DHA Protects Your Brain Cells

DHA Protects Your Brain Cells
Omega-3 fatty acid creates molecular
self-defense mechanism by means of a “golden brick”
By Will Block

With twice as much brain, he’d still be a half-wit.
— Leo Rosten

o be kind, we won’t identify the target of Leo Rosten’s caustic gibe. You can probably think of a few candidates of your own. The other side of the coin, of course, is those individuals who are so brilliant that with only half a brain they’d still be twice as smart as most mere mortals. From current events, John Roberts comes to mind. Despite having intellect to burn, however, we doubt that Chief Justice Roberts would be any more willing than Joe Sixpack to relinquish any of his precious neurons to needless damage or death. When it comes to preserving and protecting brain cells, everyone is smart enough to see the wisdom of doing that—even if not everyone behaves accordingly.

So how should one behave—and what causes neuronal damage and death in the first place? We’ll take those questions in order. First, eat a healthy diet, get plenty of exercise, don’t smoke, don’t abuse alcohol or other substances, and try to maintain your sanity in a crazy world in which too many institutions are run by half-wits. Supplements help too, especially the omega-3 fatty acids. These are a special type of polyunsaturated fatty acids (PUFAs) that are also known as fish oils, because they’re the key components of oils in which certain fish—coldwater fish, such as shad, mackerel, salmon (especially Chinook), herring, anchovies, and tuna (especially fresh bluefin)—are very rich.

DHA Is Brain Food

When your mom told you that fish was brain food, she was right (moms are always right), in more ways than one. For starters, the cell membranes of the neurons in your central nervous system contain large amounts of DHA (docosahexaenoic acid), which is one of the two most important omega-3 fatty acids, the other one being EPA (eicosapentaenoic acid). Although every cell in your body contains DHA, its highest concentrations are found in two organs you would not want to do without: your brain and your eyes (sperm is also rich in DHA). That should give you some idea of how important DHA is. (For more evidence, see the sidebar “How Long Can We Go without DHA?”. And see “Omega-3 Fish Oils Reduce Mortality from All Causes” in the July 2004 issue of Life Enhancement.)

In your brain, DHA is found mainly in “excitable” cell membranes, i.e., those at the synaptic junctions between neurons, where neurotransmission takes place; it’s also found, however, in nonneuronal cells, such as glia.* In your eyes, DHA is found primarily in retinal pigment epithelial cells and in the photoreceptor cells of which the retina is primarily composed.


*Glia, or glial cells, are brain cells whose main function is to carry out a variety of support, transport, growth, and housekeeping tasks for the all-important neurons (there are about 50 glia for each neuron). It is believed, however, that glia may also be involved in the encoding and transfer of information in the brain.


How Long Can We Go without DHA?

A good indication of how vital DHA is to our brains and eyes is the fact that these organs retain their DHA tenaciously, even during prolonged dietary deprivation of the essential fatty acids.* They do so, presumably, at the expense of the DHA content of other cells of the body. In experiments in which researchers tried to reduce the DHA content of the brains and retinas of rodents and nonhuman primates through dietary deprivation, it was found that it took more than one generation to do so!1,2 Eventually, the effects of this deprivation were observed as impairment of retinal function.


*There are two essential fatty acids: alpha-linolenic acid (ALA), an omega-3 fatty acid that is the precursor to EPA and DHA, and linoleic acid, an omega-6 fatty acid that is the precursor to arachidonic acid. The essential fatty acids are also the precursors to other important classes of compounds called eicosanoids and docosanoids.


Does this mean that we humans can go without essential fatty acids for years or decades at a time? No, it doesn’t. For one thing, we’re not rodents or nonhuman primates (although certain politicians we can think of are uncannily reminiscent of rats or baboons), so we can’t be sure that these results would apply to us as well. For another thing, we consist of more than just brains and eyes, and we naturally—in both senses of that word—want to optimize the health and well-being of all parts of our bodies. That means maintaining optimal, not merely adequate, amounts of omega-3 fatty acids at all times, preferably through supplementation.

Finally, and most importantly, we know from many previous studies that supplementing with omega-3 fatty acids produces palpable health benefits, especially in terms of cardiovascular and brain function. In the face of hard clinical evidence of that kind, any theoretical arguments to the contrary are meaningless.

References

  1. Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal omega-3 fatty acid deficiency on retina and brain in rhesus monkeys. Proc Natl Acad Sci USA 1986; 83:4021-5.
  2. Weisinger HS, Armitage JA, Jeffrey BG, Mitchell DC, Moriguchi T, Sinclair AJ, Weisinger RS, Salem N Jr. Retinal sensitivity loss in third-generation n-3 PUFA-deficient rats. Lipids 2002;37:759-65.

Without DHA, your brain cells would deteriorate and die. In fact, the brains of Alzheimer’s disease victims are markedly deficient in DHA. This may be the result of oxidative damage caused by free radicals, whose destructive effects are implicated in Alzheimer’s and many other diseases of aging, and in the aging process itself. It may also be due to a decreased dietary intake of DHA or its precursor, alpha-linolenic acid (ALA), or to impaired transport of DHA to the brain from the liver, where most of our DHA is synthesized from ALA. [This synthesis is, unfortunately, rather inefficient. It’s therefore important that we get DHA (and EPA) from fish or, better yet, from omega-3 fish-oil supplements, a more reliable source for maintaining optimal levels on a daily basis.]

DHA Is Important for Memory and Neuroprotection

In addition to being required for proper brain and retinal development, DHA has been found to be important in several other physiological functions, including memory1 and neuroprotection.2 The value of good memory is obvious. Less obvious, perhaps, because it’s a somewhat abstract concept that seldom enters our thinking, is neuroprotection. But think about it now: how good would your memory be if the neurons upon which it depended—indeed, if the zillions of established neuronal connections that constitute your memories—were not protected from harmful influences? The question answers itself.

But what are these harmful influences, and what can you do to protect yourself from them? Regular readers of this magazine can probably guess that among the most damaging phenomena in our brains and eyes, and throughout our bodies, is free radical-induced oxidative stress.

Oxidative Stress and Amyloid-Beta: A Vicious Circle

The primary source of free radicals is cellular respiration, the process that provides the chemical energy upon which all life processes depend. There are other sources as well, however, among the most pernicious of which is a protein called amyloid-beta. Ironically, its production is thought to be induced by free radicals in the first place; thus, amyloid-beta is both an effect of and a cause of oxidative stress. As if it weren’t bad enough that amyloid-beta forms the destructive senile plaques found in the brains of Alzheimer’s victims, it compounds the damage by promoting further oxidative stress, which induces the formation of more amyloid-beta, which … .

The Need for Neuroprotection

Lipids are especially vulnerable to oxidative stress via a chemical process called peroxidation, which irreversibly degrades them. In the cell membranes of neurons, most lipids are of a special kind called phospholipids (the two most prevalent ones are phosphatidylcholine and phosphatidylserine), and one of the prevalent fatty acids in these phospholipids is DHA. If the DHA, or any other component of the cell membrane, is attacked and degraded by free radicals, the neuron will be damaged and may die. Usually the death occurs by apoptosis (pronounced ap-oh-TOE-sis); this is a kind of cellular suicide, also called programmed cell death, which is induced by a variety of factors, including cell damage and advanced age.


The lipid bilayer (top of diagram) that constitutes neuronal cell membranes consists largely of phospholipids, such as phosphatidylcholine and phosphatidylserine. One of the principal fatty acids of which the phospholipids are composed is DHA. Under conditions of neuronal stress, especially oxidative stress, free DHA (an omega-3 fatty acid) and arachidonic acid (an omega-6 fatty acid) are released into the neurons, where they undergo the metabolic processes shown in the diagram. (Adapted from Ref. 3.)

To prevent undue cell damage, whether it leads to premature apoptosis or not, we need to protect our neurons. Nature has endowed us with a variety of mechanisms (none of them perfect, obviously) for doing this, and it has recently been discovered that one such mechanism involves our friend DHA.3,4

Oxidative Stress Triggers the Release of DHA …

Previous studies had shown that, under normal conditions, there is hardly any free DHA in the brain, because almost all of it is bound up in the cell-membrane phospholipids. Under certain stimulatory conditions, however, such as neurotransmission, ischemia (reduced blood supply), neurotrauma, and brief, non-cell-damaging seizures, some DHA is released from the phospholipids, and some of that DHA is metabolized (the rest is reincorporated into the phospholipids). This illustrates, by the way, the fact that cell membranes are more than just passive containers that hold the cell together—they are often active participants in metabolic processes.

The release of DHA from cell membranes occurs mainly under conditions of oxidative stress, which affects the DHA. Thus, at the same time that some of the cells’ DHA molecules are being attacked and degraded through lipid peroxidation, other DHA molecules undergo a series of enzyme-catalyzed reactions that lead to a metabolite (a product of a metabolic process) with an unexpected property: a strong neuroprotective action against further oxidative cell damage. Using a garden analogy, it’s as if a flower that was being choked by a weed developed a weed-killing chemical in response.

… Which Leads to Neuroprotection by NPD1

The discovery of DHA’s molecular self-defense mechanism was made recently by a team of researchers at Louisiana State University in New Orleans (see the sidebar on Hurricane Katrina for how they fared). They call the DHA metabolite neuroprotectin D1, or NPD1 for short.* In experimental studies on human neuronal cells, they demonstrated that NPD1 is a strong inhibitor of molecular signaling pathways that promote cellular injury or apoptosis, and they concluded that its biological activity is characterized by potent anti-inflammatory actions. In the course of this work, the researchers found that DHA itself, not just NPD1, is a strong inhibitor of oxidative stress-induced apoptosis, and they believe that DHA also produces neuroprotective metabolites other than NPD1.


*Strangely, the researchers characterized NPD1 by the highly inaccurate (indeed, meaningless) chemical name 10,17S-docosatriene. From their own elucidation of its molecular structure,4 however, it’s clear that the compound is 10,17S-dihydroxydocosahexaenoic acid.


More Fallout from Katrina


Dr. Nicolas Bazan
The work described in the accompanying article was done at the Louisiana State University Neuroscience Center in New Orleans. When Hurricane Katrina struck the Gulf Coast on August 29, the Center’s director and research team leader, Dr. Nicolas Bazan, was in Poland, where he was attending a conference on neurodegenerative diseases. On September 9, he told a reporter for the New York Times syndicate that he had been able to reestablish contact with only about half of his roughly 115 colleagues at the Center.1

At that time, Dr. Bazan expected that the Center would not be able to resume its research activities until late November or early December, interrupting what he called the most exciting period in his scientific career. His problem pales, of course, compared with losing one’s home or life. It’s just one of innumerable examples of the kind of societal disruptions whose collective ripple effects will be felt for many years to come.

Elsewhere it was reported that at LSU, Tulane University, and other research centers in the New Orleans area, Katrina damaged facilities and may have caused the loss of irreplaceable data, tissue samples, genetically engineered organisms, etc.2 LSU is reported to have lost about 8000 laboratory rodents, dogs, and primates that were being used in research. Fortunately, according to the Centers for Disease Control and Prevention, the bioweapons laboratories in the region reported no breakdowns in security. (But if there had been any, would they have admitted it?)

  1. Pallarito K. Scientists discover how fish oil protects the brain. New York Times syndicate, Sep 9, 2005.
  2. Barclay L. Research lost in Katrina flood: a newsmaker interview with Paul K. Whelton, MD, PhD. Medscape Medical News 2005. Sep 22, 2005. www.medscape.com/viewarticle/513289.

One example of NPD1’s potent neuroprotective action is its ability to reduce brain damage caused by stroke. When the LSU researchers induced strokes in laboratory animals by interrupting the blood supply to the middle cerebral artery, they found that NPD1 significantly reduced the volume of the infarct (the brain tissue killed by the stroke). In other experiments, they found a nice one-two punch in the following facts: (1) DHA tended to inhibit the formation of amyloid-beta in aging human neuronal cell cultures under oxidative stress, and (2) the amyloid-beta that did form stimulated the production of NPD1, which tended to inhibit neuronal apoptosis induced by the amyloid-beta. Thus the amyloid-beta got hit from both sides.

Both DHA and NPD1 Are Reduced in Alzheimer’s

The neuroprotective actions of DHA and NPD1 are believed to occur through their ability to upregulate (stimulate) the expression of genes that code for certain beneficial proteins, and to downregulate (suppress) the expression of genes that code for certain deleterious proteins. This apparently occurs not just in the brain but also in the DHA-rich retina, where NPD1 promotes the survival of retinal pigment epithelial cells. Their protection is especially important because damage or apoptosis of these cells impairs the survival of the underlying photoreceptor cells, and that is a dominant factor in age-related macular degeneration, an incurable disease that gradually destroys central vision.

Unfortunately for the victims of Alzheimer’s, that disease disrupts the expression of the genes that code for the enzymes responsible for NPD1 synthesis from DHA. According to the LSU researchers, this may explain, at least in part, why NPD1 levels in the hippocampus of Alzheimer’s brains are reduced to only about one-tenth of those in healthy, age-matched controls (the DHA levels are reduced by about half). This results in the effective loss of NPD1’s neuroprotective action during the brain-cell degeneration for which the disease is so notorious. (The hippocampus, by the way, is the primary seat of memory function and is progressively destroyed by Alzheimer’s disease.)

DHA and NPD1 Protect Neuronal Life

In summarizing their work, the LSU researchers stated,4

Taken together, these data suggest that NPD1 induces an antiapoptotic, neuroprotective gene-expression program that regulates the secretion of amyloid-beta peptides, resulting in the modulation of inflammatory signaling, neuronal survival, and the preservation of brain cell function. Agonists [stimulators] of NPD1 biosynthesis or NPD1 analogs may be useful for exploring new therapeutic strategies for Alzheimer’s disease and related neurodegenerative disease.

Dr. Nicolas Bazan, the lead investigator of the team, put it more succinctly in an interview on September 9:5

DHA is an essential building block for the structure of brain cells. And now we are finding that this building block also makes a “golden brick” (neuroprotectin D1) that helps the life of the neurons to continue.

You may not have any genuine golden bricks lying around the house, but it’s good to know that their figurative cousins are hard at work inside your brain, doing the best they can to preserve and protect it from harm—thanks to a precious form of brain food, DHA.

References

  1. Salem N Jr, Litman B, Kim HY, Gawrisch K. Mechanisms of action of docosahexaenoic acid in the nervous system. Lipids 2001;36:945-59.
  2. Kim HY, Akbar M, Lau A, Edsall L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J Biol Chem 2000;275:35215-23.
  3. Bazan NG. Neuroprotectin D1 (NPD1): a DHA-derived mediator that protects brain and retina against cell injury-induced oxidative stress. Brain Pathol 2005;15:159-66.
  4. Lukiw WJ, Cui J-G, Marcheselli VL, Bodker M, Botkjaer A, Gotlinger K, Serhan CN, Bazan NG. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J Clin Invest 2005 [online preprint].
  5. Pallarito K. Scientists discover how fish oil protects the brain. New York Times syndicate, Sep 9, 2005.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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