Reduction in cerebral atrophy associated with ethyl-eicosapentaenoic acid treatment in patients with Huntington's disease.

Ultra-pure ethyl-eicosapentaenoic acid (ethyl-EPA), a semi-synthetic ethyl ester of eicosapentaenoic acid, is associated with clinical improvement in motor functioning in Huntington's disease. The aim was to determine the extent to which it might reduce the rate of progress of cerebral atrophy. High-resolution cerebral magnetic resonance imaging scans were acquired at baseline, 6 months and 1 year in up to 34 patients with stage I or II Huntington's disease who took part in a randomized, double-blind, placebo-controlled trial of ethyl-EPA. For each subject and each pair of structural images, the two-timepoint brain volume change was calculated in a double-blind manner. Significant group-level reductions in brain atrophy were observed in the head of the caudate nucleus and the posterior thalamus. These findings show that treatment with ethyl-EPA is associated with significant reduction in brain atrophy, particularly in the caudate and thalamus. No other drug tested in Huntington's disease has shown this effect.

Docosahexaenoic acid-induced changes in phospholipids in cortex of young and aged rats: a lipidomic analysis.

The age-related decline in cognitive function has been associated with biochemical changes that can be attenuated following n-3 polyunsaturated fatty acid treatment. Dietary supplementation with docosahexaenoic acid (DHA) has been shown to reverse age-related changes in synaptic function. Here, lipidomic analyses were undertaken to examine changes in lipid classes and phospholipid species in cortical tissue of young (2-4 months) and aged (20-22 months), control- and DHA-treated (10mg daily) rats following treatment for 8 weeks, aiming to explore the mechanism of DHA action. Dietary supplementation normalised the age-related decrease in unsaturation index, reduced the levels of arachidonic acid-containing phospholipids in both young and aged animals, and gave rise to production of new phosphatidylserine and phosphatidylinositol species. These findings suggest that DHA may mediate some of its effects through alterations in the membrane lipid composition that can consequently affect the production of pro-inflammatory mediators and signalling molecular species.

Triacylglycerol content of arachidonic acid varies inversely with total triacylglycerol in liver and plasma.

In both liver and plasma from rats, hamsters, guinea pigs and monkeys, the correlation coefficients between percentage composition of arachidonic acid and the total triacylglycerol varied from -0.43 to -0.81 (P less than 0.01). No such relationship was present between percentage compositions of any of the essential fatty acids in phospholipids and total phospholipids.

Changes of vascular reactivity induced by low vasopressin concentrations: interactions with cortisol and lithium and possible involvement of prostaglandins.

Arginine vasopressin in physiological concentrations potentiated the vascular effects of various vasoconstrictor agents. By using the isolated rat mesenteric artery preparation, the pressor effects of norepinephrine, angiotensin II, and potassium chloride were all significantly increased when vasopressin was added to the perfusion buffer. Cortisol and lithium both inhibited the potentiating effect of vasopressin but had no effect on the control pressor response to norepinephrine. When the vascular effects of norepinephrine were first blocked with indomethacin and then restored by the addition of prostaglandin E2, the potentiation by vasopressin was almost completely prevented. This suggests that vasopressin may be acting by stimulating prostaglandin biosynthesis. Cortisol and lithium may exert their inhibitory effects by preventing the activation of prostaglandin synthesis by vasopressin. These findings may be of clinical significance because the phenomena occur well within the range of vasopressin levels found in human plasma.

Physiological cortisol levels block the inhibition of vascular reactivity produced by prolactin.

Cortisol in concentrations similar to the unbound levels of the hormone in human plasma can reverse the inhibition of vascular reactivity produced by prolactin. In the rat mesenteric vascular bed, cortisol alone in similar concentrations had no significant effect on the pressor responses to norepinephrine: the action of cortisol was seen only when prolactin was present. The relationships between the effects of different concentrations of prolactin and cortisol suggest that at some point there is a competitive interplay between the effects of the two hormones. There is indirect evidence that this interplay is at the level of prostaglandin synthesis or release. We suggest that cortisol has no effect on basal prostaglandin production but blocks the synthesis or release occurring in response to polypeptide hormone stimulation.

Prolactin and zinc effects on rat vascular reactivity: possible relationship to dihomo-gamma-linolenic acid and to prostaglandin synthesis.

Ovine PRL at low concentrations potentiated pressor responses to norepinephrine and angiotensin in an isolated perfused rat mesenteric vascular preparation. Higher concentrations inhibited these pressor responses. Pressor responses to potassium which depend on extracellular calcium entry into the muscle were unaffected by PRL at any concentration. Either cortisol or lithium could completely block the PRL effect. Dihomo-gamma-linolenic acid (DHGL) and prostaglandin E1 had effects similar to those of PRL in that they potentiated norepinephrine responses at low concentrations, inhibited at high ones, and had no effect on potassium responses. Arachidonic acid and prostaglandin E2 potentiated both norepinephrine and potassium responses and had no inhibitory effects at high concentrations. Neither lithium nor cortisol blocked the effects of DHGL or arachidonic acid. Zinc had actions similar to those of PRL and DHGL, but which could be blocked only by lithium and not by cortisol. These results are consistent with the concept that PRL increases synthesis of the 1 series of prostaglandins by mobilizing DHGL. They provide further evidence that zinc may play a role in some actions of PRL.

Seasonal and sexual variations in the responsiveness of rabbit hearts to prolactin.

Rabbit hearts perfused by the Langendorff technique were studied. The addition of ovine prolactin (NIH-P-S-10) to the perfusate in a concentration of 50 ng/ml produced rapid increases in both the amplitude and rate of contraction in 33 adult male hearts studied in winter. Prepubertal male animals showed no response, and only 1 out of 12 adult females responded. Pretreatment for 10 days with 2.5 mg/day testosterone propionate led to minimal inotropic but not chronotropic responses in 2 out of 4 prepubertal males and 2 out of 4 adult females to prolactin. Clear responses to prolactin were seen in 5 adult males pretreated with reserpine. Propanolol consistently reversed both the inotropic and chronotropic actions of prolactin. The original experiments were performed in January and February. When tested in May, adult males failed to respond to prolactin and this situation, persisted until October when responsiveness again appeared. The same prolactin preparation and procedures were used throughout indicating that the changes must have been due to seasonal variations in the cardiac responsiveness to the hormone.

Dopamine enhances the action of prolactin on rat blood vessels. Implications for dopamine effects on plasma prolactin.

It has been claimed that dopamine enhances peripheral uptake of prolactin. Dopamine at 2.1 x 10(-9)M, a concentration which had no effect by itself, enhanced both the potentiation of rat mesenteric vascular reactivity caused by 50ng/ml ovine prolactin and the inhibition of reactivity caused by 500ng/ml prolactin. These observations are consistent with the proposal that dopamine can interact peripherally with prolactin.

Release of fatty acids by perfused vascular tissue in normotensive and hypertensive rats.

The release of fatty acids from perfused mesenteries of spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY) was studied. The release of the prostaglandin precursors dihomogammalinolenic acid, arachidonic acid, and eicosapentaenoic acid was reduced in SHR when compared with age-matched WKY. The release of all other fatty acids detected in the effluent was also reduced. The differences in fatty acid release were evident even when tissue levels of the fatty acids were similar or higher in SHR than in controls. The addition of evening primrose oil and fish oil into the diet partially corrected these defects. Evening primrose oil and fish oil both attenuated increases in blood pressure, but fish oil was more potent than primrose oil. Although both diets reduced vascular reactivity, primrose oil was more effective with lower doses of norepinephrine whereas fish oil blunted the effects of both low and high doses of norepinephrine. The possible mechanisms for the effects of primrose oil and fish oil on vascular reactivity are briefly discussed.

Essential and other fatty acids in plasma in schizophrenics and normal individuals from Japan.

Plasma phospholipid and cholesterol ester fatty acid levels were measured in samples from normal individuals, schizophrenics, and patients with affective and paranoid disorders in Japan. The schizophrenics were divided into groups with normal and reduced platelet sensitivity to the aggregation-inhibiting effects of prostaglandin (PG) E1. As in samples from schizophrenics in several other countries, linoleic acid levels were significantly below normal, as was the ratio of linoleic acid to its metabolites. Phospholipid fatty acid levels were normal in patients with paranoid or affective disorders. When the schizophrenics were divided into those with and without an abnormal response to PGE1, oleic acid was higher and eicosapentaenoic acid lower in those patients with an abnormal response. This study lends further support to the idea that schizophrenics may differ from controls in their essential fatty acid and eicosanoid metabolism.

Fatty acid levels in the brains of schizophrenics and normal controls.

Essential fatty acids are important constituents of the brain. There is evidence that levels in blood of certain essential fatty acids and their eicosanoid derivatives may be abnormal. We now report that in the frontal cortex of schizophrenic patients there are significant differences from normal in the fatty acid composition of phosphatidylethanolamine. These differences from normal were not found in the cerebellar cortex.

Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent, and impulsive offenders.

Plasma phospholipid essential fatty acids and some of their main metabolites, prostaglandins, were measured among habitually violent and impulsive male offenders, who all had alcohol abuse problems, and nonviolent control persons. Linoleic acid (18:2n-6), the precursor of the n-6 fatty acids, was below normal in intermittent explosive disorder, but the dihomogammalinolenic acid (DGLA) (20:3n-6) and some subsequent n-6 acids were at the same time elevated among all offenders. Also, a monounsaturate, oleic acid (18:1n-9) was elevated. The high DGLA correlated with low cholesterol level in intermittent explosive disorder. The arachidonic acid metabolites PGE2 and TxB2 were elevated in violent antisocial personality. The PGE1/DGLA ratio was low in intermittent explosive disorder. The number of registered violent crimes and violent suicidal attempts correlated with high phospholipid DGLA values. The possibility that the high phospholipid DGLA is connected with low free DGLA pool, and therefore low PGE1 formation, among these offenders is discussed.

Essential fatty acids in plasma phospholipids in schizophrenics.

Blood samples were taken from schizophrenics and control patients in three different centers. The phospholipids were extracted from plasma and their fatty acid composition analyzed. Similar and consistent differences between schizophrenics and controls were observed at all three centers. The n-6 essential fatty acid levels were significantly reduced, whereas n-3 essential fatty acids were elevated.

Influence of agents which modulate thromboxane A2 synthesis or action on R3230AC mammary carcinoma.

The effects of agents which modulate thromboxane A2 synthesis or action, were tested in the R3230AC transplanted mammary tumour. Three different inhibitors of thromboxane A2 synthesis or action (copper, dipyridamole and diazepam) all caused an increase in tumour growth. Colchicine and melatonin, both stimulators of thromboxane A2 synthesis, inhibited the growth of the tumour significantly.

Prostaglandin A2 at low rates of infusion restores the antidiuretic effect of vasopressin in lithium-treated rats.

To test the effect of prostaglandin A2 (PGA2) on renal function, infusions of PGA2 (0-7 ng/kg/min), arginine-vasopressin (AVP) (1-25 ng/kg/min) and PGA2 plus AVP were administered to male rats made resistant to the antidiuretic effect of AVP by pre-treatment with lithium. In non-lithium-treated control rats, AVP had its expected antidiuretic action but in lithium-treated rats neither urinary volume nor osmolarity was changed. Prostaglandin A2 alone had no effect on urine output in lithium-treated rats; AVP plus PGA2 infused together evoked a near normal antidiuretic response. This antidiuretic action of PGA2 contrasts with the diuretic action reported by others. However, our infusion rates were 300-4000 times lower than those of other workers and it is suggested that PGs may have opposite actions on the kidney depending on their concentration. The effect of indomethacin (a blocker of prostaglandin synthesis) on urine flow was tested in five groups of rats on different régimes of liquid intake. Urine flow was reduced in the three groups with the highest urine volumes before treatment, and increased in the two groups with the lowest urinary volumes, again indicating that PGs may have both diuretic and antidiuretic actions.

Effects of low-dose marine oils on intimal hyperplasia in autologous vein grafts.

The effects of low-dose cod-liver oil on intimal hyperplasia of vein grafts were examined in 45 adult mongrel dogs undergoing peripheral arterial reconstruction. Fifteen animals served as the control group, 15 animals were fed a fish-oil supplement containing 240 mg of eicosapentaenoic acid daily, and a further 15 animals received 480 mg of eicosapentaenoic acid daily. Segments of undistended external jugular vein were anastomosed to bilaterally divided femoral arteries. The grafts were harvested at 6 weeks and intimal thickness was measured with a computerized interactive image analyzing system. Serum cholesterol level, prothrombin time, partial thromboplastin time, bleeding time, and platelet counts were measured before the operation and at 2, 4, and 6 weeks after the operation. Plasma levels of thromboxane B2 and prostaglandin F1 alpha and serum levels of eicosapentaenoic acid were measured before and 4 weeks after the operation. Serum cholesterol level increased similarly and significantly in all animals. Serum levels of eicosapentaenoic acid rose proportionately with the oral ingestion of fish oil but did not affect coagulation parameters. Plasma thromboxane B2 and prostaglandin F1 alpha were not significantly affected by the ingestion of marine oils. Intimal thickness was 39 +/- 5 microns in the control dogs. Ingestion of 240 mg of eicosapentaenoic acid reduced intimal thickness to 24 +/- 3 microns at 6 weeks (p less than 0.01). Increasing the dose by a factor of 2 did not decrease intimal thickness further, the intima being 23 +/- 2 microns (p less than 0.005). Our data indicate that small doses of fish oil will reduce intimal proliferation in autologous vein grafts and that marine oils may exert their beneficial effects on intimal hyperplasia by a mechanism other than their known effects on prostanoid metabolism.

Abnormalities in dihomo-gamma-linolenic acid release in the pathogenesis of hypertension.

Spontaneously hypertensive rats (SHR) respond to angiotensin and norepinephrine with an exaggerated pressor response. We have investigated the possibility that increased vascular reactivity in SHR may be related to a reduced synthesis of prostaglandin E1 (PGE1) resulting from a defect in the release of its precursor, dihomo-gamma-linoleic acid (DGLA). Isolated perfused mesenteric vascular beds of SHR and age matched Wistar-Kyoto rats (WKY) were perfused with Kreb's bicarbonate buffer. The effluent was collected and the fatty acid composition determined by gas chromatography. In SHR the release of DGLA, arachidonic acid, eicosapentaenoic acid, and virtually all other fatty acids detected in the effluent were reduced when compared to their normotensive controls. This difference could not be explained by low tissue fatty acid levels because these were higher in SHR. Evening primrose oil (EPO) when added to the diet increased the release of DGLA but not of other prostanoid precursors. EPO also reduced vascular reactivity and reduced blood pressure in SHR. It is suggested that the defect in the release of DGLA may be involved in the pathogenesis of hypertension because it occurs early before hypertension has actually occurred.

Thymic changes in muscular dystrophy and evidence for an abnormality related to prostaglandin synthesis or action.

In Bar Harbor 129 dystrophic mice, thymic development is abnormal. Before weaning, the thymus is slightly smaller than in phenotypically normal littermates; after weaning, however, the lymphoid elements undergo rapid atrophy. The epithelial elements, in contrast, display hyperlasia. Thymectomy has no influence on the course of the disease, and it is possible that the thymic changes are a reflection of a fundamental metabolic abnormality. Thymic lymphoid tissue development seems to require normal levels of PGE1. Levels that are either too high or too low both result in abnormalities. We have investigated the effects of PGE1 in smooth muscle and have demonstrated that while some PGE1 is required for both calcium release and calcium removal, high levels of PGE1 block both processes. We propose that the muscular dystrophies are related to defects in PG synthesis and action. Myotonic dystrophy may be due to PGE11 excess, whereas Duchenne dystrophy may in part be due to PGE1 deficiency.

Age-associated reduction of prostacyclin and thromboxane synthesis is inversely related to plasma cholesterol levels: modulation by dietary cholesterol supplementation.

Abnormalities of vasoactive eicosanoid synthesis with age are reported. We observed an age-associated reduction of vascular prostacyclin production and thrombin-stimulated thromboxane A2 production in blood. Amounts of production of these eicosanoids were inversely related to plasma cholesterol levels. However, there were no such relationships in rats supplemented with cholesterol. Dietary cholesterol supplementation induced a reduction of thromboxane A2/prostacyclin ratio regardless of age. These results suggest that age-associated changes of blood cholesterol levels are closely linked with vasoactive eicosanoid synthesis and that excessive consumption of cholesterol may induce a compensatory reaction by reducing the thromboxane A2/prostacyclin ratio.

Plasma fatty acid levels in patients with acquired immune deficiency syndrome and in controls.

Polyunsaturated fatty acids (PUFAs) are known to modulate the immune system in vivo and to inactivate envelope viruses in vitro. Patients with AIDS had low total plasma lipid levels and low levels of a number of individual fatty acids. However, the C20 and C22 essential fatty acids of the n-3 series were selectively and highly significantly reduced. Normalization of these fatty acid levels in AIDS patients may be a worthwhile therapeutic aim.