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| REVIEW ARTICLE |
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| Year : 2015 | Volume
: 1
| Issue : 1 | Page : 63-68 |
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Alcohol abuse and docosahexaenoic acid: Effects on cerebral circulation and neurosurvival
Michael A Collins
Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA
| Date of Submission | 05-Jun-2015 |
| Date of Acceptance | 15-Jun-2015 |
| Date of Web Publication | 30-Sep-2015 |
Correspondence Address:
Michael A Collins
Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, 2160 S. First Avenue, Maywood, Illinois - 6053
USA
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2394-8108.162533
Alcohol abuse and alcoholism are major and yet surprisingly unacknowledged worldwide causes of brain damage, cognitive impairment, and dementia. Chronic abuse of alcohol is likely to elicit significant changes in essential polyenoic fatty acids and the membrane phospholipids (PLs) that covalently contain them in brain membranes. Among the fatty acids of the omega-3 polyenoic class, docosahexaenoic acid (DHA), which is relatively concentrated in mammalian brain, has proven particularly important for proper brain development as well as neurosurvival and protection. DHA losses in brains of chronic alcohol-treated animals may contribute to alcohol's neuroinflammatory and neuropathological sequelae; indeed, DHA supplementation has beneficial effects, including the possibility that its documented augmenting effects on cerebral circulation could be important. The neurochemical mechanisms by which DHA exerts its effects encompass several signaling routes involving both the membrane PLs in which DHA is esterified as well as unique neuroactive metabolites of the free fatty acid itself. In view of indications that brain DHA deficits are a deleterious outcome of human alcoholism, increasing brain DHA via supplementation during detoxification of alcoholics could potentially fortify against dependence-related neuroinjury. Keywords: Alcohol, docosahexaenoic acid (DHA), and neuroprotection
How to cite this article:
Collins MA. Alcohol abuse and docosahexaenoic acid: Effects on cerebral circulation and neurosurvival. Brain Circ 2015;1:63-8 |
| Introduction | |  |
A growing body of research indicates that essential fatty acids of the polyenoic omega-3 class-specifically, 18:3 α-linolenic acid (ALA), 20:5 eicosapentaenoic acid (EPA), and 22:6 docosahexaenoic acid (DHA)-have or subserve neuroprotective and/or anti-inflammatory functions in the mammalian nervous system. In contrast, essential fatty acids of the omega-6 class, and notably 20:4 arachidonic acid (ARA), tend to foster pro-neuroinflammatory or prooxidative actions either directly or via metabolic products. Comprehensive reviews have covered the burgeoning story of omega-3 (and omega-6) fatty acids in connection with widespread neurotoxic insults including ischemic stroke and trauma, neurodegenerative diseases such as Alzheimer's, Parkinson's, depression, epilepsy, [1] and brain aging. [2] However, experimental research on brain omega-3 fatty acids in reference to "alcohol use disorders" has been infrequently compiled. Alcoholism and alcohol use disorders affect people ranging from young (fetal alcohol damage, adolescent binge drinking) to the aged and often result in permanent neurodamaging effects on the brain structure and neuronal function. [3] This article draws together experimental reports on alcohol and brain omega-3 fatty acids, chiefly DHA, including insights on the anti-inflammatory and protective consequences of DHA supplementation.
Omega-3 fatty acids in mammalian brain principally consist of DHA, with concentrations equal to or even greater than those of omega-6 ARA; brain concentrations of EPA and ALA are much lower. Like ARA, DHA is covalently esterified largely in the 2-position of a membrane phospholipid (PL), with phosphatidylserine (PS) having the greatest proportion for DHA followed by phosphatidylethanolamine (PE), although the distribution can differ among species. DHA is likely to be free or liberated (nonesterified) in small quantities and, as such, is believed to be a principal source of neuroactive metabolites. Although DHA is biosynthesized peripherally and to a limited extent centrally from omega-3 ALA and EPA via elongation and desaturation, by far its major mammalian source is the diet. [4]
| Effects of Chronic Alcohol on Brain Omega-3 Fatty Acids | | |
Initial studies during the late 1970's and the following decade were driven by concerns that membrane PL and fatty acid changes due to alcohol might be essential to understand the neurophysiology of alcohol tolerance and/or dependence (e.g., withdrawal signs, hyperanxiety, and seizures). Whereas these first reports with mice, rats, or other animals did not call specific attention to omega-3 fatty acids or DHA in particular, they nevertheless showed that alcohol treatments often, but not always, rather selectively depleted brain DHA content. In adult male mice, chronic alcohol exposure (which in animal studies is generally defined as at least a week, and is usually longer) via liquid diet or vapor chamber for 10 days, blood alcohol levels (BALs) not stated, caused modest but significant DHA reductions of 11-19% in crude synaptosomal fractions from the whole brain, [5],[6] and the DHA depletion was augmented by high saturated fat diets. [6] Also, in a short-term model of tolerance/dependence, an alcohol-liquid diet given for a week (peak BAL ~130 mg/dL), adult mice incurred comparable reductions in DHA in synaptic plasma membranes (SPMs), with few changes in other fatty acids or any PL. [7] On the contrary, brain synaptosomes or SPM from adult mice similarly alcohol-treated (BAL ~200 mg/dL) demonstrated no significant omega-3 or other fatty acid alterations. [8]
Results with rats and other animal models were also variable. In adult rats given alcohol-liquid diet for 3 weeks (BAL ~310 mg/dL at sacrifice), DHA in brain mitochondrial membranes was increased in PS and slightly decreased in phosphatidylcholine (PC), whereas it was unchanged in synaptosomal PL species. [9] Omega-3 fatty acids in brain SPM preparations from adult rats subjected to short-term (subchronic) but severe binge alcohol intoxication, i.e., the Majchrowicz gavage model involving three doses daily for ~4 days (9-12 g alcohol/kg/day; peak BAL ~350 mg/dL), were unchanged. [10] However, in brain microsomes from rats fed alcohol for 35 days (12.4 g alcohol/kg/day; BAL not stated) the DHA concentrations in the PS component were significantly (and selectively) reduced over 50%, [11] and brains of neonatal chicks chronically consuming alcohol (18 days; peak BAL ~140 mg/dL) contained significantly reduced DHA in microsomal fractions. [12] However, guinea pigs on alcohol-liquid diets for 3 weeks (BAL not stated) had no DHA changes in SPM PL except for PE where DHA was slightly increased, [13] along with increases in PS. There have been further dissimilar results with respect to alcohol and PS in the absence of any DHA assays. Studies with chronic alcohol-ingesting rats reported increased PS [14] (as mentioned, a major source of esterified synaptic DHA) but the opposite result of decreased PS was found in a very long-term alcohol-sugar water study. [15] Parenthetically, in these and other contemporaneous studies, the typical procedure of whole brain extraction rather than brain regions for synaptosomes, SPM, and/or microsomal preparations could have obscured otherwise significant regional reductions in the PL and omega-3 fatty acids including DHA. Additionally, differences in the length of alcohol exposure, BALs attained, whether the animals were sacrificed with alcohol "on board" or during some phase of withdrawal (sometimes not clearly specified), and how they were sacrificed (e.g., post-mortem PL or omega-3 changes [16] ) could confound lipid assay results.
With respect to humans, unlike brain studies of subjects with mental and psychiatric disorders, [17] only a few postmortem brain omega-3 fatty acid or DHA determinations in chronic alcoholics have been reported. A relatively early report documented substantial lipid loss, along with demyelination in the brains of chronic alcoholics. [18] Specifically concerning omega-3 fatty acids, in a study with relatively low numbers, DHA in the frontal cortex of bipolar patients, when combined with normal controls, was over 40% decreased in the subjects with "high severity" of alcohol abuse relative to those with low alcohol abuse severity, indicating a DHA-depleting effect of heavy alcohol consumption. [19]
| Alcohol and Dietary or Supplemented DHA | | |
Aside from the above alcohol tolerance and dependence studies, it became clear that animals seriously low in omega-3 intake and with significant brain DHA deficits demonstrated impaired learning and cognition as well as reduced visual acuity. [20] This gave impetus to considerations that alcohol-dependent effects on DHA and other omega-3 fatty acids could be significant factors in (chronic) alcohol's effects on cognitive dysfunction, brain development, and even preference for alcohol. [21],[22] With respect to alcohol preference, a limited study with alcohol-preferring or "P" rats indicated that a diet high in DHA significantly suppressed free-choice alcohol consumption (15% alcohol) compared to those on low DHA-containing diets. [22] In adult cats maintained on diets with restricted but adequate amounts of essential fatty acids, alcohol feeding for 8 months (1.2 g alcohol/kg/day; peak BAL ~110 mg/dL, 2 h after feeding) caused depletion of brain levels of DHA and omega-3 docosapentaenoic acid (DPA), and compensatory increases in omega-6 DPA. [23] The reciprocal change in DHA and omega-6 DPA, in which the latter is thought to "replace" the former in PL, was postulated to underlie alcohol's neuropathological and cognitive effects. In a key study, chronic alcohol intake markedly affected primate brain DHA; monkeys chronically consuming alcohol in moderate amounts (2.6 g alcohol/kg/day; peak BAL 82-135 mg/dL) had brain cortex concentrations of DHA that decreased 20% after 2.5 years of alcohol consumption and nearly one-third after 5 years when compared to control monkeys. [24] Retinal DHA was similarly reduced and generally there was increased omega-6 DPA in these tissues, reflecting a reciprocal and potentially neuropathological change similar to that in felines. Unfortunately, with these valuable animals, omega-3 DHA levels in other brain regions were neither reported nor were possible neuronal losses mentioned.
The impact of maternal alcohol intake on fetal brain has been widely studied in rats and mice, given that it is one of the foremost reasons for developmental human brain damage (i.e., fetal alcohol spectrum disorders or alcohol teratogenicity). Consequently, brain omega-3 and omega-6 fatty acids have received experimental scrutiny in fetal as well as perinatal alcohol experiments. Prenatal alcohol exposure with controlled diets in pregnant mice resulted in reduced omega-3/omega-6 ratios in the PC and PE components of pups at postnatal day 3 and postnatal day 10; importantly, omega-3 enriched diets normalized this change. [25] Also, the effects on brain lipids of omega-3 deficient diets in rat pups postnatally treated with alcohol were studied. [26] Pups raised on omega-3 deficient diets had reduced percentages of forebrain and cerebellar DHA, as expected. Alcohol effects were inconsistent in these studies, however, with omega-3 fatty acids decreased in cerebellar PE but not in PC elsewhere. Focusing on alcohol and developmental neurodamage, prenatal alcohol studies in rats revealed that fetal neuronal apoptosis was associated with decreases in fetal HC levels of DHA and PS, [27] which as mentioned is the PL containing the major percentage of DHA. Extending the alcohol exposure into the developmental period resulted in inhibition of the synthesis of PS containing DHA. [28] Notably, improvements in cognition have been reported in animals receiving supplements of PS that generally have high DHA content, [29] and postnatal supplementation with DHA and PS also improved antioxidant activities in developing brain. [30] Antioxidant "rescue" by omega-3 fatty acids in a prenatal ethanol-treated rat model is indicated by evidence that postnatal supplementation restored offspring brain levels of glutathione and prevented regional lipid peroxidation [31] while reversing long-term hippocampal synaptic plasticity deficits. [32]
| DHA and Alcohol-Induced Neuroinflammation | | |
Neuroinflammatory activation involving microglia, astroglia, and transmigrated immune cells is a possible prelude to and even a triggering event for neurodegeneration. [33] Neuroinflammatory signaling was first linked to alcohol treatments involving chronic intake and moderate BALs. [34] It was also evident with repetitive "binge" alcohol intoxication protocols that significant neuroinflammatory protein changes were initiated in adolescent or adult mouse and rat brain. [35],[36] Moreover, when subchronic neurotoxic intoxication mirrored binge alcohol abuse with BALs of 350 mg/dL and higher specifically in the Majchrowicz adult rat model, [37] significant neuroinflammatory protein changes coincided well with the evident regional neurodegeneration in hippocampus (HIP), entorhinal cortex (ERC), and olfactory bulb. [38] Our recent studies with this model have centered on important proteins primarily associated with the following brain PL-associated neuroinflammatory pathways: phospholipase A2 (PLA2) enzymes from three families (calcium-dependent or cPLA2, calcium-independent or iPLA2, and secreted or sPLA2), aquaporin-4 (AQP4) water channels, and poly (ADP-ribose) polymerase-1 (PARP-1).
Concomitant with increased oxidative stress markers (4-hydroxynonenal-linked proteins), neurotoxic binge alcohol intoxication caused regionally-specific elevations in cPLA2 IVA, its active phosphorylated form (p-cPLA2), and sPLA2 IIA - enzymes that mobilize ARA substrate for cyclooxygenases and lipoxygenases (neuroinflammatory eicosanoid formation). On the other hand, iPLA2 VIA, which may be neuroprotective via influencing mitochondrial free radical production, [39] was reduced in HIP. AQP4, a largely astroglial water channel that can promote proinflammatory cytokine-related neuroinflammation, [40] was increased and PARP-1 also was potentiated. PARP-1 is a nuclear DNA repair enzyme but its overactivation due to chronic neuronal oxidative stress/DNA damage can foster a type of regulated necrosis, termed parthanatos. [41] In this binge alcohol rat model, apoptosis has been found to be negligible, [42] which leaves neuroinflammatory necrosis as a major death pathway.
Coinciding with these in vivo experiments, binge alcohol-induced neuroinflammation and neurodegeneration were assessed in organotypic rat HIP+ERC slice cultures, first with adolescent-age slices taken from 7-day-old rat pups and cultured for several weeks [43] and subsequently with HIP+ERC slices from the same regions that were of adult brain age (~60 days), thus more closely matching the in vivo adult studies. Binge alcohol treatment of the adolescent cultures promoted increased AQP4 and neurodegeneration, with the latter precluded by an AQP4 inhibitor [44] or by an sPLA2 inhibitor. [43] Alcohol binging of the adult-age slice cultures enhanced brain oxidative stress footprints (3-nitrotyrosinated proteins) and elevated the levels of cPLA2, p-cPLA2, sPLA2, AQP4, and PARP-1, analogous to the in vivo neuroinflammatory results. [38] It also depleted levels of iPLA2 and endogenous DHA. Since iPLA2 is regulatory for endogenous DHA turnover, [45] its decreased levels could be responsible in part for the DHA depletion. Also, binge alcohol increased brain slice levels of omega-3 DPA (22:5), suggesting that alcohol treatment might be blocking the desaturation step that forms DHA. A third reasonable possibility for DHA decrements is lipid peroxidation, which has been implicated in previous animal studies as a feature of alcohol withdrawal. [46]
Added DHA had a robust ameliorating effect in the binged organotypic HEC+ERC brain slice cultures. DHA cotreatment with binge alcohol inhibited adolescent-age brain slice AQP4 potentiation while abolishing neurodegeneration. Similarly, in the adult-age brain slices, DHA coexposure with binge ethanol blocked elevations in an oxidative stress footprint (3NT-proteins), reflecting the anti-inflammatory actions of the fatty acids and provided effective neuroprotection. Perhaps most surprisingly, the omega-3 fatty acid abolished the potentiation by binge alcohol of HIP+ERC slice levels of cPLA2, p-cPLA2, sPLA2, PARP-1, and (as with the adolescent-age slice cultures) AQP4. [38] The decline of iPLA2 levels was prevented as well while the levels of DHA were normalized. Overall, these organotypic brain slice findings with binge alcohol were in accordance with the considerable in vivo evidence of DHA's potency in preventing oxidative stress and neuroinflammation in a variety of brain insult conditions. [47]
| DHA Protective Mechanisms: Increased Cerebral Circulation | | |
Omega-3 fatty acids and especially DHA appear to consistently augment or improve cerebral circulation, as summarized in a recent thorough review of available studies. [48] For example, diets enriched in DHA and other nutrients are found to increase cerebral blood flow (CBF) in an Alzheimer's disease mouse model. [49] In ischemic gerbils, chronic pretreatment with DHA (ethyl ester) prevented postischemic brain hypoperfusion and also attenuated edema [50] (possibly involving suppression of AQP4 but not explored). Studies with ageing monkeys indicated that DHA supplementation positively affected the coupling between functional CBF and neuronal activity. [51] However, no changes in CBF were observed in neonatal mice treated with omega-3 rich triglyceride emulsion treatments and subjected to ischemia although the emulsions were neuroprotective acutely. [52] Studies in alcohol-treated animals are needed but in alcoholics there is substantial support for cerebral hypoperfusion, especially during withdrawal, [53] making indications from positron emission tomography studies in alcoholics that DHA might increase CBF during early abstinence especially relevant. [54]
| DHA Protective Mechanisms: Signaling and Its Active Metabolites | | |
As with most pleiotropic molecules, how DHA exerts its neurosurvival and neuroprotective effects is uncertain but challenging directions are receiving attention. At the neurocellular level, its stimulatory effects encompass a host of anti-inflammatory or survival genes and gene products, namely, Akt, Bcl-2, PPARgamma, and other transcription factors. [55],[56] Orphan receptors termed free fatty acid receptors (GPR120 and GPR40) also are activated by DHA [57] but the brain significance is unclarified. It could also be significant that DHA, either directly or via metabolites, can inhibit cyclooxygenases producing proinflammatory ARA-derived eicosanoids and toll-like receptors that increase proinflammatory cytokines in response to brain protein danger signals. [58]
Considerable evidence indicates that DHA's neuroprotective activity is crucially related to membrane PS and DHA esterification. Supplementation of different cultures with DHA are reported to promote increased total PS levels selectively in neuronal cell lines; [59] conversely, DHA deficiency in vivo results in reduced PS specifically in neuronal tissues, [60] as well as impairment of long-term potentiation. [61] In addition to PS and linked DHA involvement, there is active research interest in metabolic docosanoid derivatives of free DHA. Although oxygenated brain metabolites of DHA were noted some time ago, [62] attention has recently been focused on a potent stereospecifically hydroxylated derivative called neuroprotectin-1 (NPD1; 10R,17S-dihydroxy-docosa-4Z,7Z,11E,15E,19Z-hexaenoic acid) that arises centrally from the action of 15-lipoxygenase-1. [63] NPD1 is highly neuroprotective against a range of brain insults and it is generated from DHA in vivo in response to conditions of injury involving brain oxidative stress, protein misfolding, and perhaps toxic insults that could include alcohol, although the last suggestion is untested. NPD1 is but one of a number of stereospecific hydroxylated metabolites of DHA termed specialized proresolving mediators - molecules that suppress or counter-regulate inflammation and stimulate clearance of inflammatory debris, particularly in blood and immune cells. In addition to protectins (e.g., NPD1), these mediators include resolvins and maresins formed by different lipoxygenases. [64] It is, however, uncertain if resolvins and maresins derived from DHA are part of DHA's neuroprotective and anti-oxidative repertoire in the brain.
A further appealing brain metabolite of DHA with neuroactivity that does not arise initially from enzymatic oxygenation is synaptamide, which is an ethanolamide derivative analogous to the ARA-derived cannabinoid, anandamide. [65] Although the activity of synaptamide at cannabinoid receptors is not impressive, the DHA-derived amide is a highly potent neurogenic factor through unknown mechanisms and its brain levels are potentiated significantly by fish oil or DHA supplementation. Whether synaptamide has brain antioxidant or neuroprotective effects in alcohol models certainly remains a possibility.
In summary, animal studies with DHA have utilized a range of models involving diverse species and alcohol administration techniques, markedly differing BALs, and varying lengths of exposures; hence, there is a clear need for (more) compatible experimental alcohol studies in vivo to unequivocally establish the effectiveness of DHA supplementation on cerebral circulation and prosurvival mechanisms. Nevertheless, if one considers the existing evidence for DHA's propitious prosurvival and cerebral circulatory effects, it is worth reiterating what was proposed in a general sense almost 30 years ago, i.e., [66] DHA might well be a reasonable, safe supplemental therapy during withdrawal of alcoholics that could potentially counteract some of the detrimental actions of chronic alcohol abuse on the brain neurocellular/neurovascular environment and endogenous omega-3 fatty acids.
Acknowledgments
Nuzhath Tajuddin, Edward J. Neafsey, Kwan Moon, Kim Nixon, Toni Pak, and Hee-Yong Kim are recognized for their contributions to the research reviewed and associated with the below grant.
Financial support and sponsorship
Support provided by NIH U01 AA018279 and the Loyola University Chicago Research Fund Committee are gratefully acknowledged.
Conflicts of interest
There are no conflicts of interest.
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