbon (n-6) PUFA results in characteristic scaly skin disorder and excessive epidermal water loss. Arachidonic acid, a 20-carbon (n-6) PUFA is metabolized via the cyclooxygenase pathway into predominantly prostaglandin E2 (PGE2) PGF2 alpha, and PGD2 and via the lipoxygenase pathway into predominantly 15-hydroxyeicosatetraenoic acid (15-HETE). The prostaglandins modulate normal skin physiological processes at low concentrations and inflammatory reactions at high concentrations. Similarly, the very active epidermal 15-lipoxygenase transforms dihomogammalinolenic acid (DGLA) into 15-hydroxy eicosatrienoic acid (15-HETrE), eicosapentaenoic acid (EPA) into 15-hydroxyeicosapentaenoic acid (15-HEPE) and docosahexaenoic acid (DHA) into 17-hydroxydocosahexaenoic acid (17-HDoHE), respectively. These monohydroxy acids exhibit anti-inflammatory properties. In contrast, the 18-carbon (n-6) PUFA is transformed into 13-hydroxy-9,11-octadecadienoic acid (13-HODE), which exerts antiproliferative properties in the tissue. Thus, the supplementation of diets with appropriate purified vegetable oils and/or fish oil may generate local cutaneous anti-inflammatory metabolites which could serve as a less toxic in vivo monotherapy or as adjuncts to standard therapeutic regimens for the management of skin inflammatory disorders.

(n-6)-Fatty acids in plasma lipids of children with atopic bronchial asthma.

It has been suggested that atopy is associated with an impairment in the delta 6-desaturation of (n-6)-polyunsaturated fatty acids and subsequently low levels of eicosanoid precursors. To evaluate this hypothesis we analyzed the fatty acid composition of plasma phospholipids and plasma cholesterol esters in a well-defined group of children with atopic bronchial asthma (n = 17) and age-matched healthy controls (n = 10). Atopic children showed significantly higher levels of linoleic acid and lower proportions of arachidonic acid in plasma lipids. No differences were observed with respect to gamma-linolenic acid (GLA) and dihomo-gamma-linolenic acid (DHLA). It is concluded that there is no biochemical evidence for a delta 6-desaturation defect in atopic children and therefore no justification for the supplementation of GLA and DHLA; e.g., by the use of evening primrose oil preparations.

Cytotoxic action of cis-unsaturated fatty acids on human cervical carcinoma (HeLa) cells in vitro

The effect of n-3 and n-6 fatty acids (FAs) on the growth of human cervical carcinoma (HeLa) cells was studied. Of all the FAs tested, docosahexaenoic acid (DHA, 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3) were found to be the most potent in their cytotoxic action on HeLa cells and the potency of various fatty acids with regard to their cytotoxic action was as follows: DHA > EPA > dihomo-gamma-linolenic acid (DGLA) = gamma-linolenic acid (GLA) > linoleic acid (LA) > arachidonic acid (AA) > alpha-linolenic acid (ALA). The cycloxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaretic acid (NDGA), the antioxidants vitamin E, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT), the superoxide anion quencher superoxide dismutase (SOD), the hydroxyl and hydrogen peroxide quenchers mannitol and catalase, respectively, and the calmodulin antagonists trifluoperazine (TFP) and chlorpromazine (CPZ) could all block the cytotoxic action of GLA, which was used as a representative cytotoxic FA, on HeLa cells. On the other hand, copper and iron salts and buthionine sulfoxamine, a glutathione (GSH) depletor, potentiated the cytotoxic action of suboptimal doses of GLA. GLA-induced radical generation and lipid peroxidation in HeLa cells could be blocked by indomethacin, NDGA and calmodulin antagonists. The cytotoxic action of cis-unsaturated fatty acids (c-UFAs) is not dependent on the alteration in the protein kinase C levels since no alteration in the diacylglycerol levels was observed. Hydroxy and hydroperoxy products of GLA were found to be toxic to HeLa cells, whereas prostaglandin (PG)E 1, PGF 2α, and prostacyclin stimulated cell growth. From these results, it is evident that radicals are the modulators of the cytotoxic action of c-UFAs, that their formation is a calmodulin-dependent process, and that lipoxygenase products may mediate the tumoricidal action of FAs.

Effect of in vitro incorporation of prostanoid precursors, superoxide radical and hydrogen peroxide on platelet function

The level of cyclic adenosine monophosphate (cAMP) in human platelets is known to be an important regulator of platelet function. The polyunsaturated fatty acids (PUFA) dihomo-gamma-linolenic acid (DHLA), and eicosapentaenoic acid (EPA), precursors of the prostaglandin (PG) 1 and 3 series respectively, were studied for their ability to stimulate platelet cAMP and/or PGE 1 levels, and to inhibit platelet aggregation (PAg). Incubation of washed platelets (1 × 10 8/ml) with 125 μM DHLA increased intraplatelet levels of PGE 1 from 197±7 to 1622±9.7 picograms/10 8, cAMP from 3±0.8 to 31±1.9 picomoles/10 8, and inhibited collagen-induced PAg. Addition of 1 μmole of xanthine per unit of xanthine oxidase (a superoxide radical generating system) to the incubating medium potentiated the effects of both fatty acids, whereas 240 μM Hydrogen Peroxide (H 2O 2) inhibited these effects. These results suggest that: (1) DHLA may be more effective in inhibiting PAg than EPA, which has been reported to reduce the incidence of coronary diseases in some human populations; (2) That superoxide radical may activate the platelet cyclooxygenase system to increase lipid peroxidation of these PUFA prostanoid precursors and may result in the inhibition of PAg, whereas H 2O 2 may have an opposite effect.

EICOSANOIDS IN RHEUMATOID ARTHRITIS

Eicosanoids are potent mediators in the cellular microenvironment. Eicosanoids have different effects depending on tissue or organ, the polyunsaturated fatty acid content of the diet of the individual, and the net effect of local microenvironmental factors--as eicosanoids, cytokines, and hormones modulate each others' effects through a complex, multilevel network of interactions. In general, eicosanoids have significant net proinflammatory effects. In RA, the net proinflammatory effects of the prostanoids is underscored by the effectiveness of the cyclooxygenase antagonists (NSAIDs), and recent data indicate a proinflammatory effect of the leukotrienes. Changes in the dietary polyunsaturated fatty acid composition to increased intake of marine n-3 fatty acids and/or dihomogamma-linolenic acid may favorably modulate eicosanoid synthesis towards less inflammatory or antiinflammatory eicosanoids and may ameliorate disease activity in RA. Recent advances in the biochemistry and molecular biology of the eicosanoid receptors and the synthetic pathways of eicosanoids will provide opportunities for advances in the therapeutics for RA, including selective cyclooxygenase (PGHS-2) antagonists, selective eicosanoid receptor antagonists and agonists, and selective inhibitors of PGH2 isomerases and enzymes of the 5-lipoxygenase pathway.

Essential fatty acid metabolism in patients with essential hypertension, diabetes mellitus and coronary heart disease

Mortality and morbidity from coronary heart disease (CHD), diabetes mellitus (DM) and essential hypertension (HTN) are higher in people of South Asian descent than in other groups. There is evidence to believe that essential fatty acids (EFAs) and their metabolites may have a role in the pathobiology of CHD, DM and HTN. Fatty acid analysis of the plasma phospholipid fraction revealed that in CHD the levels of gamma-linolenic acid (GLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are low, in patients with HTN linoleic acid (LA) and AA are low, and in patients with non-insulin dependent diabetes mellitus (NIDDM) and diabetic nephropathy the levels of dihomo-gamma-linolenic acid (DGLA), AA, alapha-linolenic acid (ALA) and DHA are low, all compared to normal controls. These results are interesting since DGLA, AA and EPA form precursors to prostaglandin E 1, (PGE 1), prostacyclin (PGI 2), and PGI 3, which are potent platelet anti-aggregators and vasodilators and can prevent thrombosis and atherosclerosis. Further, the levels of lipid peroxides were found to be high in patients with CHD, HTN, NIDDM and diabetic nephropathy. These results suggest that increased formation of lipid peroxides and an alteration in the metabolism of EFAs are closely associated with CHD, HTN and NIDDM in Indians. Since insulin resistance and hyperinsulinemia and features of obesity, NIDDM, HTN and CHD, diseases that are common in Indians, and as decreased insulin sensitivity is associated with decreased concentrations of polyunsaturated fatty acids (PUFAs) in skeletal muscle phospholipids and, possibly, in the plasma, the possibility is raised that changes in the metabolism of EFAs may have a fundamental role in the pathobiology of these conditions. If this is true, this suggests that supplementation of GLA, DGLA, AA, EPA and/or DHA may be indicated to prevent CHD, HTN and NIDDM in Indians.

A differential cholinergic regulation of haloperidol induced increase in dopamine release in dorsal and ventral neostriatum of the rat. Relevance to extrapyramidal motor side effects

Lithium has actions on the immune system similar to its paradoxical effects in manic-depression in that both inhibition and stimulation of the immune system have been reported. In many disorders of immunity and inflammation there are unpredictable relapses and remissions similar to those which occur in manic/depression. We propose that in such recurrent disorders of immunity lithium may have a therapeutic role. A key aspect of this role is likely to be an effect on T suppressor lymphocytes. Lithium may prove able both to reduce excess suppressor function and to enhance the activity of defective T suppressors. There is evidence that prostaglandin (PG) E1 is a key determinant of both mood and suppressor cell activity. Excess PGE1 formation will be associated with mania when it occurs in the brain and with excess suppressor function in the immune system. Since stores of the PGE1 precursor dihomogammalinolenic acid (DGLA) are limited, excess PGE1 formation may be followed by depletion of DGLA and a fall in PGE1. Since PGE1 blocks mobilisation of arachidonic acid, a lack of PGE1 is likely to be associated with arachidonate mobilisation and an excess of 2 series PGs. This will be associated with depression in the nervous system and failure of T suppressor function with auto-immune attack in the immune system and over production of 2 series PGs. Lithium limits DGLA mobilisation and so can prevent both excess PGE1 formation and a subsequent DGLA depletion. Multiple sclerosis fits this model well since in remission T suppressor function is excessive while in relapse it is defective. Other recurrent and relapsing disorders such as rheumatoid arthritis and related conditions, familial Mediterranean fever, asthma, migraine and inflammatory disorders of the skin and the bowel may also fit the model.