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British Journal of Nutrition (2007), 98, Suppl. 1, S46–S53 q The Authors 2007 Polyunsaturated fatty acids in the pathogenesis and treatment ofmultiple sclerosis Laurence S. Harbige1,2* and Mohammad K. Sharief 31Centre for Bioscience Research, School of Science, University of Greenwich at Medway, United Kingdom2Medway School of Pharmacy,University of Kent and University of Greenwich, United Kingdom3Department of Neurology, King's, Guy's and St Thomas' Hospital, London, United Kingdom Epidemiological, biochemical, animal model and clinical trial data described in this overview strongly suggest that polyunsaturated fatty acids,particularly n-6 fatty acids, have a role in the pathogenesis and treatment of multiple sclerosis (MS). Data presented provides further evidencefor a disturbance in n-6 fatty acid metabolism in MS. Disturbance of n-6 fatty acid metabolism and dysregulation of cytokines are shown tobe linked and a "proof of concept clinical trial" further supports such a hypothesis. In a randomised double-blind, placebo controlled trial of ahigh dose and low dose selected GLA (18 : 3n-6)-rich oil and placebo control, the high dose had a marked clinical effect in relapsing-remittingMS, significantly decreasing the relapse rate and the progression of disease. Laboratory findings paralleled clinical changes in the placebogroup in that production of mononuclear cell pro-inflammatory cytokines (TNF-a, IL-1b) was increased and anti-inflammatory TGF-b markedlydecreased with loss of membrane n-6 fatty acids linoleic (18 : 2n-6) and arachidonic acids (20 : 4n-6). In contrast there were no such changes in thehigh dose group. The improvement in disability (Expanded Disability Status Scale) in the high dose suggests there maybe a beneficial effect on neuronal lipids and neural function in MS. Thus disturbed n-6 fatty acid metabolism in MS gives rise to loss of membrane long chain n-6 fattyacids and loss of the anti-inflammatory regulatory cytokine TGF-b, particularly during the relapse phase, as well as loss of these important neural fatty acids for CNS structure and function and consequent long term neurological deficit in MS.
Multiple sclerosis: Linoleic acid: Gamma-linolenic acid: Arachidonic acid: Clinical trials: Cytokines Background to multiple sclerosis and its pathogenesis by pro-inflammatory cytokines such as tumour necrosisfactor-a (TNF-a), interleukin-1b (IL-1b) and interferon-g Multiple sclerosis (MS) is a CNS-specific demyelinating dis- (IFN-g)15. Furthermore studies have shown that these cyto- ease, and is the most common neurological disorder that kines exert direct myelinotoxic properties16,17 and prolong occurs in young adults1,2. The majority of patients with MS the disease process in experimental autoimmune encephalo- have the relapsing-remitting form of the disease, characterised myelitis (EAE), an animal model of MS18,19,20. TNF-a, by attacks (relapses) interspersed with periods of recovery IL-1b and IFN-g have all been shown to be present in (remission). The disease is most prevalent (30 – 100 þ cases CNS active lesions in MS and elevated amounts of these per 100 000 people) in Western Europe, Southern Canada, cytokines are secreted from MS peripheral blood mono- Northern United States, Southern Australia and New Zealand nuclear cells (PBMC)21 – 25. Many studies, including our and of low frequency (0 – 19 per 100,000) in Asia, Central own, have also shown that an increase in these inflammatory America, Africa and Greenland (See Fig. 1). Between 2 and cytokines coincides with the relapse phase of the dis- 3 million people Worldwide are thought to live with MS.
ease25 – 33. Furthermore some studies have shown that Although the aetiology of MS remains unknown there is transforming growth factor-beta1 (TGF-b1), a potent anti- strong evidence for the presence of autoimmune mechanisms inflammatory and immunosuppressive cytokine, is reduced in the disease pathogenesis3,4. Studies have shown that during the relapse phase and increases as the patient MS patients have a much higher number of neuroantigen enters remission25,34,35. In addition we have demonstrated e.g. myelin basic protein (MBP) and myelin oligodendrocyte that the balance between biologically active TGF-b1 and glycoprotein (MOG) autoreactive T-cells, which are in an the pro-inflammatory TNF-a, IL-1b and IFN-g is dysregu- increased state of activation compared with healthy controls, lated during MS relapse-remission25. The actual processes and which increase during exacerbation4 – 13.
of axonal damage e.g. chronic inflammation, demyelination Cytokines from activated T cells and macrophages have and astrogliosis in MS is complex but white matter inflam- been strongly implicated in the pathogenesis of MS14. For mation and demyelination are considered to determine dis- example, the up-regulation of adhesion molecules on endo- ease severity, whilst recent studies suggest that axonal thelial cells and the subsequent infiltration of activated T damage in MS begins in the early stages of the disease cells into the CNS are immunopathogenic events controlled and contributes to disability36,37. Furthermore some have * Corresponding author: Dr Laurence Harbige, fax 0044 (0)1813319805, email [email protected]

Polyunsaturated fatty acids and multiple sclerosis reduced in the plasma, platelets, erythrocytes, leucocytes andcerebrospinal fluid with changes in the unsaturated fatty acidcomposition of brain white matter in MS patients, much ofthis early work being undertaken at the National Hospital,Queen Square in London49 – 60. But there are also inconsistentreports61 – 64and Love et al.65 observed that reduced linoleicacid was not specific to MS and occurred in patients withacute non-neurological illness. However many of these differ-ences between studies are perhaps not surprising given cul-tural and ethnic differences, dietary variability (particularlywhen someone is ill), possible desaturase gene polymorphism,disease variability, serum verses cellular fatty acids and meth-odological differences for example total lipid fatty acidsverses phospholipids fatty acid analysis.
Previously we proposed nervonic acid as a marker of CNS myelin damage in MS66 and found that MS patients consum-ing a diet rich in polyunsaturated fatty acids particularly lino- Fig. 1. Geographical distribution of multiple sclerosis (from Adams C (1989) leic acid had an inverse relationship between erythrocyte colour atlas of multiple sclerosis and other myelin disorders, wolfe medicalpublications ltd, with permission).
membrane linoleic acid and nervonic acid (24 : 1)67. A similarfinding was described by Homa et al.68, showing a decrease inerythrocyte lignoceric acid (24 : 0) in sunflower oil (rich in considered metabolic disturbances in some MS patients to linoleic acid) supplemented MS patients. In an open, uncon- be behind primary oligodendrocyte damage with secondary trolled 2 year fish oil intervention study by Nordvik et al.69 in MS, they observed significant reductions in plasma totalphospholipid nervonic and lignoceric acids with time and Nutritional epidemiology of multiple sclerosis clinical improvement. Taken together the above indicate thatnervonic and lignoceric acids could be useful pathogenic bio- Over half a century ago Roy Swank40 found a positive markers of myelin damage and/or biomarkers for monitoring relationship between fat intake as well as annual milk pro- fatty acid treatments. We also found that the atypical erythro- duction and MS in Scandinavian countries. Furthermore cyte electrophoretic response of MS patients was positively studies by Alter et al.41 implicated animal fat rich in satu- correlated with membrane linoleic acid and could be corrected rated fatty acids as a causal factor in MS and Wolfgram42 by a diet rich in polyunsaturated fatty acids particularly lino- in an analysis of World Health Organisation (WHO) annual leic acid67. This is in agreement with Field and Joyce71 who mortality statistics found a similar geographical distribution found an increase in erythrocyte electrophoretic response in between MS coronary heart disease and cancer of the MS patients supplemented with evening primrose oil (EPO).
colon. In the multivariate analysis (inclusive of socioeco- However, Field et al.71, Field and Joyce70 interpreted their nomic and medical services) of 20 countries Arganoff and electrophoretic results, without an analysis of membrane Goldberg43 not only implicated meat and dairy fats in posi- fatty acids, as an effect of the gamma-linolenic (GLA, tive correlations with MS, as noted previously, but also veg- 18 : 3n-6) component of the oil. EPO contains about 70 % lino- etable, seed, nut and fish, foods rich in both the n-6 and n-3 leic acid and 8 – 10 % GLA, therefore it is more likely that the polyunsaturated fatty acids, in negative correlations with MS.
effect observed by Field et al was due to the linoleic acid com- Several other studies also confirmed strong MS associations ponent of the oil rather than the GLA.
with dairy and other animal fats44 – 46. Similar observations We have also investigated the metabolic relationships have also been made more recently by Esparsa et al.47 in a between the n-6 fatty acids in both healthy controls and MS large study (36 countries) assessing the impact of diet on PBMC total phospholipids (Figs. 2, 3 and 4). Both controls MS mortality. They found that the higher the saturated and MS patients (remission phase) demonstrate a positive cor- fatty acid intake the higher the MS mortality and the higher relation between linoleic acid (18 : 2n-6) and arachidonic acid the polyunsaturated to saturated fatty acid ratio the lower (20 : 4n-6) as expected, although these n-6 fatty acids were the MS mortality. However the large single country study, low in a proportion of the MS patients studied (Fig. 2). More- the Nurses' Health Study in the USA failed to show any over, the relationship between linoleic acid (18 : 2n-6) and relationship between MS and fat intake in women48. Thus dihomo-g-linolenic acid (DGLA), and also between DGLA the majority of epidemiological studies indicate that foods (20 : 3n-6) and arachidonic acid (20 : 4n-6) is clearly disturbed rich in saturated fatty acids are detrimentally associated in MS compared with healthy controls (Figs. 3 and 4). This with MS, whilst polyunsaturated fatty acid rich foods are ben- may indicate a problem with D6 and D5 desaturation and / eficially associated with MS.
or a greater requirement for these n-6 fatty acids in manyof the MS patients studied, about 20 – 30 percent of thepatients showed lower than normal PBMC phospholipid Biochemical and metabolic studies of fatty acids in DGLA and arachidonic acid. In agreement with our findings multiple sclerosis Homa et al.55 has also reported a similar disturbance in the There is much evidence that the n-6 fatty acids particularly relationship between linoleic acid and arachidonic acid in MS linoleic (18 : 2n-6) and arachidonic acids (20 : 4n-6) are erythrocyte membrane lipids compared to healthy controls.

L. S. Harbige and M. K. Sharief Fig. 3. Relationship between linoleic acid (18 : 2n-6) and dihomo-g-linolenicacid (20 : 3n-6) in peripheral blood mononuclear cell total phospholipids of healthy controls and multiple sclerosis.
Fig. 2. Relationship between linoleic acid (18 : 2n-6) and arachidonic acid(20 : 4n-6) in peripheral blood mononuclear cell total phospholipids of healthycontrols and multiple sclerosis.
Fatty acids and animal models of multiple sclerosis Experimental autoimmune encephalomyelitis (EAE) is an Furthermore when we compared MS and healthy control experimentally induced CD4þT cell mediated autoimmune- PBMC total phospholipid 20 : 2n-6 we found a significant 2 inflammatory and deyelinating disease in rodents often used fold higher 20 : 2n-6 in MS patients in remission compared as an animal model of MS. Studies in guinea pig and rat to healthy controls and a significant 4 fold higher 20 : 2n-6 EAE treated with linoleic acid alone or a high linoleic and in the relapse phase of the disease. It appears that in MS low g-linolenic (GLA) acid rich oil (ratio 7 : 1) respectively, there is a very active elongation of 18 : 2n-6 to 20 : 2n-6 in have shown partial suppression of the incidence and severity PBMCs and that this is even higher in the relapse phase of EAE73,74. In a series of experiments we demonstrated (accounting for the low 18 : 2n-6) indicating a disturbance in important disease modifying effects of linoleic acid-rich oil the normal metabolism or a higher requirement for DGLA (containing no GLA) and GLA-rich oil on clinical and histo- and arachidonic acid (20 : 2n-6 maybe further D8 desaturated pathological manifestations of EAE. Depending on dose GLA to DGLA?) by these n-6 fatty acid (20 : 4n-6) rich cells72, or was completely protective in EAE, whereas linoleic acid had both. This may also be reflective of the demand of cells and a dose dependent action on the clinical severity of EAE, myelin in the brain which are also n-6 fatty acid-rich although not abolishing it75,76. Natural recovery in EAE is (20 : 4n-6 and 22 : 4n-6), significantly Stanley Rapoport of mediated by expansion of suppressor lymphoid cells77 some the NIH has shown that the human brain requires 4 times of which have been characterised as TGF-b producing the amount of arachidonic acid (20 : 4n-6) than docosahexae- CD4þT cells by Karpus and Swanborg78. Furthermore admin- noic acid (22 : 6n-3) on a daily bases (ISSFAL 2006). In istration of TGF-b protects in acute and relapsing EAE79,80 relation to 20 : 2n-6, although not discussed by the authors, and prostaglandin inhibitors such as indomethacin augment the Nordvik et al.69 study demonstrated a reduction with EAE81. In-addition during the natural recovery phase from time of 20 : 2n-6 running parallel with clinical improvement, EAE TGF-b secreting T cells can inhibit EAE effector cells a similar finding to the nervonic and lignoceric acids men- and TGF-b is expressed in the CNS78,82,83. Consistent with tioned earlier. Therefore 20 : 2n-6 may also be a useful these findings the protective effect of GLA-rich oil in EAE is marker of disease progression and/or monitoring fatty acid linked to increased T cell TGF-b transcription and increased treatments in MS.
production of PGE 76

Polyunsaturated fatty acids and multiple sclerosis reductions in the relapse rate and disability progression asmeasured by the Expanded Disability Status Scale (EDSS)69which quantifies disability in MS in eight functional systems(pyramidal, cerebellar, brainstem, sensory, bowel and bladder,visual, cerebral, other). It also appears based on open studiesby us and by Roy Swank that long term low saturated fatdiets containing both n-6 and n-3 fatty acids improve thecourse of the disease89 – 93.
Based on our MS fatty acid metabolic data and experimen- tal animal model work, described above, we undertook a ran-domised double-blind placebo controlled trial to determine theeffects of supplementation with a selected GLA (18 : 3n-6)-rich borage oil. This oil, BGC20-884 was high in sn-2 GLA,low in monoenes and contained only natural levels of vitaminE. This study evaluated two doses of BGC20-884 (low dose -5 gram and high dose - 14 gram per day) and a placebo control(polyethylene glycol 400) on the clinical course and PBMCcytokine and membrane fatty acid profiles of 36 patientswith active MS over 18 months94. Patients were diagnosedand assessed using international criteria for MS. Relapserate and EDSS (Expanded Disability Status Scale) wereassessed every three months and blood taken and PBMCs iso-lated for cytokine studies and membrane fatty acids. Highdose reduced the relapse rate (Fig. 5) and disability progression as measured by EDSS (Fig. 6) compared with the placebo con-trol and low dose BGC20-884 treatment. In patients where we had follow up samples available PBMC cytokine changeswere found to run parallel with the clinical findings e.g. theplacebo control group showed significant decreases in theTGF-b/TNF-a and TGF-b/IL-1b ratios and associated loss of n-6 fatty acids particularly linoleic (18 : 2n-6) and arachidonic Fig. 4. Relationship between dihomo-g-linolenic acid (20 : 3n-6) and arachido- acid (20 : 4n-6) over time. Consistent with our findings nic acid (20 : 4n-6) in peripheral blood mononuclear cell total phospholipids of healthy controls and multiple sclerosis.
linoleic and arachidonic acids over time in MS erythrocytephospholipids. In contrast high dose BGC20-884 treatment showed no changes in TGF-b/TNF-a and TGF-b/IL-1b Clinical trials and intervention studies in multiple sclerosis ratios and no changes in membrane n-6 fatty acids compared with the placebo group. We also found positive correlationsbetween PBMC phospholipid arachidonic acid composition Clinical trials to test the efficacy of linoleic acid-rich sun- flower oil in MS patients by Miller et al.84 and Bates et al.85 and DGLA and TGF-b1 production (r ¼ 0·36, P , 0·001, over 2 years showed a reduction in the relapse rate and sever- n ¼ 74) ex vivo when all samples were included in the ity of the disease relapse, but Paty et al.86 found no such analysis. The EDSS improvement in the high dose group effect. Nevertheless, Dworkin et al.87 in a statistical revalua-tion of the combined data of all three trials revealed signifi-cantly reduced relapse rate and severity, and in mildlyaffected a decrease in the long term progression of the disease.
The Millar et al.84 study based in two centres London and Bel-fast is particularly interesting as they observed that "the sever-ity of the relapses, differed markedly between the treated andthe control groups at both centres" relapses being twice assevere in the control group. Compared with current b-inter-feron treatment of MS the efficacy of linoleic acid-rich sun-flower oil in the Miller et al study is quite remarkable. Fishoil rich in long chain n-3 fatty acids has also been studiedin MS88, no significant differences between fish oil treatedand untreated MS patients was observed, there was, however,a trend for less deterioration in the fish oil treated group. In a 2 Fig. 5. Mean annualised relapse rate per patient for multiple sclerosis year open intervention study MS patients given fish oil and patients receiving high (n ¼ 11) and low dose (n ¼ 7) GLA-rich oil or placebo advised to lower their saturated fat intake had significant control (n ¼ 10) over 18 months.

L. S. Harbige and M. K. Sharief as arachidonic acid are important in the growth and differen-tiation of oligodendrocytes and in myelination104 – 108 whichwould therefore be of importance in the stimulation, growthand recovery of these cells in MS. These findings provide alink between, dietary, metabolic, immunological and neuro-biological aspects of MS and therefore for the first time wecan begin to make sense of the wealth of apparently uncon-nected aspects of MS, particularly in relation to dietary fats.
More basic research is still required such as characterisationof possible desaturase gene polymorphisms, lymphocyte desa-turase gene expression and analysis of specific lymphocytephospholipid classes and their fatty acid composition in Fig. 6. Disability progression as measured by the EDSS (Expanded DisabilityStatus Scale) in multiple sclerosis patients receiving high (n ¼ 11) and low relation to cytokine and chemokine gene expression and pro- dose (n ¼ 7) GLA-rich oil or placebo control (n ¼ 10) over 18 months.
duction. This should be undertaken in well defined MS patientgroups e.g. active MS and primary and secondary chronic pro-gressive forms of the disease and over an extended period of also suggests there maybe a beneficial effect on neuronal time. Furthermore large well controlled clinical trials with lipids and neural function in MS. The study thus further sup- different doses of well characterised and safe fatty acid formu- ports our hypothesis of dysregulation of fatty acid metabolism lations as well as manipulation of dietary saturated fatty acids and cytokines in MS25,76.
could be undertaken. Clinical trials should include MRI, MR To summarise and extend this section on clinical trials there spectroscopy and analysis of lesion burden and cortical gray is evidence to show a beneficial effect of n-6 and possibly n-3 matter density in order to investigate any possible effects of fatty acids in MS. The mechanisms by which the n-3 or the polyunsaturated fatty acids on myelination, neuronal, dentritic, n-6 fatty acids influence the immune-inflammatory response glial and neurite packing densities. In addition biochemical in MS are however likely to be different72. Both the n-6 (ara- monitoring of peripheral blood cell membrane phospholipid chidonic acid) and n-3 (docosahexaenoic acid) fatty acids are fatty acids, particularly lymphocytes, should be undertaken important for neural structure and function95 – 101 and this as well as immunological studies such as T-cell and macro- aspect may explain studies where improvements in EDSS phage pro- and anti-inflammatory cytokine gene expression have also been reported. Furthermore requirements for essen- and production, T regulatory cells and anti-myelin antibodies.
tial polyunsaturated fatty acids increase as a function of the In this way a more complete picture will emerge of the clinical amount of saturated fat in the diet102 and we have recently and therapeutic significance and the metabolic, immunological found significant positive correlations between dietary total and neurological bases to the role of polyunsaturated fatty saturated and total monounsaturated fatty acids and delta-6 acids in the pathogenesis and treatment of MS.
and delta-5 desaturase gene expression in human PBMC103.
The level of dietary saturated and monounsaturated fattyacids should not therefore be ignored and may be important Conflict of interest statement factors in some of the trials discussed above and relate tothe MS epidemiological correlations, mentioned earlier in BGC20-884 and related intellectual property are patented by this overview, in relation to an increased requirement for poly- BTG International Ltd with LSH and MKS as named inven- unsaturated fatty acids in MS.
tors. LH and MKS co-wrote the manuscript. At the time ofthe trial there were no conflicts of interests. Subsequently tothe trial findings BGC20-884 and related intellectual property Conclusions and perspectives is now the subject of patents held by BTG International Ltdwith LSH and MKS as named inventors. LH wrote the text Taken overall the epidemiological, biochemical, experimental and MKS was the lead trial neurologist.
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