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Biomedical subjects

D F Horrobin

Publications and source records attributed to D F Horrobin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Essential fatty acid metabolism in long term primary cultures of rat cardiomyocytes: a beneficial effect of n-6:n-3 fatty acids supplementation.

In long term (21 days) primary cultures of neonatal rat cardiomyocytes, utilized as a model of in vitro senescence, we investigated the dual effect of the time length in culture and of the supplementation with n-6:n-3 fatty acid mixtures on linoleic (LA) and alpha-linolenic acid (ALA) metabolism. Cardiomyocytes were divided into groups receiving: (1) control medium; (2) control medium plus n-3 fatty acids; (3) and (4) control medium plus n-6 and n-3 fatty acids in the ratio 1:2 or 2:1, respectively. In control cells. senescence caused a reduction in the conversion of LA and ALA, and the decrease in their metabolites was bypassed by the different supplementations. The fatty acid composition of cardiomyocyte lipids was therefore affected by both senescence and supplementation, as evidenced by the n-6:n-3 fatty acid ratio and the unsaturation index (U.I.) in cellular lipids. The final result of ageing in culture and of fatty acid supplementations was in all the groups of cells but one (n-6:n-3, 2:1) an unbalance in the n-6:n-3 fatty acid ratio. All the supplementations were able to counteract the decrease in the U.I. observed with senescence, but only the n-6:n-3 (2:1) was able to do so by increasing the cellular content of the fatty acids which are precursors of anti-aggregation eicosanoids without altering the n-6:n-3 fatty acid ratio.

Animals↗
PubMed1999

Age-related changes in synaptic function: analysis of the effect of dietary supplementation with omega-3 fatty acids.

Depolarization-induced transmitter release in synaptosomes prepared from the hippocampus of aged rats is decreased compared with release from young animals. Although the underlying cause of this deficit is not known, some evidence suggests that increased membrane rigidity may contribute to these age-related synaptic changes. One possible consequence of the decreased transmitter release in the hippocampus of aged rats is a reduced ability to sustain long-term potentiation in perforant path-granule cell synapses, a pathway in which maintenance of long-term potentiation and increased glutamate release have been coupled. The observation that there is an age-dependent impairment in long-term potentiation is consistent with this view. If the age-related deficits in release and long-term potentiation are a consequence of increased membrane rigidity, it must be predicted that any manoeuvre which reverses membrane rigidity should reverse these functional deficits. In the present study, we investigated the effect of dietary manipulation of aged rats with omega-3 fatty acids on synaptic function. The data obtained indicate that an eight-week modified feeding schedule reversed the age-related impairments in long-term potentiation and depolarization-induced glutamate transmitter release. We also report that the concentrations of both docosahexanoic acid and arachidonic acid, two main polyunsaturated fatty acids in neuronal membranes, were decreased in the hippocampus of aged rats, and were restored by dietary manipulation. The data are consistent with the hypothesis that these deficits results from a change in membrane composition.

Aging↗
PubMed1999

New gene targets related to schizophrenia and other psychiatric disorders: enzymes, binding proteins and transport proteins involved in phospholipid and fatty acid metabolism.

Phospholipids make up about 60% of the brain's dry weight. In spite of this, phospholipid metabolism has received relatively little attention from those seeking genetic factors involved in psychiatric and neurological disorders. However, there is now increasing evidence from many quarters that abnormal phospholipid and related fatty acid metabolism may contribute to illnesses such as schizophrenia, bipolar disorder, depression and attention deficit hyperactivity disorder. To date the possible specific proteins and genes involved have been relatively ill-defined. This paper reviews the main pathways of phospholipid metabolism, emphasizing the roles of phospholipases of the A2 and C series in signal transduction processes. It identifies some likely protein candidates for involvement in psychiatric and neurological disorders. It also reviews 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.

Alzheimer Disease↗
PubMed1999

Concentration- and time-dependent effects of gamma-linolenic acid supplementation to tumor cells in culture.

Gamma-linolenic acid (GLA) supplemented to neuroblastoma SK-N-BE, tubal carcinoma TG and colon carcinoma SW-620 cells was incorporated into phospholipids in all the cell lines (although to different extents), in a concentration- and time-dependent manner. All the cell lines were able to metabolize GLA to arachidonic acid, SK-N-BE being the most active. Supplementation with low GLA concentrations for short periods was not sufficient to impair cell proliferation; only higher amounts of GLA had an anti-proliferative effect also in short times. In these conditions, the antiproliferative effect of GLA is probably due to cellular dysfunction caused by fatty acid modifications.

Arachidonic Acid↗
PubMed1999

Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis. Possible candidate genes.

Depression and bipolar disorder are two of the commonest illnesses in the developed world. While some patients can be treated effectively with available drugs, many do not respond, especially in the depression related to bipolar disorder. Depression is associated with diabetes, cardiovascular disease, immunological abnormalities, multiple sclerosis, cancer, osteoporosis and ageing: in each case depressed individuals have a worse outcome than non-depressed individuals. In all of these conditions there is now evidence of impaired phospholipid metabolism and impaired fatty acid-related signal transduction processes. Impaired fatty acid and phospholipid metabolism may be a primary cause of depression in many patients and may explain the interactions with other diseases. Several novel gene candidates for involvement in depression and bipolar disorder are proposed.

Aging↗
PubMed1999

Effects of oral supplementation with evening primrose oil for six weeks on plasma essential fatty acids and uremic skin symptoms in hemodialysis patients.

Abnormalities in plasma composition of essential fatty acids (EFAs) may be associated with the etiology of pruritus and other skin problems in patients undergoing hemodialysis. To study whether an oral supplementation with omega-6 (n-6) EFAs would restore deranged plasma EFAs and ameliorate skin symptoms, 9 and 7 dialysis patients were randomly assigned to receive either gamma-linolenic acid (GLA)-rich evening primrose oil (EPO) or linoleic acid (LA) (2 g/day each) for 6 weeks. Plasma concentrations of EFA were analyzed by gas chromatography and uremic skin symptoms were assessed for dryness, pruritus and erythema by questionnaire and visual inspection in a double-blind manner. The patients given EPO exhibited a significant (p < 0.05) increase in plasma dihomo-gamma-linolenic acid (a precursor of anti-inflammatory prostaglandin E1) with no concomitant change in plasma arachidonic acid (a precursor of pro-inflammatory prostaglandin E2 and leukotriene B4). In contrast, those given LA exhibited a significant (p < 0.05) increase in LA but not in any other n-6 EFAs, whereas they exhibited a significant (p < 0.05) decrease in plasma docosahexaenoic acid. The patients given EPO showed a significant (p < 0.05) improvement in the skin scores for the three different uremic skin symptoms over the baseline values and a trend toward a greater improvement (0.05 < p < 0.1) in pruritus scores than those given LA. Results indicate that GLA-rich EPO would be a more favorable supplemental source than LA in terms of shifting eicosanoid metabolism toward a less inflammation status through modifying plasma concentrations of their precursor n-6 EFAs. Further studies are required to confirm the efficacy and safety of EPO therapy for the treatment of uremic pruritus.

Administration, Oral↗
PubMed1998

The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia.

The neurodevelopmental hypothesis of schizophrenia is becoming an important feature of research in the field. However, its major drawback is that it lacks any biochemical basis which might draw the diverse observations together. It is suggested that the membrane phospholipid hypothesis can provide such a biochemical basis and that the neurodevelopmental phospholipid concept offers a powerful paradigm to guide future research.

Brain↗
PubMed1998

Regulation of tight junction permeability and occludin expression by polyunsaturated fatty acids.

Tight junctions (TJ) are the topical most structure in epithelial and endothelial cells and play a key role in the control of permeability and prevention of tumour cell invasion of endothelium. In this study we examined the effects of a range of polyunsaturated fatty acids on the function of TJs and the expression of occludin, a key molecule in the TJs of the human vascular endothelial cell line, ECV304. Treatment of the endothelial cells with gamma linolenic acid, an anti-cancer PUFA, increased the transendothelial cell resistance (TER) and reduced the paracellular permeability to large molecules. The effects were seen without any changes in the viability of the endothelial cells. Occludin, a recently identified molecule, which plays a major role in tight junctions was up-regulated by this fatty acid as revealed by both Western blotting and immunofluorescence. Other fatty acids were also tested. Eicosapentaenoic acid (EPA) also exerted an up-regulatory effect, but LA and AA down-regulated the expression. We conclude that GLA and EPA which also have other anti-cancer effects, regulate the expression of occludin in endothelial cells and thus contribute to the modification of the TER of these cells.

Arachidonic Acid↗
PubMed1998

A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy.

Untreated streptozotocin-diabetic (7 weeks duration) rats showed reductions (all p < 0.01; percentages in brackets) in motor and sensory nerve conduction velocity (MNCV; 14%, SNCV; 17%) and in sciatic nerve contents of nerve growth factor (NGF; 57%), substance P (SP; 53%) and neuropeptide Y (NPY; 39%). Treatment with a gamma-linolenic acid-alpha-lipoic acid conjugate (GLA-LA; 35 mg x day(-1) x rat(-1)) attenuated (p < 0.05) these reductions to MNCV (8%), SNCV (5%), NGF (19%), SP (23%), NPY (20%), such that the values in GLA-LA-treated diabetic rats did not differ significantly from those of control non-diabetic animals. Treatment with alpha-lipoic acid alone at 100 mg/kg i.p. was without effect on these variables except for NGF (33% reduction, p < 0.05) and treatment with the antioxidant, butylated hydroxytoluene (1.5% dietary supplement) did not affect any deficits. These data show that GLA-LA is effective in improving both electrophysiological and neurochemical correlates of experimental diabetic neuropathy.

Animals↗
PubMed1998

Changes in dietary fatty acids alter phospholipid fatty acid composition in selected regions of rat brain.

1. Eighty rats were randomized into four groups receiving one of the following diets: rat chow containing (1) 6% soybean oil, (2) 6% primrose oil, (3) 6% fish oil, (4) a combination of 4.5% primrose and 1.5% fish oil. 2. Following two months of each regimen, the rats were sacrificed by microwave irradiation and the brain's fatty acid composition was analysed with gas chromatography for each of the following regions: frontal cortex, striatum, occipital cortex, hippocampus, hypothalamus, cerebellum and pituitary. 3. Linoleic acid was decreased by both primrose and fish oil supplementations. The fish oil substitution resulted in a significant elevation of 20:3n-6, a decrease of 22:4n-6 and a non-significant decrease of 20:4n-6, probably reflecting inhibition of delta-5-desaturation. At the same time the fish oil diet significantly elevated 22:5n-3 while 22:5n-6 was decreased. 4. The primrose oil diet lowered the n-3/n-6 ratio in all regions except in the cerebellum. In contrast, the fish oil diet elevated the n-3/n-6 ratio in all regions. 5. The results demonstrate that changes in dietary fat composition can alter the fatty acid composition of the adult rat brain and that these effects are region specific. 6. This is of interest since metabolites of essential fatty acids may be involved in physiological and pathological processes in the brain and it has been hypothesized that dietary intake of fats may influence the outcome of psychiatric disorders such as schizophrenia.

Animals↗
PubMed1998

Schizophrenia: the illness that made us human.

Any hypotheses concerning the origins of humans must explain many things. Among these are: 1, the growth in brain size around two million years ago; 2, the presence of subcutaneous fat; 3, the near absence of change or cultural progress for around 2 million years after the brain grew in size; 4, the cultural explosion which began somewhere between fifty thousand and one hundred thousand years ago with the emergence of art, music, religion and warfare; 5, the further cultural explosion around ten thousand to fifteen thousand years ago which developed with the emergence of agriculture and which has continued since. Since the brain, like subcutaneous fat, is particularly rich in lipids, and since the microconnections of the brain are substantially lipid in nature, it is suggested that changes in lipid metabolism are what differentiated humans from the great apes. The growth in brain size and in the quality of subcutaneous adipose tissue may have occurred because of changes in the proteins which regulate the rate of delivery of fatty acids to tissues, notably lipoprotein lipases and fatty acid binding proteins. The creativity which occurred one hundred thousand years ago may have resulted from changes in phospholipid-synthesizing, -remodelling and -degrading enzymes which largely determine the microconnectivity of neurons. Family studies and adoption studies indicate that schizophrenia in a family member is associated with an increased risk of the illness in other family members. It is also associated with an increased risk of schizotypy, manic-depression, dyslexia, sociopathy and psychopathy. On the other hand it is also an indication of an increased likelihood of high creativity, leadership qualities, achievements in many fields, high musical skills and an intense interest in religion. I propose that the characteristics which entered the human race about one hundred thousand years ago and which ended around two million years of cultural near-stagnation are precisely those shown by the families of people with schizophrenia. I propose that these features are caused by variations in phospholipid biochemistry which are responsible both for schizophrenia and for our humanity. This would help to explain why schizophrenia is present to approximately the same degree in all races. It is the illness which made us human prior to the separation of the races.

Animals↗
PubMed1998

Essential fatty acid status in cell membranes and plasma of patients with primary Sjogren's syndrome. Correlations to clinical and immunologic variables using a new model for classification and assessment of disease manifestations.

In 41 primary Sjögren's syndrome patients we compared fatty acid levels within erythrocyte phospholipids, plasma phospholipids, plasma triglycerides and plasma cholesterol esters, with the immunopathological and clinical disease status. Docosahexaenoic acid was the essential fatty acid (EFA), the levels of which correlated (inversely) most closely with the clinical disease status (r=-0.33 to -0.50). Levels of dihomogammalinolenic acid and eicosapentaenoic acid correlated inversely to levels of IgM rheumatoid factors (r=-0.33) and anti-SSA/Ro antibodies (r=-0.40) respectively. Moreover, levels of anti-SSA/Ro antibodies (r=-0.34-0.40) correlated with levels of the proinflammatory arachidonic acid. Sigma n-3 EFA/sigma n-6 EFA ratios correlated significantly to the quantitative estimates of immunopathological and clinical disease status. Our data are in agreement with current understanding of pro- and anti-immunoinflammatory roles within EFA metabolism, and support the rationale for intervention studies.

8,11,14-Eicosatrienoic Acid↗