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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 451 records · Page 25Linked to original sources

Roles of prostaglandins suggested by the prostaglandin agonist/antagonist actions of local anaesthetic, anti-arrhythmic, anti-malarial, tricyclic anti-depressant and methyl xanthine compounds. Effects on membranes and on nucleic acid function.

We have recently found that local anaesthetic, anti-malarial, anti-arrhythmic, tricyclic antidepressant and methyl xanthine compounds behave as prostaglandin antagonists at drug concentrations readily attainable in human body fluids. We have also found that various hormones, including prolactin, vasopressin and angiotensin when present in physiological concentrations can be potent stimulators of prostaglandin synthesis. Cortisol has no effect on basal prostaglandin systhesis but in physiological concentrations is able to reverse the effects of other hormones. The drugs are thought to act mainly by interfering with either calcium interactions with membranes, or with cyclic nucleotide synthesis or degradation or with nucleic acid function. We propose that prostaglandins play crucial roles at all three points. The hypothesis leads to new approaches to many aspects of cell regulation, to the functions of many systems, especially the neuromuscular, cardiovascular, renal and respiratory systems. It also has profound implications for drug design and evaluation and for the understanding of many clinical disorders.

Anesthetics, Local↗

The roles of prostaglandins and calcium accumulation in muscular dystrophy.

There is good evidence that abnormal calcium accumulation may be a final common pathway of muscle degeneration in the muscular dystrophies. Prostaglandins are able to promote calcium entry into cells and excess prostaglandin activity coupled with a defect in intracellular calcium release could cause toxic accumulations of calcium in intracellular organelles such as mitochondria. Serotonin stimulates prostaglandin synthesis while tricyclic antidepressants inhibit calcium release from intracellular organelles thus possibly accounting for the models of muscular dystrophy reported using this combination. The prostaglandin/calcium hypothesis can account for the effects of vitamin E, steroids and local anaesthetic-like drugs in muscular dystrophy. Since many drugs already in clinical use for other purposes can be used to control prostaglandin synthesis or action this hypothesis has immediate potential clinical applications.

Animals↗

Age-related changes in oxidative mechanisms and LTP are reversed by dietary manipulation.

Aged rats exhibit an impaired ability to sustain long-term potentiation in dentate gyrus which correlates with a decrease in arachidonic acid concentration. Here we confirm the previous finding that dietary supplementation with arachidonic acid and its precursor, gamma-linolenic acid, reversed the impairment in LTP in aged rats and report that there is a significant correlation between membrane arachidonic acid concentration and response to tetanic stimulation. We observed that age was associated with decreases in the concentration of vitamins C and E and increased activity of superoxide dismutase, indicative of a compromise in antioxidative defenses; these changes were paralleled by increases in interleukin-1beta (IL-1beta) concentration and lipid peroxidation. Dietary manipulation restored polyunsaturated fatty acid concentrations to values observed in tissue prepared from young rats and reversed the age-related changes in vitamins E and C, IL-1beta concentration and superoxide dismutase activity. We propose that these changes reverse the increase in lipid peroxidation and thereby the age-related change in polyunsaturated fatty acids.

Aging↗

Age-related changes in LTP and antioxidant defenses are reversed by an alpha-lipoic acid-enriched diet.

Among the age-related changes identified in rat hippocampus are impairments in LTP and glutamate release. These deficits have been coupled with decreased arachidonic acid concentration. In this study we compared LTP and glutamate release in groups of aged and young rats fed for 8 weeks on a control diet or on a diet enriched in alpha-lipoic acid. Dietary supplementation in aged rats restored hippocampal arachidonic acid concentration to levels observed in tissue prepared from young rats. We observed that aged rats that received the experimental diet sustained LTP in perforant path-granule cell synapses in a manner indistinguishable from young rats whereas the age-related impairment in glutamate release was reversed in synaptosomes prepared from dentate gyrus obtained from these rats. The evidence presented supports the hypothesis that the alpha-lipoic acid-enriched diet has antioxidant properties, because the age-related increase in superoxide dismutase activity and decrease in alpha-tocopherol concentration were reversed. The finding that the age-related increase in interleukin-1 (IL-1)beta concentration was also reversed suggests a possible role for this cytokine in ageing.

Aging↗

Lipid metabolism, human evolution and schizophrenia.

There are only small genetic differences between humans and the great apes. Yet these differences must be very important. Major known differences include the accumulation of subcutaneous fat, the expansion of breasts and buttocks, the growth of the brain and the connectivity of neurons. All these involve lipid metabolism yet, because fat leaves no fossils, lipids are rarely mentioned in discussions of human evolution. This paper attempts to identify some candidate areas of lipid metabolism which may be important in human evolution. It draws attention to abnormalities in phospholipid metabolism in schizophrenia and suggests that these may have proved important in enhancing brain connectivity in the later stages of evolution of modern humans.

Animals↗

Increased levels of cytosolic phospholipase A2 in dyslexics.

Research findings are increasingly reporting evidence of physiological abnormalities in dyslexia and sites for dyslexia have been identified on three chromosomes. It has been suggested that genetic inheritance may cause phospholipid abnormalities in dyslexia somewhat similar to those found in schizophrenia. A key enzyme in phospholipid metabolism, Type IV, or cytosolic, phospholipase A2 (cPLA2), releases arachidonic acid (AA), a 20-carbon fatty acid, which is the major source of production of prostaglandins and leukotrienes. An entirely new assay, which for the first time has enabled determination of the amount of the enzyme rather than its activity, was used to measure cPLA2 in dyslexic-type adults and controls and the two groups were found to differ significantly, the dyslexic-types having more of the enzyme. A report elsewhere of schizophrenics having even greater amounts of the enzyme suggests that dyslexia may be on a continuum with schizophrenia, as may be other neurodevelopmental disorders - which have also been described as phospholipid spectrum disorders.

Adult↗

Gene targets related to phospholipid and fatty acid metabolism in schizophrenia and other psychiatric disorders: an update.

Phospholipids make up about 60% of the brain's dry weight and play key roles in many brain signal tranduction mechanisms. A recent review(1)identified the increasing evidence that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. This current paper reviews the main pathways of phospholipid metabolism, emphasizing the role of phospholipases of the A2 in signal tranduction processes. It also updates the chromosomal locations of regions likely to be involved in these disorders, and relates these to the known locations of genes directly or indirectly involved in phospholipid and fatty acid metabolism.

Bipolar Disorder↗

Long-term potentiation in aged rats is restored when the age-related decrease in polyunsaturated fatty acid concentration is reversed.

Several age-related changes have been identified in rat hippocampus; among these are deficits in glutamate release and long-term potentiation in dentate gyrus. These deficits correlate with a decrease in the concentration of arachidonic acid in hippocampus. In this study, the effects of dietary supplementation for 8 weeks with omega -6 or omega -3 fatty acids were assessed in groups of aged and young rats. The data presented indicate that dietary supplementation in aged rats restored the concentrations of arachidonic acid and docosahexanoic acid in hippocampal preparations to those observed in tissue prepared from young rats. In parallel, aged rats which received the experimental diets sustained long-term potentiation in a manner indistinguishable from young rats. The evidence presented supports the view that an age-related increase in reactive oxygen species production is linked with the decrease in polyunsaturated fatty acids and that a diet enriched in eicosapentanoic acid has antioxidant properties which may play a key role in reversal of the observed age-related deficits.

Aging↗

Eicosapentaenoic acid treatment in schizophrenia associated with symptom remission, normalisation of blood fatty acids, reduced neuronal membrane phospholipid turnover and structural brain changes.

The administration of the omega-3 fatty acid eicosapentaenoic acid (EPA) to a drug-naive patient with schizophrenia, untreated with conventional antipsychotic medication, led to a dramatic and sustained clinical improvement in both positive and negative symptoms. This was accompanied by a correction in erythrocyte membranes of abnormalities in both n-3 and n-6 highly unsaturated fatty acids and with reduced neuronal membrane phospholipid turnover, as evidenced by serial 31-phosphorus cerebral magnetic resonance spectroscopy. Using recently developed techniques of image segmentation, subvoxel registration and quantitation, analysis of serial high-resolution 3D cerebral MRI scans showed that, in the year before EPA treatment, cerebral atrophy was taking place and that this atrophy was reversed by six months of EPA treatment. These results demonstrate that EPA can reverse both the phospholipid abnormalities previously described in schizophrenia and cerebral atrophy. They provide strong further evidence in support of the membrane phospholipid model of schizophrenia.

Adult↗

The effects of lithium gamma-linolenic acid in reversing LPBM5 MuLV induced suppression of hematopoietic progenitor cells in vitro.

Lithium gamma linolenic acid (Li-GLA), was evaluated for its possible role as an antiviral agent. Li-GLA 15 micrograms ml-1 was administered to both normal and LP-BM5 MuLV retroviral infected murine bone marrow cultures. After 2 weeks of treatment, numbers of progenitors being produced by infected/treated cultures were reduced to some 10% that of normal cultures. In the remaining 4 weeks, numbers of CFU-GM and BFU-E hematopoietic progenitors returned within normal range. The efficacy of Li-GLA in relieving retroviral hematopoietic bone marrow suppression correlates to a reduction in interleukin-4 (IL-4) secretion, normally elevated in association with LP-BMP5 infection. These data indicate that this reduction in bone marrow suppression of LP-BMP5 infected cells may be due to a killing of infected cells by the Li-GLA, rather than stimulating hematopoiesis as with other lithium compounds. To conclude this may indicate the possible dual effect of administration of LiGLA to virally infected individuals in reducing viral titre and to lower the toxicities associated with long term drug therapy.

Animals↗

Lipid peroxidation in human breast cancer cells in response to gamma-linolenic acid and iron.

Lipid peroxidation in human breast cancer (ZR-75-1) cells and cancer cell killing were confirmed by using ultraviolet (UV)-spectrophotometry and mass spectrometry (MS). ZR-75-1 cells and human normal fibroblast CCD-41-SK (41Sk) cells were cultured with gamma-linolenic acid (GLA) and ferrous iron Fe (II) combinations. Formation of lipid peroxide and cytotoxic effect were highest in ZR-75-1 cells treated with GLA + Fe (II), though 41Sk cells showed little evidence of either lipid peroxidation or cytotoxity. These results indicate a cancer-cell-specific lipid peroxidation mechanism in association with the selective cancer cell killing effect in response to GLA.

Antineoplastic Agents↗

The effect of n-6 fatty acids on normal and v-Ki ras transformed NIH-3T3 cells.

The effect of exogenous gamma-linolenic acid (18:3n-6) was examined on NIH-3T3 and a subclone expressing the v-Ki-ras oncogene (DT). 18:3n-6 inhibited DT cell growth more readily than NIH-3T3 cell growth. In comparison, linoleic acid (18:2n-6) had no effect on the growth of either cell line. DT cells elongated and desaturated both 18:2n-6 and 18:3n-6 to dihomo-gamma-linolenic acid (20:3n-6) and arachidonic acid (20:4n-6) to a much greater extent than NIH-3T3 cells and had a much higher membrane fluidity. The presence of the ras gene or its product appears to increase the metabolism of polyunsaturated fatty acids and potentiate the cytostatic actions of 18:3n-6.

3T3 Cells↗

Natural killer cell functions are related to the cell membrane composition of essential fatty acids: differences in healthy persons and patients with primary Sjögren's syndrome.

To examine whether abnormalities in essential fatty acid (EFA) metabolism are associated with the impaired natural killer (NK) cell functions in primary Sjögren's syndrome, we measured the levels of phospholipid fatty acids in blood mononuclear cells with (MD) and without monocyte depletion (MC), and NK cell activity before and after indomethacin-boosting. We found MD levels of 20:3n6 (dihommo-gamma-linolenic acid), and basal and indomethacin-enhanced NK cell activity significantly reduced, in 10 primary Sjögren's syndrome patients as compared with 10 healthy controls. In the controls the relative (%) increase in indomethacin-enhanced NK cell activity correlated with the level of MD 18:2n6 (linoleic acid) (r = 0.97, p less than 0.001). In the patients the relative (%) indomethacin-enhanced NK cell activity correlated with the 20:4n6 (arachidonic acid)/20:3n6 ratio in the MC (r = 0.90, p less than 0.001). This ratio has been assumed to be an important determinant for the production of prostaglandin 1 and 2. The present data suggest that in healthy persons, as opposed to primary Sjögren's syndrome patients, the level of MD 18:2n6 is a determinant for the sensitivity of NK cells to monocyte-derived prostaglandins. Furthermore, in patients with primary Sjögren's syndrome the MC levels of 20:3n6 and 20:4n6 may be regulating factors for the production of NK cell suppressing prostaglandins.

Adult↗

The regulation of prostaglandin biosynthesis by the manipulation of essential fatty acid metabolism.

Two of the most widely used groups of drugs in medical practice are the non-steroidal anti-inflammatory agents and the steroids. Both act by modulating the conversion of essential fatty acids to prostaglandins, leukotrienes and related substances. The actions of these drugs are therefore likely to be modified by variations in the levels of substrates, notably arachidonic acid and dihomogammalinolenic acid, available for metabolism by lipoxygenase and cyclo-oxygenase enzymes. Yet most doctors who use the drugs and many scientists who carry out research on them seem unaware of the factors which determine the concentrations of the substrate essential fatty acids. This paper reviews in detail the metabolism of essential fatty acids and the interactions between nutrient intake and subsequent metabolism which determine the concentrations of the individual fatty acids. It is concluded that the efficacy of drug therapy as far as the steroids and the non-steroidal anti-inflammatory drugs are concerned could be substantially enhanced by greater knowledge of the factors which determine the availability of substrates to the key enzymes.

Animals↗

The vascular response to zinc varies seasonally: effect of pinealectomy and melatonin.

The effect of physiological concentrations of zinc on the in vitro pressor responses of male Wistar rat mesenteric preparations to norepinephrine was systematically studied over a 2-year period. A marked seasonal variation in the response of the preparations was observed over a range of zinc concentrations from 3.5 X 10(-11) to 3.5 X 10(-6) M. All concentrations of zinc inhibited pressor responses during the winter (November to March), but during the spring months (April to May) zinc became very much less effective and low concentrations of zinc potentiated the response. Inhibition of the pressor response at this time only occurred at zinc concentrations above 3.5 X 10(-7) M. In the summer months. (June to September) the zinc effect shifted back towards the winter situation with lower concentration of zinc potentiating and higher concentrations inhibiting vasoconstriction. Pinealectomy of the rats a week prior to preparation of the mesenteric beds very significantly enchanced pressor responses to norepinephrine in the winter months but had much less effect in the summer. The seasonal variation noted in preparations from control rats was maintained following pinealectomy but the amplitude was reduced. Perfusion of melatonin (4.3 X 10(-10) M through preparations from pinealectomized rats enhanced the inhibitory effect of zinc compared to the response to zinc from similarly perfused preparations from control rats. Thus, the rat mesenteric vascular bed is an in vitro model of seasonal variation in vascular reactivity which is sensitive to physiological concentrations of zinc. The origin of the seasonal rhythmicity remains speculative particularly in view of the fact that the rats were maintained under constant photoperiod. That the pineal may modulate the seasonal effect of zinc is suggested by the shift in response to zinc following pinealectomy. Melatonin reversed the effect of pinealectomy on this preparation implicating it as a possible mediator of normal vascular reactivity to zinc. A possible influence of magnetic radiation in evaluating the occurrence of seasonally varying phenomena in vitro should be considered.

Animals↗