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Raw Avocado Kale Pesto with Zucchini Noodles

Raw Avocado Kale Pesto with Zucchini Noodles

Serves 4

• 4 medium zucchini
• 1 cup cherry tomatoes, sliced in half
• 3-4 cloves garlic
• 2 avocados
• 1/4 cup cold pressed olive oil
• 1/4 cup nutritional yeast (optional)
• 1/2 cup pine nuts plus some for garnish
• 1 small bunch kale, de-stemmed and torn into small pieces (about 1 BIG handful)
• 1 tablespoon lemon juice
• pinch Himalayan salt and fresh cracked pepper

1. Spiralize the zucchini. Set aside in a colander to drain excess liquid)

2. Start food processor running. Drop cloves of garlic in, one at a time. 

3. Add avocado, olive oil, nutritional yeast, pine nuts and lemon juice. Pulse until blended.

4. Add kale and plus until kale is well chopped and incorporated.

5. Season to taste with salt and pepper, then toss with the zucchini noodles and tomatoes.

*Chef’s note: Be careful of the source of your pine nuts. Some contain nuts that are not digestible and can cause problems. Please do your research and make sure you are getting your nuts from a good source.

http://www.rawmazing.com

  FYI - actually I don't even use pine nuts, just other seeds and nuts or sprouts on top.

Korean Kimchi

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Korean Kimchi
Pro biotic Spicy Korean style Kimchi. Rich on pro-biotics

Korean Kimchi
Gewicht
200 gr
Prijs 3.25
chinese kool*, rode chili peper*, diakon
rettich* zee zout, kimchee saus; tomaat,
vis saus, chili peper
- *van biologische teelt

Pickled Kale Stalks

Basic                                                   (Below) It’s a good idea to remove the bottom inch or so of the stalks, but                                                                  not necessary.

mason jar(s) [½ gallon total]

• 2 lbs kale, leaves removed (one large bunch, we grew russian red)
• 4 cups boiling water
• ½ cup  Apple Cider Vinegar
• ½-1 whole head garlic peeled and crushed
• 1 bunch dill, crudely chopped (preferably with flowers)
• 2 tablespoons whole peppercorns
• 2 tablespoons kosher salt

Real Farmacy Flare (Suggested):

• 1 small bunch green onion
• 1 habanero pepper, split lengthwise (we grew habaneros because we love spice! Wimps are advised to use one jalapeno. Super-wimps one cayenne or peperoncini, though you may want to up the vinegar in this case.)
• 1 small bell pepper, split lengthwise

Directions

Boil water in medium saucepan.

Add salt and stir until dissolved.

In mason jar, add crushed garlic and dill.

Pack in kale stalks, onion, and peppers.

Add apple cider vinegar.

Fill with boiling brine.

Top with peppercorns.

Tightly screw on lid and use a towel to give it a good shake.

Remove lid and sift out any air bubbles by stirring with a wooden spoon.

Reseal the jar and refrigerate.

Kale stalks will begin to become delicious within 3-5 hours. Enjoy!

Read more at http://www.realfarmacy.com/pickled-habanero-kale-stalks/#ZFduGCLJHWMUOYA3.99 

The Healing Power of Cannabis Oil On Lyme Disease and Lyme Co-infections

Amazing Results: The Healing Power of Cannabis Oil On Lyme Disease and Lyme Co-infections

September 12, 2013 by Shelley M. White

The beginning of my journey with Lyme disease is similar to most. My ending, however, is playing out quite differently than most. I found a tick behind my ear at the age of fourteen, and had various health problems for seven years before I was finally diagnosed with Lyme disease, Lupus, Mycoplasma, Bartonella, and Babesia. After two years my Lupus, Mycoplasma, Bartonella and Babesia are entirely eradicated. As far as my Lyme disease goes, I now have zero symptoms. My remaining ones are a result of withdrawals from the prescriptions I so naively started taking when I was initially diagnosed. How am I already returning to a healthy lifestyle only two years after forgetting to read, write, walk and talk? Well, a wealth of credit is owed to the Buhner protocol. I would not be where I am today without it. Still, I had one last giant “hump” in healing to get over after a year on the protocol. So I took a shot in the dark which, for me, turned out to be the path to light. I decided to make my own cannabis oil and began taking it every waking hour. I now owe my life to this fascinating herb and am hopeful some of you will find strength and encouragement through this information.

For a year and a half I had over ten seizures a day. I tried every treatment I could find, exhausting outlets in both conventional and holistic medicine. Desperately searching for answers, I stumbled across what turned out to be one of the most profound facts I have ever learned. Marijuana contains one of the most potent anticonvulsants in the world. Controversy over the subject was meaningless at that point, as the herb offered a possible solution to one of my most debilitating symptoms. As it turned out, smoking marijuana not only controlled my seizures, it completely cured them. With that in mind, I moved forward with my research. If it could do for seizures what no other plant or prescription could do, what could it do for Lyme? What I found was nothing short of fascinating, and essentially lifesaving.

Cannabis has over 700 healing components which, to the best of my knowledge, is more than any other plant known to mankind.  Since my Lyme disease had reacted to and benefited from literally every herb I had taken, I figured it would without a doubt react to cannabis as well. Indeed, it did. Smoking marijuana had sometimes made me feel sick in the past, and I realized this could possibly be because it caused a Herxheimer reaction from bacteria die off each time. Experimenting what thankfully turned out to be an anything but crazy theory, I smoked an exceptionally large amount one night and suffered from a massive Herxheimer reaction. The next day, when it subsided, I felt I had regained a little chunk of my brain back. Since smoking the herb out of a regular pipe also means inhaling a lot of toxins, I began using a vaporizer to get more cannaniboids. My rate of improvement significantly sped up when I did this. Naturally, this motivated me to take treatment one step further and find out what the results of taking cannabis oil would do for me.  After only a month of taking it I was able to return to work and school, and began to drive and have a social life again. Now, I am finally planning to move out and be independent for the first time in years. Basically, I am returning to a lifestyle that I was once unsure I would ever see again thanks to the immense healing power of cannabis oil.

Understandably, some will negate this article due to preconceived notions regarding cannabis, ones we were all conditioned to believe from a young age. Even I once held strong beliefs that cannabis was harmful to my health, but I could not be more thankful that I was proven otherwise. For me, the tangible proof stemming from first-hand experience will always trump the mere words of others.

Please browse through the CE website to find more links about the medicinal benefits of this herb. You can start here.

http://www.collective-evolution.com

Insights into Lyme Disease -chapter 1 -Steven Harris MD, By Connie Strasheim

CHAPTER 1
STEVEN HARRIS, MD
Redwood City, California

Biography

Steven J. Harris, M.D. has been in private practice since 2001. Dr. Harris is a medical doctor (MD), board certified in Family Practice. His private practice was operated as a sole proprietorship until 2006, after which time he formed a California medical corporation, Pacific Frontier Medical, Inc.

Since 2001, Dr. Harris has focused his practice on the diagnosis and treatment of Lyme disease and other tick-borne co-infections. He believes that chronic, persistent Lyme is an epidemic in the United States, but that there are many effective treatments available to those infected. His approach to Lyme disease incorporates strategies found in conventional, functional and complementary medicine.

Dr. Harris has taken a leadership role in CALDA (The California Lyme Disease Association), a research, patient advocate and education group which has been largely responsible for spearheading favorable legislation protecting patients’ rights, expanding Lyme disease awareness and fostering continued public health education.

Dr. Harris is also an active member of ILADS, (The International Lyme and Associated Diseases Society). This is a professional medical society of physicians and scientists which has become the de facto authority on effective treatment for chronic Lyme disease and is a rational counterbalance to the prevailing opinions of the IDSA (Infectious Disease Society of America), which refutes the existence of chronic Lyme disease. ILADS has focused its efforts on global physician education in order to increase the number of treating physicians available to those with Lyme.

There is currently a huge shortage of treating physicians for those with chronic Lyme disease, particularly on the West Coast. As a result, over the past three years, Dr. Harris has maintained three operating practices in various cities (Malibu, Redwood City and in Dr. Tod Thoring’s practice in Arroyo Grande) in order to provide maximum geographic coverage for patients in California, Oregon and Washington. In June 2007, two new practitioners were recruited in order to increase operating efficiency and the size of the practice. Dr. Harris projects that the practice will now have more resources, with the capacity to receive twice as many patients as before.


Healing Philosophy

My healing philosophy is similar to that of Drs. Richard Horowitz, Greg Bach, Joseph Burrascano, Therese Yang and Dietrich Klinghardt. I believe that infections are a significant part of the disease process, but that (in the words of Klinghardt) “impaired physiology, biotoxin load, and immune dysregulation” are what determine the individual flavor of the disease as well as how sick people will be. I look at Borrelia burgdorferi (Bb) as one of the significant central processing organisms that make other phenomena, such as biotoxins, inorganic toxins, opportunistic infections, and the like, matter. Many people have other problems along with Bb, such as yeast, mold, viruses and metals, and while these things in themselves can make people sick, when there is no Lyme disease involved, they may not have such a profound impact upon the body. When Lyme is involved, however, these corollary factors (which are different than Lyme co-infections) begin to really wreak havoc. It’s almost as if Lyme overwhelms the body to such an extent that these factors take on a life of their own. Immune surveillance and detoxification pathways in the liver, kidneys, lymphatics and skin just can’t keep up. There are other infections that can cause serious illness, such as Brucella, Mycoplasmas, and maybe even mycobacterium (which causes tuberculosis), as well as others. But biotoxins, Herpes viruses, Epstein-Barr virus and people’s lifestyle in general, might not matter as much if Lyme wasn’t causing the body to be under so much stress.

When Lyme Disease Isn’t the Primary Cause of Symptoms

There are cases of Lyme disease where Lyme isn’t primary in the overall symptom picture; for example, in those who have Lyme and autism, although I am never really sure. I find that about one in four autistic kids have Lyme disease, but I don’t think that Lyme is usually the primary reason for these kids’ autism. It’s a contributing factor, but may not be the main reason why they have autism. Also, while it may be important for people who have conditions such as ALS, Alzheimer’s and rheumatoid arthritis, in addition to Lyme disease, to treat their Lyme, this doesn’t mean that Lyme is their central problem or even causing the majority of their symptoms.

That said, the Borrelia organism can go dormant in the body at times, especially if one keeps pounding away relentlessly at the infection. Whenever I see this happen in my patients, I find that heavy metals, mold, a parasite or some other problem often surfaces and temporarily becomes the main (biggest) issue for them. Such issues must then also be treated.

Also, the body can only do so much simultaneous work, so as a physician, I have to pick and choose the problems that I want to treat in my patients at any particular given time. So if Borrelia is their core problem, but they present twenty different obstacles to treatment, then I might need to first address some of those obstacles, and then afterwards, focus on the Borrelia. For example, when patients have significant dental infections, or even structural abnormalities, such as bad TMJ, and if they are really sick, then I find that unless I deal with these other infections or structural problems, then it is very hard to treat their Lyme infections successfully with just antibiotics. So I may recommend, for example, that they have dental work done to deal with anaerobic infections in the mouth and which cause conditions such as osteonecrosis and osteomyelitis. Once these problems are treated, then it’s much easier to treat the Lyme infections. Some physicians have an order in which they treat patients’ problems, but I don’t necessarily believe that there is a cookbook order in which to do things, because each person is unique. I do believe, in any case, that it is important to address those obstacles that interfere with the proper treatment of Lyme infections.

Antibiotic Treatments for Infections

I am a student of many doctors who came before me treating Lyme. I’m trying to stand on the shoulders of giants, but I sometimes think that those giants are standing so high up and doing such amazing work, that it’s hard for me to top that.

I don’t have a standard protocol that I use for all of my patients. My treatments for Lyme infections generally involve homeopathic, herbal, naturopathic, and sometimes even energy medicine methods, along with a strong pharmaceutical approach. I find that most of my patients need to take some pharmaceutical antibiotics to really knock out the infections. Using alternative methodologies alone makes it much less likely, statistically, that they will get over the disease.

My antibiotic approach is similar to that of Dr. Horowitz’s, and includes the use of double intracellular antibiotics, along with cell-wall and cyst-busting drugs such as metronidazole and tinidazole (5-nitroimidazoles) or nitazoxanide. I might also use macrolide and tetracycline drugs, as well as third generation cephalosporins. I don’t necessarily administer these all at the same time and some I will rotate.

I also aggressively treat co-infections, and while I don’t believe that it is mandatory to treat co-infections first, if I have to give my patients IV antibiotics for Borrelia, then I will treat their co-infections before I treat their Borrelia. With the exception of Babesia, antibiotic regimens for co-infections must also be rotated and switched on a regular basis. For Babesia, treatments are most effective when patients start with one type of medication and stay on it for a long period of time, and then over time, “stack” other medications on top of that one. Medications for Babesia include intracellular and anti-parasitic drugs such as atovaquone (Mepron or Malarone), mefloquin (Lariam), or clindamycin, quinine, nitazoxanide (Alinia), and possibly metronidazole. Using an extracellular phase drug such as primaquin can be useful, too. The most effective way to treat the Babesia species, however, is still somewhat up in the air in the medical community.

When patients first come into my office, if I know that they have Borrelia but I’m not sure whether they have co-infections, then I will order co-infection tests. In the meantime, I will either wait to treat them or start them on a medication such as Zithromax (azithromycin). Zithromax is a good drug to start with, because if it turns out that patients have Bartonella, then Zithromax combines well with rifampin (which is used for treating Bartonella). Or if patients have Babesia, then Zithromax combines well with Mepron (which is used for treating Babesia). Or if their test results show Ehrlichia, then doxycycline, minocycline, tetracycline or rifampin can all be added to the Zithromax. If patients end up having only Borrelia, then I can combine Zithromax with a cephalosporin or tetracycline drug, or even a cyst buster if it seems that their bodies are hardy and can handle aggressive treatment right away.

I often prescribe parenteral (IV or IM) therapy to patients that have strong neurological symptoms, to those who have been very sick for more than a year, who have gastrointestinal problems, or who can’t tolerate oral medications. I tend to try oral antibiotics for at least three months, before going the intravenous route. This is because if I hit patients with IV medications too fast, then they may get worse as a result of a severe Jarisch-Herxheimer reaction. This occurs when too much of a toxic load is created in the body and the organs become stressed as a result. IV medications may also perpetuate too much yeast overgrowth. For these reasons, I feel that I might be playing with fire if I start some of my patients off with IV antibiotics.

It can also be difficult to treat patients if they have a lot of co-infections, such as Bartonella, Mycoplasma, Babesia and Ehrlichia, or if they are quite ill with predominant symptoms of one or two of these co-infections. Such patients tend to get very strong reactions to treatments, which means that I can’t hit their infections as directly as I would like, because they will get too sick. Doxycycline, in particular, creates this type of scenario, especially in women. So while it may be an effective medication, I don’t like to use it in patients that have multiple, or severe, co-infections. Many practitioners like to start with doxycycline because it’s cheap and is mostly metabolized in the colon (instead of the liver and kidneys), which means that it’s fairly easy on the organs. It also has great activity against Borrelia, Anaplasma and Ehrlichia, and is somewhat effective for treating Babesia, Bartonella and Mycoplasma, but I find that people just “tank” if they take doxycycline when they have a lot of co-infections.

Doing oxidative stress, organic acid, plasma amino acids, RBC elements, mold antibody and stool tests, as well as tests for heavy metals, yeast and other environmental pollutants can help me to get an idea of what problems my patients have besides Lyme infections. Such information also helps me to determine whether they will “crash” on a particular antibiotic regimen.

Blood tests such as the C3A, C4A, CD-57, C3D, C1-Q Immune Complex and even ANA, rheumatoid factor and other immune tests of the like, tell me the amount of inflammation that patients have, which also helps me to determine the likelihood of them getting worse on a regimen. Doing a methylation panel and genetic profile can also be useful for this purpose.

A promising new test from Genelix assesses what drugs patients can tolerate, based on their genotype. As well, it measures other functions, such as how well they metabolize, assimilate and methylate. Such information enables me to determine whether my patients have liver detoxification or other problems. If test results demonstrate that they don’t tolerate antibiotics very well, for example, then I might refrain from prescribing drugs and instead put them on a detoxification protocol until their ability to tolerate medications increases.

If I suspect that my patients are sensitive to medications, I will start by prescribing them a gentle medication for Borrelia, or treat them instead for co-infections, as I watch for signs of “crashing.” In the past, I used to hit my patients hard with antibiotics, and they would eventually get better, but they would also have a flare-up or Herxheimer reaction for up to twelve or fifteen months following treatment, and that isn’t acceptable to me. When patients already feel bad, they can’t feel “more bad” for a year and a half before starting to feel good, especially if there is no promise that they are ever going to feel good in the first place! If patients do poorly on antibiotic regimens, then it means that I need to deal with other problems that they have and which are blocking the antibiotics from being fully effective. Or I might send them to a naturopathic doctor who knows a lot about detoxification, such as Drs. Claire Riendeau, Nicola McFadzean (see Dr. McFadzean’s chapter later in this book for more information on her protocol), Susan Marra and Amy Derksen, where they can receive detoxification treatments before I start them again on antibiotics.

Typical Symptoms of Different Infections


Babesia

Since tests don’t always reveal whether patients are co-infected, I also rely on clinical diagnoses to determine which infections, besides Borrelia, are present and causing problems for my patients. For example, if my female patients aren’t menopausal, (I can check hormones to verify this) and have night sweats, flushing, severe pressure-like headaches, violent nightmares or vivid dreams, significant shortness of breath in the absence of another cause, frequent sighing or dry coughing in the absence of cardiac issues, then they may have Babesia. To ascertain the diagnosis, I might give them a clinical provocation test, especially if their lab test results are negative. For the clinical provocation, I might ask them to take herbs such as cryptolepsis or artemisia, as I observe their reaction to these. Dr. Tod Thoring in Arroyo Grande makes a cryptolepsis compound which consists of cryptolepsis, smilax, and boneset, as well as a cryptolepsis, artemisia and teasel cream, which are quite effective for this purpose. I may also use the herbal formulas Enula and Mora (NutraMedix brand), or some of the rizol oils (BioPure). Positive patient response to any of these can indicate that a parasitic infection is present. I’m not always 100% certain that the parasite is Babesia, but the tests help me to better estimate what it is. I will also sometimes do a provocation test in those already known to be infected with Lyme, using hydroxychloroquine and Zithromax, or Flagyl with Zithromax, because Babesia responds to these medications, too.

Bartonella

Typical symptoms in those with Bartonella and Borrelia (unlike the Bartonella that results from Cat Scratch disease) include ice pick-like headaches, major photophobia, anxiety or psychiatric issues, and even bi-polar symptoms. Neuropathy, reflex sympathetic dystrophy (RSD) or autism may also manifest, as well as significant cardiac or gut problems. The non-blanching “streaks” that some people find on their skin may also be a telling symptom. Some argue that plantar fascial pain is found in both Babesia and Bartonella, but I think that it is more related to Bartonella. In any case, whenever extreme anxiety is patients’ overriding symptom and is found in conjunction with neuropathic symptoms, such as burning pain, then I suspect that a Bartonella-like organism is causing these symptoms.

Ehrlichia and Anaplasma

If patients have profound fatigue and severe muscle pain, especially in conjunction with high liver enzymes, low white blood cell counts and fevers, they may have Ehrlichia.

Mycoplasma

Because Mycoplasma is an intracellular organism, it’s difficult to test for, but many of my patients have it. Persistent arthritis, especially in one joint that is really swollen, or a rheumatoid arthritis presentation indicate the possible presence of Mycoplasma. In children, major psychiatric problems may also indicate that the infection is present.

Lyme (Borrelia)

People with Borrelia can have all of the aforementioned symptoms, as well as many others, because Borrelia runs the gamut of symptoms. For that reason, those with this infection may feel bad in a number of different ways. Symptoms usually migrate with this infection, however, and/or tend to flare for four to seven days per month.

Also, I think that co-infections, such as Babesia, Bartonella, Ehrlichia are generally not important factors in patients’ overall symptom picture unless Bb (Borrelia burgdorferi) is present to give them a foothold.

I do find that some of my patients have only Bb, without any other co-infections, especially those that have been sick for more than twenty years. Such patients have been living at a lower level of functionality, and may have been suffering from symptoms of generalized pain, fatigue and cognitive issues for a tremendous amount of time. Yet, because their problems tend to be mostly related to pure Lyme disease (Borrelia), they are often easier to treat than the co-infected patients.

Other Symptomatic Trends

Another trend that I have observed is that almost all of my patients that have Lyme disease (Bb) along with rheumatoid arthritis, MS (Multiple Sclerosis), Alzheimer’s or Parkinson’s, are also likely to have Babesia. If I had to guess, I would say that at least a third of all Lyme disease sufferers have co-infections, and possibly more.

Using Herbal Remedies to Treat Borrelia and Other Infections

I find that I have the most success treating my patients with herbs when I use them in conjunction with pharmaceutical antibiotics. If I were to recommend only herbs for the treatment of Lyme disease, there would be frequent treatment failures. If I prescribed only antibiotics, then I would have to use more antibiotics than if I had combined them with herbs. I think that herbs really act to heighten the effects of antibiotics, and therefore, I generally formulate a protocol using two to eight anti-microbial herbs, in addition to one to four antibiotics.

Dr. Thoring, whom I mentioned earlier, has come up with a promising herbal tincture, called BLT from Clinical Response Formulas, which contains red root, teasel, boneset, black walnut, lomatium, smilax, and stillengia. I find this product to work really well for the treatment of Borrelia and Bartonella, and it may also have some activity against Babesia.

Other herbs or herbal formulas that I use in my practice include Mora, Enula, Cumanda and Banderol from NutraMedix; cryptolepsis from Woodland Essence; the rizol oils Epsilon, My, Kappa, Gamma and Zeta from BioPure; and Dr. Zhang’s herbal products Circulation P, houttuynia, allicin, artemisia and coptis. I also use a bit of noni on occasion, as well as Borrelogen and Microbogen from David Jernigan, and some of the herbal cocktails from Monastery of Herbs. I may also recommend homeopathic remedies to my patients, such as Bioresource’s homeopathic molds, Notatum and Quentans and the homeopathic bacteria, Fermis and Subtilis. Stephen Buhner’s recommended herbs, such as andrographis, resveratrol, stephania root, and cat’s claw, are likewise important, as are chanca piedra and whole garlic. Garlic is beneficial for those who don’t have trouble metabolizing sulfur-containing foods. Finally, I use olive leaf extract and monolaurin or lauricidin for viruses, oregano oil for yeast, and products from Raintree, such as Myco, Amazon C-F and A-F for various other purposes. All of the aforementioned are just the antimicrobial herbs that I use in my practice; there are others that I recommend for supporting the body in the healing process.

Detoxification


Treatments

Before I can detoxify my patients, I have to get their adrenal glands working. I recommend a broad range of adrenal supplements for this purpose, including adaptogens such as rhodiola, Cordyceps mushroom, ashwaganda and Researched Nutritional’s Multiplex and NT Factor Energy. Vitamins B-5 and C, magnesium, molybdenum, and adrenal glandular formulas are likewise important. I also sometimes recommend Bezwecken’s Isocort, or occasionally, hydrocortisone in low doses.

To address the drainage aspect of detoxification—that is, that which involves opening up the body’s detoxification pathways so that toxins can more freely leave the body, I recommend that my patients take Burbur and Parsley from NutraMedix. These are definite staples in my practice. I also use L-Drain and K-Drain from Transformation Products, Bioresource’s Mundipur, apo-Hepat, Renelix, Itires and Toxex.

For liver support, I recommend Liver Extende, which is a sarsaparilla and artichoke complex; Hepol from Projoba and Medcaps DPO from Xymogen, as well as alpha-lipoic acid, glutathione, and other glutathione precursors. Red and green clay, especially Argiletz clay and plain USP grade bentonite, are also remarkably useful. David Jernigan’s CNS Neuro-Antitox II, a product called Detox Factors from Natural Partners, and sometimes concentrated fruit juices such as acai, mangosteen extract and goji berry are beneficial, too. In addition, Pinella from NutraMedix, red root, burdock root, beet juice, dandelion leaf and root, all aid in the functioning of various detoxification pathways. Finally, I may recommend that my patients use detox footpads and ionic footbaths, castor oil packs, and digestive enzymes such as Wobenzym, Vitalzym, Inflammaquel (Researched Nutritionals), as well as others.

Doing bodywork aids in detoxification. I have found therapies such as cranial sacral, lymphatic and abdominal massage to be beneficial for my patients, as well as upper cervical therapy, which is a technique that increases blood flow to the brain. Dr. William Amalu performs the latter and is quite good at using it in his practice. NET (Neuro-Emotional Technique) is a physiological strategy that can also be really helpful for getting the body to release toxins. Also, I recommend stretching exercises and skin brushing techniques to all of my patients.

If heavy metals are a problem, I recommend chelation therapy using agents such as chlorella, cilantro, zeolites, DMSA, DMPS and Calcium Disodium EDTA. OSR also shows a lot of promise, especially when mixed with phospholipids. Chelex from Xymogen, Metalloclear and Ultraclear from Metagenics are also good, gentle chelation products.

Finally, I give chlorella to almost all of my patients, because I think that its uses and benefits are numerous. I may also use other toxin binders, everything from Cholestyramine to activated charcoal, Nanotech Chitosan from Allergy Research Group, glucomannan and apple or citrus pectin. Other practitioners may recommend additional or different binders.

Addressing Detoxification Problems

Compromised detoxification mechanisms in those with Lyme disease are sometimes due to methylation pathway defects. To correct this type of problem, I may recommend that my patients do the Amy Yasko protocol, and in the meantime, try to get the ammonia out of their bodies, using things like yucca root, BH4, and sometimes RNA Ammonia Support Formula. Rich Van Konynenburg has developed a simplified version of the Yasko protocol that seems to have some clinical utility. I also find that Dr. Richard’s plant stem cells (Gemmo therapy) can be remarkable for fixing detoxification problems, but I tend to refer my patients out for this type of treatment.

One of the problems with patients who aren’t able to detoxify well is that they are nutritionally depleted. Intracellularly, they aren’t able to absorb their nutrients, so one of the things that I do to correct this problem is to order a urine and plasma amino acid profile and red blood cell elements test. I then recommend that they supplement their diets with whatever minerals and amino acids that they happen to be deficient in, according to their test results. Administering IV amino acids and minerals is sometimes necessary. I may also recommend that they take Peltier Electrolytes from Crayhon Research, which is kind of like glorified Gatorade, but which works well to replenish some of the cell’s missing elements. I may also send patients out for IV nutrition, to receive different Myer’s cocktails and such, to get them more nutritionally balanced.

Immune System Supplements

Various immune supplements can be beneficial for strengthening the immune system, which is another important component to healing from the Lyme disease complex. I sometimes administer intramuscular transfer factor to my patients, or I may give them Researched Nutritionals’ Transfer Factor LymPlus, or Multi-Immune Transfer Factor, the latter of which can be really useful for calming down an overactive immune system. I also use low-dose Naltrexone in my practice.

Healing the Gut

It’s important for me to support my patients’ physiology, to the extent that I am able, by adding the right kind of nutrition to their diets and which is easy for them to tolerate. Many of my patients are gluten and casein sensitive, and have lots of food allergies, so eliminating these allergens from their diets is important.

In order to heal their guts and decrease Leaky Gut syndrome, I may give them substances such as Xymogen’s IgG-2000 DF, which are bovine source immunoglobulins that calm the gut down. I may use this in conjunction with a product called Intestimax, which is a combination of marshmallow, butyrate, and glutamine that supports the integrity of the intestinal lining. Or I might give them rectal butyrate, which also calms the gut, or Ketotifen, which reduces inflammation and promotes healing of the intestine. Sygest, Juvecal and Roqueforti, as well as other spagyric homeopathics from Bioresource are likewise useful for this purpose.

After this, I will start treating their yeast problems. Yeast overgrowth must be controlled in order to fully heal the gut, and I use a broad range of remedies for getting rid of yeast; everything from cellulase to caprylic acid, pau d’ arco, and oregano oil, to the pharmaceutical medications.

Treating Hormonal Dysfunction

Balancing hormones is a remarkably important component to healing from Lyme disease. In Lyme, the HPA (hypothalamic-pituitary-adrenal axis) is severely impaired and it’s one of the more difficult areas of the body to heal. Plant stem cells seem to help the HPA-axis to some degree, but I think that hormones are one of the areas in medicine that still needs to be researched, if practitioners really want to optimize their patients’ whole endocrine system.
Bioidentical hormones, when used properly, can help to restore HPA function in some with Lyme disease. Borrelia likes to destroy the body’s connective tissue, and endocrine glands have a lot of connective tissue, so it is important to get antibiotics and other antimicrobials into those glands. Optimizing endocrine function is also important, but if practitioners improperly prescribe hormones, then their patients can get “out of whack.” For that reason, I often refer my patients to an endocrinologist or skilled naturopathic physician who can more properly deal with this aspect of their healing.

Lifestyle Recommendations for Healing


I think that “island life” (tranquility and few toxins) is probably best for the chronically ill, although this lifestyle probably isn’t realistic for most. In any case, it’s important that those with Lyme get away from sources of electromagnetic stress wherever possible. Even though there may be more healing resources in cities, those who are a little more off “the grid,” will fare better with their treatments. Living a slower paced life is also beneficial for healing, as is consuming a diet rich in organic food. It’s okay for those with Lyme to have animal protein but it needs to be really clean, healthy meat. Basically, those who are leading really clean lives, in the absence of as many environmental toxins as possible, have greater success in their healing journey.

Diet

It is important that people with Lyme maintain a non-gluten, sugar and yeast-free diet, while keeping their body’s pH up by eating foods that promote less acidic blood. For those with methylation problems, keeping sulfur-containing foods like broccoli and garlic to a minimum, as well as onions and animal protein, is a good idea. Blood type diets might be beneficial for some. I have observed that blood types A and AB have the most difficult time tolerating treatments, so such people might benefit from following a blood type diet. Eliminating dairy from the diet is especially important for those with arthritis and certain neurological conditions. Finally, those with Lyme should minimize any other food allergies that show up on their IgG and IgA blood test results.

Exercise

I think that Dr. Burrascano’s approach to exercise is right on. He advocates weight training with lightweights, as well as stretching-type exercises, but cautions against doing too much aerobic exercise. I agree that people with Lyme need to stretch and do gentle exercises, and that too much aerobic exercise, too fast, will deplete the adrenal glands, decrease T-cells, and open up the blood-brain barrier so that more Borrelia can get into the brain. Anaerobic-type exercises are more important, especially when people are just starting on a new treatment protocol.

Treatments for Symptomatic Relief


Insomnia

My approach to treating insomnia is to start by giving my patients one sleep remedy at a time, and then adding others as necessary, by “stacking” them up, one on top of the other, until patients are able to sleep well. I start by recommending natural remedies such as glycine, L-theanine and GABA. Dr. Zhang has a fantastic product called Herb Som, which contains schizandra. To overcome insomnia, it is important that those with Lyme find supplements that promote their GABA pathways.

If the natural remedies don’t work for my patients, then I will prescribe them pharmaceutical drugs. I will basically do everything under the sun to get them to sleep, so if the drugs don’t work, then as a last resort, I will refer them out to a psychiatrist for a prescription of Xyrem, which seems to help when all else fails.

Pain

To treat my patients’ nerve pain, I use everything from transdermal remedies to non-steroidal anti-inflammatory drugs. Ketoprofen cream, Kaprex from Metagenics, Kapp Arrest from Biotics, Saloxicin and Doloryx from Xymogen and UltraInflamX from Metagenics are all useful. Key and Wellness Pharmacies have transdermal neuropathy creams and gels, which are made and combined using different preparations. I also use medications such as Gabapentin and Lyrica, and occasionally, Valproic acid, Carbamazepine and Dilantin. I try to stay away from prescribing narcotic drugs, because over the long run, they increase inflammatory cytokines in the body.

If my patients’ pain cannot be relieved by any of the aforementioned strategies, then I will refer them to a pain management specialist. Kids often need more pain management than adults.

Finally, curcumin from turmeric can be extremely helpful for lowering inflammation and reducing pain, as can bee venom and urine therapy (although I don’t use the latter in my practice). Energetic work, stretching and detoxification strategies can also relieve pain, depending upon its source. Getting to the source of the pain is important for determining what the best remedy will be. If my patients’ pain is in the morning, sometimes it’s due to toxins in their bodies. If it gets worse throughout the day, then it may be that their Lyme infections are causing the pain.

Depression and Anxiety

As is true for pain, when prescribing remedies for anxiety and depression, it’s important to know the cause of these symptoms. Sometimes, I find it necessary to prescribe anti-depressants, and I refer my patients to Lyme-literate psychiatrists that I know. I’m not a big fan of drugs, but sometimes people need them, at least for a short while. To help determine the underlying cause of my patients’ anxiety or depression, I sometimes check their neurotransmitter levels using labs such as NeuroScience or Sanesco, and then recommend amino acids and other supplements to make up for any deficiencies. Just supplementing with magnesium or selenium can often be remarkably helpful, as can detoxifying the body of heavy metals, supporting its nutrition, and getting rid of ammonia and other neurotoxins.

Fatigue

Fatigue is one of the more difficult symptoms to treat, but it’s one of the most bothersome. Like other symptoms, it is important to discover its cause, which is no easy task. Provigil, NT Factor Energy, glutathione and methyl or hydroxy B-12 can be beneficial for reducing this symptom. If patients don’t have a lot of yeast, using D-ribose or even some of the Mannatech glyconutrient products may also be helpful.

Brain Fog

Thinning the blood with low dose coumadin, heparin, boluoke (lumbrokinase), serrapeptase, ginkgo or Pentoxyphylline can sometimes reduce brain fog and other cognitive symptoms. Puerarin, yucca root, NutraMedix Pinella, chlorella, and Bacopa are also good for this purpose.

Healing Emotional Trauma

Emotional trauma is a huge component of illness and can be a block to patients’ healing. I think that in a sense, cells hold on to memories. Doing therapies that access the subconscious mind, such as EMDR and hypnosis, can be helpful for releasing traumatic memories on a cellular level, as can Family Constellation work and psychotherapy. Really looking deep within the self to discover the spiritual causes of illness, as well as faithfully exploring and healing past memories is important. People with Lyme often need to “go deep” in order to heal their emotional trauma.

Who Are Those That Heal From Lyme Disease? Who Are Those That Don’t?

The people who tend to heal from Lyme disease are those who don’t know how sick they are. They are those who are out there doing things, living life and functioning amidst all of the adversity that Lyme disease brings into their lives. They are the ones who really push themselves to get better, which means that ironically, the most adrenally-depleted people might be those who are having the most success with their recovery. Such people go out and get sunshine every day. They stretch and do all the tasks that are required of them to heal, such as daily skin brushing, colonics and keeping a good diet. They are able to focus on their symptoms but not make the symptoms the focus of their lives.

Also, people who can roll with the punches, take things in stride, adapt to adversity, self-manage symptoms as they come up and make decisions on their own, are those who heal. They are of the sort who can make the decision to stop a supplement if they no longer need it, and to research new supplements but not base their life decisions upon what others tell them about those supplements. They hunker down and stay in the healing process for the long haul, and can balance immediate gratification with deferred gratification. They are open to trying new things, don’t focus on every single symptom that manifests in their bodies and don’t have to know the reason “why” for everything; for example, why certain remedies work and why certain things are happening to their bodies.

I think that it is really important for those with Lyme to have a positive attitude, too. This can be taken to a fault; some Lyme sufferers might be “happy herxing” for two years, and I think that’s ridiculous, but it’s good if they are able to adapt to adversity and to view failures as a bump in the road, instead of as a curse.

For example, the person who is able to get over a gallbladder attack, a negative reaction to a medication or an IV line complication and say, “Okay, that didn’t work, let’s try something else,” instead of becoming despondent and giving up, has an easier time healing. Those who don’t get “stuck” in persistent thoughts of disease or who don’t get post-traumatic stress from their illness or treatments also heal faster than those who do.

Toxic partners are another block to healing. It’s extremely difficult for family members to understand what the sick person is going through, and it’s a huge detriment to that person’s healing.

Likewise, when people harbor anger, blame others, get stuck and hung up on details, or have other forms of emotional distress, their healing becomes compromised.

Other impediments to healing include mold, yeast and other toxic chemicals in the environment.

Finally, people who aren’t on the Internet all of the time asking questions about Lyme disease and getting totally despondent when hearing stories about patients who kill their pastors, have an easier time healing!

The Role of Spirituality in Healing

I think that there’s a spiritual component to healing that really matters. People need to feel connected to something larger than themselves, whether that something is found within a formal religion or elsewhere. If there’s a way that those with Lyme can interface with the divine, such as through prayer or meditation, then this can make a positive difference for them in their healing journey.

How Finances Affect Healing

Lyme disease is sadly, a disease for the rich. That financial resources are directly related to one’s pace of improvement causes me more consternation in my treatment of Lyme patients than anything else. I can do ten thousand things under the sun for them, but if financial limitations are the main thrust of their stress, then it’s really hard to get them better. If they can’t pay for probiotics, for example, or some of the main detoxification supplements, then their healing becomes complicated. It’s difficult to admit, but it’s almost as if the wealthier patients are paving the way for the right protocols to emerge and get out there. Until a streamlined path to wellness becomes clearer, however, patients without financial resources will have a more difficult time getting better.

That said, I have some patients who, through the help of their friends, church, synagogue or family, have been able to make things happen for themselves, even when they thought that they couldn’t afford a particular treatment. They have done this by going beyond in their thinking. They tell themselves things like, “I am going to do this IV treatment and I’m not going to get stuck on the details about how it’s going to happen. I’m also not going to go bankrupt, or if I do, then I will refinance my house.” They find a way. So I believe that those who can completely prioritize this disease and the healing process, get better. Those who say things like, “I have $2,000 and if I don’t get better after I spend all of that, then I am going to kill myself,” surely won’t get better after spending that $2,000.

Mistakes in Treating Lyme and Less-Than-Beneficial Treatments

When health care practitioners only focus on treating co-infections, then that is a problem, as is excessively focusing on any one single aspect of healing. Having pre-defined cocktails for patients is also detrimental to their well being.

When it comes to specific treatments, I am concerned about non-frequency specific Rife machines, IV hydrogen peroxide, the salt/C protocol and colloidal silver IV’s. I think that while they have their place in healing Lyme disease, and I have seen some people improve by doing them, there may be problems with such treatments.

I am also cautious about the “latest, greatest treatments” that come down the pipeline. Over the past nine years, I have seen so many treatments that patients grab onto just because they are new, but few have long-term benefits. While it may be true that the trail-blazing practitioners are occasionally developing groundbreaking protocols, it is not prudent for those with Lyme to try every one as soon as it arrives. I believe that it would be more responsible for them to watch and wait for a year or so to see what complications arise and what benefits others receive as a result of such treatments. I saw problems arise with MMS and intracellular heat therapy, for instance, and do not want to be an agent of harm in a mad dash to get people well

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Brain Lipids and Mental Health - A Look at Recent Research

Brain Lipids and Mental Health - A Look at Recent Research

from http://integral-options.blogspot.nl/2013/09/brain-lipids-and-mental-health-look-at.html

 

The old adage is that we are what we eat. This is nowhere more true than it is in our brains. In essence, the human brain is a 3-pound lump of fat (well, okay, 2 lbs of fat, since only 2/3 of the brain is made of fats).

Here is a little background on how the brain uses lipids (another name for fats) in building its cells (neurons) and cell membranes:

Membranes – the Working Surface of Your Brain is Made from Fatty Acids 

The membranes of neurons – the specialized brain cells that communicate with each other – are composed of a thin double-layer of fatty acid molecules. Fatty acids are what dietary fats are composed of. When you digest the fat in your food, it is broken down into fatty acid molecules of various lengths. Your brain then uses these for raw materials to assemble the special types of fat it incorporates into its cell membranes.

Passing through a cell's membrane into its cell's interior are oxygen, glucose (blood sugar), and the micronutrients the cell needs to function. Metabolic waste products must exit, so the cell won't be impaired by its own pollution.

Protective Myelin is 70% Fat 

Myelin, the protective sheath that covers communicating neurons, is composed of 30% protein and 70% fat. One of the most common fatty acids in myelin is oleic acid, which is also the most abundant fatty acid in human milk and in our diet.

Monosaturated oleic acid is the main component of olive oil as well as the oils from almonds, pecans, macadamias, peanuts, and avocados.


Myelin fiber 

©1998 Dr. Norberto Cysne Coimbra M.Sc., Ph.D., Laboratory of Neuroanatomy and 
Neuropsychobiology, Faculty of Medicine of Ribeirão Preto of the University of são Paulo; Neuroscience Art Galleries

Two of the most important fats are Alpha-linolenic acid (ALA), an omega-3 fat, and Linoleic acid (LA), an omega-6 fat.

ALA is the foundation of the "omega-3" family of fatty acids. Food sources of omega-3 ALA include flax seeds, chia seeds, walnuts, sea vegetables, green leafy vegetables, and cold water fish like salmon, sardines, mackerel, and trout.

The second essential fatty acid you need is Linoleic acid (LA). LA is the foundation of the "omega-6" family of fatty acids. Food sources of omega-6 LA include expeller cold-pressed sunflower, safflower, corn, and sesame oils.

Considerable research suggests that an imbalance of omega-3 and omega-6 fatty acids may lead to a variety of mental disorders, including hyperactivity (ADHD), depression, brain allergies, and autism.  A balanced ratio of omega-3 and omega-6 fats is necessary for a healthy brain, which is structurally composed of a 1:1 ratio of omega-6 to omega-3. In the Western diet, however, we are likely to have at least twenty times more omega-6 fats (from factory-farmed meat and dairy) than omega-3 fats–an unhealthy ratio of 20:1. Some estimates suggest the ratio is as bad as 30:1.

If we consume more omega-3-rich fish (and fish oil) and flax seed oil, eat less sugar, and completely avoid trans fatty acids (found in partially-hydrogenated oils, margarine, and shortening, as well as most processed foods), we can begin to correct the imbalance and have a healthier brain.

With all of that as a background, this new study from Frontiers in Cellular Neuroscience examines the current stage of the research regarding the role of lipids in the brain, concluding "there exists realistic evidence to consider that nutritional therapies based on fatty acids can be of benefit to several currently incurable nervous system diseases."

This article has a 4.5 Impact Factor, which is considerable for an Open Access publication - so this article is getting some attention.

Full Citation: 
Hussain G, Schmitt F, Loeffler J-P and Gonzalez de Aguilar J-L. (2013, Sep 9). Fatting the brain: A brief of recent research. Frontiers in Cellular Neuroscience; 7:144. doi: 10.3389/fncel.2013.00144

Fatting the brain: A brief of recent research

Ghulam Hussain [1,2], Florent Schmitt [1,2], Jean-Philippe Loeffler [1,2] and Jose-Luis Gonzalez de Aguilar [1,2] 

1. UMR_S 1118, Université de Strasbourg, Strasbourg, France
2. Mécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Université de Strasbourg, Strasbourg, France

Fatty acids are of paramount importance to all cells, since they provide energy, function as signaling molecules, and sustain structural integrity of cellular membranes. In the nervous system, where fatty acids are found in huge amounts, they participate in its development and maintenance throughout life. Growing evidence strongly indicates that fatty acids in their own right are also implicated in pathological conditions, including neurodegenerative diseases, mental disorders, stroke, and trauma. In this review, we focus on recent studies that demonstrate the relationships between fatty acids and function and dysfunction of the nervous system. Fatty acids stimulate gene expression and neuronal activity, boost synaptogenesis and neurogenesis, and prevent neuroinflammation and apoptosis. By doing so, they promote brain development, ameliorate cognitive functions, serve as anti-depressants and anti-convulsants, bestow protection against traumatic insults, and enhance repairing processes. On the other hand, unbalance between different fatty acid families or excess of some of them generate deleterious side effects, which limit the translatability of successful results in experimental settings into effective therapeutic strategies for humans. Despite these constraints, there exists realistic evidence to consider that nutritional therapies based on fatty acids can be of benefit to several currently incurable nervous system diseases. 

Introduction

Fatty acids represent a class of lipids that are crucial components of all mammalian cells. They display a variety of biological functions to maintain vital cellular processes at various levels. Thus, fatty acids provide energy, function as signaling molecules, and sustain structural integrity of cellular membranes. They are of particular importance for the nervous system for two major reasons. First, the nervous system possesses a very high concentration of fatty acids, second only to adipose tissue (Etschmaier et al., 2011). Second, these fatty acids participate actively both in the development of the nervous system during embryonic and early postnatal life, and in its maintenance throughout adulthood and natural aging (Uauy and Dangour, 2006; Rombaldi Bernardi et al., 2012). Along with these actions, currently incurable pathological conditions of the nervous system, including neurodegenerative diseases, mental disorders, stroke, and trauma, involve deregulated contents of fatty acids. It is therefore believed that these changes contribute in their own right by as yet incompletely understood mechanisms to those pathological processes. In consequence, the roles of fatty acids in health and disease of the nervous system have been intensively investigated in the last few decades. In this piece of work, we focus mainly on studies published during the last five years to show the diversity in the fatty acids implicated in function and dysfunction of the nervous system. The detailed mechanisms of action of fatty acids at the molecular level are not treated in this article, since they are the subject of other recently published reviews (Georgiadi and Kersten, 2012;Yamashima, 2012). 

Some Aspects of the Biochemistry of Fatty Acids

According to the IUPAC definition, fatty acids are “aliphatic monocarboxylic acids derived from or contained in esterified form in an animal or vegetable fat, oil or wax” (IUPAC, 1997). Naturally occurring fatty acids mostly consist of an unbranched 4–28 carbon chain that is usually composed of an even number of carbon atoms. On the basis of the carbon chain length, fatty acids are classified into short- (less than six carbon atoms), medium- (6–12 carbon atoms), long- (14–22 carbon atoms), and very long chain fatty acids (more than 22 carbon atoms). Fatty acids in which the aliphatic chain is fully composed of single bonds between carbon atoms are named as saturated fatty acids (SFAs), whereas fatty acids with one or more than one carbon–carbon double bond are called unsaturated fatty acids. Based on the number of double bonds, unsaturated fatty acids are further divided into mono-unsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs; Table 1). Long chain SFAs have relatively high melting points that make them to appear solid at room temperature. Therefore, the body possesses a mechanism to introduce double bonds in the carbon chain, which lowers the melting point and permits functioning in a physiological environment. There are four fatty acid desaturases documented in humans that selectively catalyze the introduction of a double bond in different positions of the carbon chain. Δ-9 desaturase, also known as stearoyl-CoA desaturase (SCD), is charged with synthesizing MUFAs, mainly palmitoleic acid (16:1) and oleic acid (18:1), by introducing a double bond between carbon atoms nine and 10 from the carboxylic acid end (Figure 1; Enoch et al., 1976). Δ-4, Δ-5, and Δ-6 desaturases introduce a double bond at carbon positions 4, 5, and 6, respectively, and work cooperatively with elongases, which are responsible for the extension of the aliphatic chain. The combined actions of desaturases and elongases are implicated in the synthesis of PUFAs (Nakamura and Nara, 2004). 

FIGURE 1  

FIGURE 1. Biosynthesis of fatty acids. Medium- to long chain SFAs are successively transformed by the action of elongases (E) into palmitic acid (16:0), which is then either elongated to stearic acid (18:0), and other long chain SFAs, or desaturated, together with stearic acid (18:0), by δ9 desaturase to produce de novo MUFAs of the n-7 and n-9 series, such as palmitoleic acid (16:1) and oleic acid (18:1). In the case of PUFAs, δ6 and δ5 desaturases work cooperatively with elongases to introduce double bonds and extend the aliphatic chain in a successive manner, from ALA (18:3 n-3) to EPA (20:5 n-3) in the n-3 series, and from LA (18:2 n-6) to AA (20:4 n-6) in the n-6 series. Afterward, these end products are further elongated, desaturated, and submitted to peroxisomal β-oxidation (all three steps indicated by OX) to yield DHA (22:6 n-3) and docosapentaenoic acid (22:5 n-6), respectively. Finally, AA (20:4 n-6) is the precursor of potent pro-inflammatory eicosanoids. EPA (20:5 n-3) produces less potent (dashed arrow) eicosanoids and, together with DHA (22:6 n-3), gives rise to docosanoids with anti-inflammatory properties (i.e., resolvins and protectins). GLA, γ-linolenic acid; DHGLA, dihomo-γ-linolenic acid.

TABLE 1  

TABLE 1. Most typical fatty acids.

According to the position of the first double bond from the methyl end of the fatty acid chain, the most important PUFAs for humans can be divided into two families: n-6 and n-3 PUFAs. Linoleic acid (LA, 18:2 n-6) is the parent fatty acid of n-6 PUFAs, which produces principally arachidonic acid (AA, 20:4 n-6), whereas α-linolenic acid (ALA, 18:3 n-3) is the parent fatty acid of n-3 PUFAs, which gives rise mainly to eicosapentaenoic acid (EPA, 20:5 n-3) and subsequently docosahexaenoic acid (DHA, 22:6 n-3; Figure 1). Both LA (18:2 n-6) and ALA (18:3 n-3) cannot be synthesized indigenously by the human body, so that they must be supplied with food, and such fatty acids are termed as essential fatty acids (Ruzickova et al., 2004; Lands, 2012). In spite of the fact that the body is able to metabolize these essential fatty acids, the efficiency of conversion is low. Hence, the availability not only of essential precursors but also of some of their metabolites, such as EPA (20:5 n-3) and DHA (22:6 n-3), greatly depends on dietary support (Brenna et al., 2009). Alternatively, PUFAs can also be made available by enzymatic processing of membrane phospholipids by phospholipases (Lee et al., 2011). Whatever pathway is involved, several PUFAs can be metabolized by cyclo-oxygenases, lipo-oxygenases, or cytochrome P450 mono-oxygenases to produce other compounds with important biological functions. AA (20:4 n-6) and, to a lesser extent, EPA (20:5 n-3) are transformed into potent pro-inflammatory eicosanoids. Additionally, EPA (20:5 n-3) and DHA (22:6 n-3) generate opposing anti-inflammatory docosanoids, including resolvins and protectins such as neuroprotectin-D1 (NPD1; Bazan, 2009; Figure 1). 

Evidence of the Importance of Fatty Acids for Health and Disease of the Nervous System

Fatty Acids and Brain Development 

Mother’s own resources, via placenta and milk, provide most of the n-3 PUFAs necessary for brain development during fetal and early postnatal life. Due to this high demand of the developing nervous system in the progeny, maternal brain levels of DHA (22:6 n-3) exhaust during pregnancy and lactation period (Chen and Su, 2012). Thus, enhanced provision or adequate supply of n-3 PUFAs at these stages can yield positive effects on offspring brain development. For instance, increased expression of neuron specific enolase, glial fibrillary acidic protein, and myelin basic protein was observed in pups from mice fed on n-3 PUFA enriched diet, administered from two months prior to mouse conception to end of lactation period (Tian et al., 2011). Similarly, postnatal supplementation of ALA (18:3 n-3), the parent precursor of n-3 PUFAs, enhanced cell proliferation and early neuronal differentiation, while its deprivation resulted in increased proportion of apoptosis in the dentate gyrus of unweaned pups. This ameliorating effect was offset by maternal ALA (18:3 n-3) deficiency during gestation period, suggesting that ALA (18:3 n-3) is not only required at postnatal stages but is also essential for fetal brain development (Niculescu et al., 2011). Importantly, such diets given at perinatal stages may have long lasting consequences in the adulthood. Thus, the abundance of n-3 PUFAs in the diet of pregnant females revealed essential for the development of the glutamatergic system and normal behavior performance in the adult offspring (Moreira et al., 2010a). Also, motor coordination was ameliorated in adulthood when rats were fed on DHA (22:6 n-3) and EPA (20:5 n-3) supplementation starting from gestation stage to postnatal age of 90 days (Coluccia et al., 2009). Finally, n-3 PUFA enriched diets also improved reference and working memory in offspring rats when supplied to mother at gestation stage (Chung et al., 2008). 

Frequently, the impact of dietary fatty acids depends on a balance between different types. In a study to assess the effects of quality and quantity of several high fat diets, mice were nourished with various concentrations and types of fats mingled with normal chow. It was noticed that these diets not only modified the lipid profile in brain but also altered spatial memory and learning ability of the pups in a different manner (Yu et al., 2010). In another study, when mice were fed on diets supplemented with either SFAs or MUFAs, MUFAs promoted insulin sensitivity and cortical activity while SFAs did not (Sartorius et al., 2012). Lastly, it is noteworthy that the intake of sufficient quantity of MUFAs prevented the age related deletion of mitochondrial DNA in the brain of aged animals (Ochoa et al., 2011). 

Fatty Acids and Neurodegenerative Disorders

The altered amounts of different classes of fatty acids in the nervous system may contribute positively or negatively to any given neuropathological process (Table 2). Using APP-C99-transfected COS-7 cells, a cellular model of Alzheimer’s disease-like degeneration, a study was carried out to investigate the class of fatty acids that was thought to influence the production of Aβ peptide, which is a major neuropathological hallmark of disease. It was shown that palmitic acid (16:0), stearic acid (18:0), upstream n-3 PUFAs, and AA (20:4 n-6) triggered higher secretion of Aβ peptide compared to long chain downstream n-3 PUFAs and MUFAs (Amtul et al., 2011a). These findings were corroborated in vivo by using a transgenic mouse model of early-onset Alzheimer’s disease that expresses the double-mutant form of human APP, which is the precursor protein responsible for the synthesis of Aβ peptide. Decreased levels of Aβ peptide and less accumulation in the form of amyloid plaques were observed in the brain of mice nourished with a diet enriched in n-3 PUFAs, mainly DHA (22:6 n-3; Amtul et al., 2011a). Not only extraneously supplied but endogenously synthesized n-3 PUFAs can suppress the synthesis of Aβ peptide and the formation of amyloid plaques. Lebbadi et al. (2011) crossed 3xTg-AD mice, a model of Alzheimer’s disease, with transgenic mice expressing Δ-3 desaturase (Fat-1) from Caenorhabditis elegans, which endogenously converts n-6 PUFAs into n-3 PUFAs. It was observed that the double transgenic 3xTg-AD/Fat-1 mice had increased brain levels of DHA (22:6 n-3) and lower levels of Aβ peptide. Similarly, MUFAs, mainly oleic acid (18:1 n-9), were also shown to inhibit the production of Aβ peptide and amyloid plaques both in vitro and in vivo (Amtul et al., 2011b). In contrast, n-6 PUFAs, such as AA (20:4 n-6), aggravated Alzheimer’s disease neuropathology, by increasing the synthesis of Aβ peptide (Amtul et al., 2012). 

TABLE 2  

TABLE 2. Changes in brain fatty acid composition in pathological conditions.

The results obtained in experimental models of Alzheimer’s disease have been confirmed, at a certain extent, by studies performed on human brain. Thus, decreased levels of PUFAs and MUFAs, particularly DHA (22:6 n-3) and oleic acid (18:1 n-9), respectively, were observed in the brain of Alzheimer’s disease patients (Martïn et al., 2010). However, other studies reported that, although the abundance of DHA (22:6 n-3) varied highly among patients, the mean quantity of this PUFA did not differ significantly when compared to healthy brains (Fraser et al., 2010). This study also showed that levels of stearic acid (18:0) were reduced remarkably in frontal and temporal cortex, while those of oleic acid (18:1 n-9) were increased in both parts; also, levels of palmitic acid (16:0) appeared increased in the parietal cortex (Fraser et al., 2010). These a priori puzzling abnormalities in MUFAs could be a result of alterations in the expression of MUFA synthesizing genes. Thus, levels of MUFAs in hippocampus, frontal cortex and temporal cortex were elevated in Alzheimer’s disease patients, as was the expression of the SCD isomers SCD1, SCD5a, and SCD5b. In addition, the ratio of MUFAs to SFAs, an index of desaturase activity, was reported to be negatively correlated with the degree of cognitive performance (Astarita et al., 2011). 

Less is known about the changes of fatty acids in other neurodegenerative conditions.Fabelo et al. (2011) reported that lipid rafts from brain cortices of patients with Parkinson disease displayed significantly decreased levels of n-3 and n-6 PUFAs, particularly DHA (22:6 n-3) and AA (20:4 n-6), respectively, while SFAs, mainly palmitic acid (16:0) and stearic acid (18:0), were noted augmented, as compared to control subjects. In another study, the effects of diets rich in n-3 or n-6 PUFAs were assessed on cuprizone-induced experimental demyelination, an animal model for multiple sclerosis. It was observed that n-3 PUFAs from various sources affected the pathological phenotype differently; for example, a diet containing n-3 PUFAs from salmon ameliorated the behavioral deficits induced by cuprizone, whereas a diet containing n-3 PUFAs from cod affected similarly as n-6 PUFA enriched or control diet did, suggesting that not only the type of PUFA but its origin is also to consider when prescribing a diet based remedy (Torkildsen et al., 2009). Contrasting these findings, other studies did not corroborate the protective effects of n-3 PUFAs against multiple sclerosis and concluded that neither n-3 nor n-6 PUFAs had any effect on disease progression or remedial influence (Wergeland et al., 2012). Moreover, dietary administration of EPA (20:5 n-3) even accelerated disease progression in mice expressing a mutated form of Cu/Zn-superoxide dismutase (SOD1), which is a model of neuromuscular degeneration as caused by amyotrophic lateral sclerosis (Yip et al., 2013). 

Fatty Acids and Traumatic Injury to the Nervous System 

Several recent studies have provided evidence that n-3 PUFAs can exert protection against neuronal injury triggered by hypoxia or ischemia. In neonates, these fatty acids protected neurons following hypoxia/ischemia by modulating the microglial inflammatory response through inhibition of the nuclear factor-κB (NF-κB) dependent pathway (Zhang et al., 2010). However, it is important to mention that consistent increased intake of n-3 PUFAs can also affect adversely in some cases. In this respect, a diet rich in EPA (20:5 n-3) and DHA (22:6 n-3) enhanced the risk for intracerebral hemorrhagic stroke in rats, and caused oxidative damage to the brain, probably due to the fact that a high PUFA content increased the danger of lipid peroxidation. Alternatively, n-3 PUFA intake was reported to affect blood viscosity, vasoconstriction, platelet aggregation, and blood clotting ultimately leading to hemorrhaging (Park et al., 2009). 

There is also evidence that certain fatty acids have the potential to improve the recovery of the injured spinal cord. Hirakawa et al. (2010) reported that trans-2-decenoic acid ethyl ester, a medium-chain fatty acid derivative, increased the expression of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in cultured cortical neurons and at the site of injury in a rat spinal cord injury model. Indeed, the administration of trans-2-decenoic acid ethyl ester ameliorated functional recovery and reduced lesion size in response to injury, by increasing the expression of ERK1/2, brain-derived neurotrophic factor (BDNF), and anti-apoptotic Bcl-2. Similarly, DHA (22:6 n-3) pre-treatment in an acute spinal cord injury model diminished the extent of functional deficits as compared to that observed in the control group, and this protective effect was associated with increased survival of precursor cells, sparing of white matter and axonal preservation (Figueroa et al., 2012; Lim et al., 2013b). In the same way, mice carrying the Fat-1 transgene for boosting endogenous synthesis of n-3 PUFAs showed better outcome after spinal cord injury (Lim et al., 2013a). Finally, in relation to diabetes, it was shown that the augmentation of epoxy-fatty acid resources, as obtained by inhibiting soluble epoxide hydrolase, resulted in a dose dependent anti-allodynic effect on neuropathic pain due to glucose toxicity (Inceoglu et al., 2012). 

Fatty Acids and Neurological Disorders 

Particular changes in brain fatty acid composition appear to be intimately connected to a series of neurological diseases, as recently reported in several studies. Thus, Conklin et al. (2010) observed a reduction in the quantity of both saturated and unsaturated fatty acids of various types, including n-3 and n-6 PUFAs, in the cingulate cortex of depressive patients. Similar alternations in n-3 PUFAs, including EPA (20:5 n-3) and DHA (22:6 n-3), were also shown by others (Lin et al., 2010). In another study, it was noticed that the altered concentrations of MUFAs and PUFAs were region-specific. In fact, no changes in n-3 and n-6 PUFAs were found in hippocampus and orbitofrontal cortex of patients with depression but concentrations of MUFAs, such as oleic acid (18:1 n-9), and SFAs, such as palmitic acid (16:0), appeared augmented (Hamazaki et al., 2012). A partial confirmation of these findings emerged from another study showing lowered expression of genes involved in PUFA and MUFA synthesis in the frontal cortex of depressed patients (McNamara and Liu, 2011). It is also noteworthy that lifelong n-3 PUFA deficiency perturbed normal endocannabinoid function in prelimbic prefrontal cortex and accumbens, and this effect was related to impaired emotional behavior (Lafourcade et al., 2011). Although less investigated, several studies also detected changes in fatty acids in patients with schizophrenia. A decrease in docosatetraenoic acid (22:4 n-6) was observed in the nuclei of the amygdala of these patients but other PUFAs, including DHA (22:6 n-3) and AA (20:4 n-6), remained unchanged (Hamazaki et al., 2010, 2012). Interestingly, the decrease in total membrane PUFAs found in erythrocytes of young patients with schizophrenia correlated with the degree of demyelination in brain white matter (Peters et al., 2009). 

Lastly, several lines of evidence support the anticonvulsant effects of certain fatty acids in animal models of epileptogenesis, and the administration of PUFA enriched diets has been envisaged to treat epileptogenic convulsions. Using the pentylenetetrazol-induced epilepsy rat model, Porta et al. (2009) showed that a PUFA containing diet increased the threshold level for pentylenetetrazol to induce convulsions. A contemporary study confirmed that rats nourished with n-3 PUFAs exhibited greater resistance to pentylenetetrazol-induced seizures (Taha et al., 2009). In the kindling model of epilepsy, intracerebroventricular injection of DHA (22:6 n-3), or its derivative NPD1, limited the progression in the hippocampus of the electrically induced neuronal hyperexcitability characteristic of seizures (Musto et al., 2011). In contrast, other studies did not corroborate these findings, since DHA (22:6 n-3) or EPA (20:5 n-3) showed neither anticonvulsant activity nor protection against pentylenetetrazol-induced seizures (Willis et al., 2009). 

Cellular Roles of Fatty Acids in the Nervous System

Actions of Fatty Acids in the Hippocampus

Many recent studies have investigated the implication of fatty acids in learning and memory processes occurring in the hippocampus (Figure 2). In general, n-3 PUFAs were shown to foster neuronal activity and hence counteract memory deficits. It is well known that increased c-Fos expression is an indicator of neuronal activity in response to extracellular signals like growth factors, and it is initiated when neurons fire action potentials. Commonly, the activity of c-Fos decreases as age extends and spatial memory goes off. Provision of n-3 PUFAs restored c-Fos expression in the hippocampus, and enhanced neuronal activity ultimately leading to the amelioration of memory deficits in aged mice (Labrousse et al., 2012). Dietary DHA (22:6 n-3) also enhanced the expression of F-ATPase involved in mitochondrial ATP synthesis in the CA1 region of the hippocampus, whereas its deficiency led to decreased glucose transporter expression and defective glucose transport in the cerebral cortex (Harbeby et al., 2012). The stimulatory action of n-3 PUFAs on gene expression also appears to affect neurotransmission. In fact, recent proteomics studies performed on mouse brain deficient in DHA (22:6 n-3) revealed a loss of synaptic proteins associated with altered synaptic transmission (Sidhu et al., 2011). In contrast, expression of vesicular glutamate transporters 1 and 2, which are implicated in glutamatergic neurotransmission, was increased in response to ALA (18:3 n-3) exposure (Blondeau et al., 2009). Similarly, DHA (22:6 n-3) provision to rats with traumatic brain injury enhanced learning ability, by modulating the expression levels of synapsin-1, cAMP response element-binding protein-1 and calcium/calmodulin-dependent protein kinase-2 in the hippocampus of treated animals (Wu et al., 2008, 2011). DHA (22:6 n-3) also ameliorated spatial memory in rats by increasing the expression of subtypes of endocannabinoid/endovanilloid receptors (Pan et al., 2011). Last, n-3 PUFAs augmented the expression of a series of transcription factors involved in learning and memory, including retinoic acid receptor, retinoic X receptor and peroxisome proliferator-activated receptor (Dyall et al., 2010). 

FIGURE 2  

FIGURE 2. Multiple effects of fatty acids in the hippocampus. n-3 and n-6 PUFAs exert a variety of positive actions that promote formation, storage and processing of learning and memory in the hippocampus. In contrast, SFAs display rather negative actions. Green arrows indicate stimulatory effects while orange arrows represent inhibitory effects.

Many positive actions of DHA (22:6 n-3), and likely other n-3 PUFAs, may therefore converge to enhance synaptic transmission, and ameliorate spatial learning and memory (Connor et al., 2012). In a mouse model of systemic lupus erythematosus and Sjögren’s syndrome, which is characterized by behavioral abnormalities, reduced aged hippocampal neurogenesis and loss of long-term potentiation (LTP), the dietary supplementation with n-3 PUFAs corrected LTP at synapses in the medial perforant pathway/dentate gyrus and enhanced the amount of adult-born neurons in the hippocampus (Crupi et al., 2012). Similarly, docosapentaenoic acid (DPA, 22:5 n-3) also ameliorated hippocampal function by attenuating the reduction in LTP in aged brain (Kelly et al., 2011). Finally, in vitro studies showed that treatment of differentiated PC12 cells with EPA (20:5 n-3) resulted in activation of the neuroprotective PI3-kinase/Akt signaling pathway, a mechanism that might account for the increase in LTP observed in vivo following EPA (20:5 n-3) treatment (Wu et al., 2008;Kawashima et al., 2010). 

In Alzheimer’s disease, Aβ peptide induces neuronal apoptosis through degradation of the adaptor protein insulin receptor substrate-1 in a c-Jun N-terminal kinase (JNK)-dependent manner. An n-3 PUFA enriched diet prevented the phosphorylation of JNK, and ultimately protected neurons from death in vitro and improved cognitive deficit in vivo (Ma et al., 2009). Also, lower levels of phosphorylated tau protein and improved brain function were observed by crossing 3xTg-AD mice with Fat-1 expressing mice to enhance the endogenous production of n-3 PUFAs (Lebbadi et al., 2011). Nevertheless, it is noteworthy that 12/15-lipo-oxygenase adversely affected Alzheimer’s disease pathology by synthesizing pro-inflammatory and pro-oxidant hydroperoxyacids resulting from the oxidation of PUFAs, so that genetic ablation of this enzyme ameliorated cognitive function (Yang et al., 2010). 

Neuroinflammation is one of the distinctive features of aged or diseased brain, as demonstrated by the activation of glial cells and the increase in the expression of a variety of pro-inflammatory factors. In this respect, it was reported that n-3 PUFA provision restored spatial memory loss in aged animals by suppressing pro-inflammatory interleukin-1β and reverting to normal the morphology of microglia and astrocytes in the hippocampus (Labrousse et al., 2012; Park et al., 2012). n-3 PUFAs also yielded protecting effects to neurons by blocking microglia activation in a transgenic mouse model of systemic lupus erythematosus and Sjögren’s syndrome (Crupi et al., 2012). In the same way, DPA (22:5 n-3) inactivated microglia attenuating neuroinflammation and counteracting spatial learning deficit in aged brain (Kelly et al., 2011). Contrary to the protective effects of PUFAs, SFAs stimulated the secretion of pro-inflammatory cytokines and induced apoptosis in astrocytes. Particularly, palmitic acid (16:0), lauric acid (12:0), and stearic acid (18:0) triggered the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 by engaging toll-like receptor-4 (TLR-4). Moreover, palmitic acid (16:0) also activated caspase-3 and modified the Bax/Bcl-2 ratio in these glial cells for apoptotic demise. Interestingly, these pro-inflammatory actions of SFAs could be reverted by n-3 PUFAs like DHA (22:6 n-3; Gupta et al., 2012; Wang et al., 2012). 

Another way by which n-3 PUFAs can afford neuroprotection is by preventing apoptosis. The mouse model of infantile neuronal ceroid lipofuscinosis, a neurodegenerative disease caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency, manifests enhanced endoplasmic reticulum- and oxidative stress that lead to apoptotic cell demise. In PPT1-deficient cells from such mice, intervention of n-3 PUFAs attenuated stress and repressed apoptotic death casting a protection to neuronal cells (Kim et al., 2010; Wu et al., 2011). Similarly, differentiated PC12 cells treated with EPA (20:5 n-3) showed lower rates of apoptosis and suppressed activity of the apoptotic effector caspase-3 (Boudrault et al., 2009; Kawashima et al., 2010). Conjugated LA (18:2 n-6) also protected neurons from mitochondrial dysfunction and demise. Treatment of cortical neurons with this fatty acid following excitotoxic glutamate exposure resulted in decreased glutamate-induced loss of mitochondrial function, increased Bcl-2 expression and prolonged neuronal survival (Hunt et al., 2010). In the same manner, administration of fish oil, that is a rich source of n-3 PUFAs, protected hippocampal neurons from diabetic insult by precluding the expression of apoptosis inducing genes in both CA1 region and cultured cells, and by increasing the expression of anti-apoptotic genes, such as Bcl-2 and Bcl-xL (Zhang and Bazan, 2010;Zhao et al., 2012). Together with caspase-3, ceramides, resulting from the hydrolysis of sphingomyelin by sphingomyelinase, are well-known apoptosis inducing factors. Treatment with DPA (22:5 n-3) inactivated sphingomyelinase and caspase-3 in the hippocampus of elderly rats (Kelly et al., 2011). On the other hand, n-3 PUFA withdrawal modulated the phosphorylation of glycogen-synthase kinase-3β and ERK1/2, predisposing more hippocampal neurons to damage in an in vitro oxygen and glucose deprivation model of ischemia (Moreira et al., 2010b). Along with this, a decrease in the release of PUFAs from cell membranes in the rat hippocampus, as a result of reduced phospholipase-A2 activity, caused alterations in membrane fluidity that could account for loss of spatial memory and cognitive impairment in Alzheimer’s disease (Schaeffer et al., 2011). However, the protective effects of n-3 PUFAs under certain conditions seemed to be limited to some of the members of this class of fatty acids. Thus, only DHA (22:6 n-3) offset the expression of AMPA receptors in the membrane of hippocampal neurons and attenuated neurotoxicity leading to improved cognitive function. Other members of the n-3 PUFA family, especially EPA (20:5 n-3), lacked such a protective effect against AMPA-mediated toxicity (Ménard et al., 2009). 

Synaptogenesis is one of the mechanisms by which memory process takes place. Hence, the loss of synapses is characteristic of neurodegenerative conditions and aging. For instance, cortical or hippocampal neurons incubated with the neurotoxic prion-derived peptide PrP82–146, and pre-treated with DHA (22:6 n-3) or EPA (20:5 n-3), showed less loss of synaptophysin-1 and reduced accumulation of prion peptide (Bate et al., 2010). ALA (18:3 n-3) also stimulated the expression of genes involved in synaptic function, like VAMP-2, SNAP-25 and synaptophysin-1, that led to improved stability and physiology of synapses (Blondeau et al., 2009). Similarly, the chronic supplementation of n-3 PUFAs yielded anti-depressant effects by increasing the expression of synaptophysin-1 in the hippocampus (Venna et al., 2009). However, another study performed on SH-SY5Y cells reported that DHA (22:6 n-3) did not affect the neurotransmission machinery, as evaluated by the expression of synaptotagmin-1, syntaxin-1A, and synaptobrevin-1, although the release of noradrenaline by these cells was enhanced (Mathieu et al., 2010). 

Hippocampal neurogenesis also contributes to learning and memory processes. The mouse model of systemic lupus erythematosus and Sjögren’s syndrome typically exhibits age-dependent reduced hippocampal neurogenesis. Supplementation of diet with n-3 PUFAs to these mice enhanced the density of bromodeoxyuridine (BrdU)- and doublecortin positive cells in the hippocampus, suggesting an ongoing neurogenesis (Crupi et al., 2012). Similar neurogenesis enhancement was also reported in response to ALA (18:3 n-3) treatment (Blondeau et al., 2009). In addition, AA (20:4 n-6) even increased neurogenesis at postnatal stages when administered at gestation period (Maekawa et al., 2009). Several in vitro studies revealed that not only n-3 PUFA precursors, such as EPA (20:5 n-3), but also naturally derived metabolites, including the neurotrophic N-docosahexaenoylethanolamine, stimulated neurogenic differentiation of neural stem cells (Katakura et al., 2013; Rashid et al., 2013). The importance of the stimulatory role of PUFAs for neurogenesis is also illustrated by experiments reporting increased expression of fatty acid binding proteins (FABPs) in the ischemic hippocampus. FABPs are carriers of PUFAs in the cytoplasm, and their expression declines with age in association with reduced synaptic activity and other cellular functions. CA1 and dentate gyrus regions in the hippocampus showed augmented levels of FABP-5 and FABP-7 after ischemia, suggesting elevated transportation of PUFAs in these regions to restore cellular neurophysiology (Liu et al., 2010; Ma et al., 2010). More importantly, at post-ischemic stages, the subgranular zone in the dentate gyrus of the hippocampus, a niche of adult neurogenesis, displayed a concomitant increase in the neuronal expression of FABPs and the fatty acid receptor GPR40, representing compensatory processes of newborn cells (Boneva et al., 2011a,b; Yamashima, 2012). Finally, it is noteworthy that many of the beneficial actions of PUFAs on hippocampal function were associated with an increase in the production of BDNF, which is a member of the neurotrophin family of growth factors involved in supporting growth, differentiation and survival of neurons (Wu et al., 2008, 2011; Blondeau et al., 2009; Venna et al., 2009;Avraham et al., 2011; Vines et al., 2012). 

Actions of Fatty Acids in the Hypothalamus 

The central regulation of energy balance involves a number of neuronal circuits in the hypothalamus that either exert anorexic actions or stimulate food intake. In this respect, it was recently shown that certain fatty acids could influence the control of energy homeostasis by the hypothalamus. In general, dietary supplementation with fish oil, rich in n-3 PUFAs, normalized several hypothalamic neurochemical systems in food restricted animals (Avraham et al., 2011). However, supplementation of diet with SFAs induced endoplasmic reticulum stress and expression of cytokines via TLR-4 signaling in the hypothalamus, and this effect resulted in resistance to anorexigenic signals (Milanski et al., 2009). At the cellular level, treating hypothalamic mHy-poE-44 cells with palmitic acid (16:0) increased the expression of the orexigenic neuropeptide-Y, suggesting that this fatty acid could enhance food intake (Fick et al., 2011). Moreover, palmitic acid (16:0) faded insulin signaling and enhanced endoplasmic reticulum stress and caspase-3 cleavage in the same cell line, which resulted in apoptosis in a JNK-dependent manner (Mayer and Belsham, 2010). In another study, exposure to palmitic acid (16:0) displayed no effects on insulin resistance and inflammatory process activation but corroborated the stimulation of endoplasmic reticulum stress and apoptosis, along with the activation of mitogen-activated protein kinase (Choi et al., 2010). 

Actions of Fatty Acids in the Nigrostriatal Pathway 

Growing evidence supports a link between the dietary intake of n-3 PUFAs and the function (or dysfunction) of the nigrostriatal pathway involved in the control of movement (Figure 3). This relationship was particularly investigated in a number of animal models of Parkinson disease, which is a neurodegenerative condition primarily characterized by the loss of dopaminergic neurons connecting the substantia nigra to the striatum. In several recent studies, n-3 PUFAs were shown to be beneficial by reverting disease phenotype. In the MPTP model of Parkinson disease, pre-treatment of mice with n-3 PUFAs bestowed protection by increasing the expression of BDNF and involving its TrkB receptor (Bousquet et al., 2009; Balanzá-Martïnez et al., 2011). In other studies, it was found that exposure to the n-3 PUFA ethyl-eicosapentaenoate derivative lowered the expression of Bax and caspase-3, and enhanced cortical dopamine levels (Bousquet et al., 2008; Meng et al., 2010). Furthermore, n-3 PUFAs also yielded protective influence indirectly, by attenuating inflammation-causing factors. These fatty acids targeted the NFκB signaling pathway in microglia to suppress their over-activated response and hence protect dopaminergic neurons (Boudrault et al., 2009; Zhang et al., 2010; Ji et al., 2012; Zhou et al., 2012). 

FIGURE 3 



FIGURE 3. Conflicting effects of n-3 PUFAs in the nigrostriatal pathway.n-3 PUFAs are commonly endowed with a wide range of helpful effects, as illustrated by the protective benefit that these fatty acids offer to dopaminergic neurons in the nigrostriatal tract against apoptotic and pro-inflammatory cues. However, extreme caution should be exercised since these same PUFAs may not provide complete safety to halt degeneration induced by parkinsonian toxins or even trigger adverse effects, which eventually aggravates the extent of the pathological process.

Other findings, however, did not support the beneficial effects of n-3 PUFAs on Parkinson disease. It was reported that treatment with ethyl-eicosapentaenoate, although minimized pro-inflammatory cytokines and yielded positive effects on procedural memory deficit, it was unable to preclude the loss of nigrostriatal dopamine in MPTP mice (Shchepinov et al., 2011; Luchtman et al., 2012). Similarly, the parkinsonian neurotoxin 6-hydroxydopamine caused lesions in the medial forebrain bundle of rats and motor deficits that remained unaffected by fish oil derived n-3 PUFAs (Delattre et al., 2010). A chronic intervention of a DHA (22:6 n-3) containing diet modified neither the number of cortical glial cells nor the expression of α-synuclein, which is typically involved in disease pathogenesis (Muntané et al., 2010). The use of different animal models of Parkinson disease and the different ways of treating these mice to counteract the pathological process may explain the observed discrepancies. In this respect, it is important to mention that some studies indicated even adverse effects of n-3 PUFAs on Parkinson disease pathogenesis. Indeed, the presence of DHA (22:6 n-3) augmented neuritic injury and astrocytosis in mice transgenic for a Parkinson disease causing mutation in human α-synuclein. In addition, DHA (22:6 n-3) triggered oligomerization of α-synuclein, through the activation of retinoic X receptor and peroxisome proliferator-activated receptor-γ2. Interestingly, its withdrawal from diet was found to be beneficial against the deleterious effects caused by it provision (Yakunin et al., 2012). Finally, structural and conformational modifications in α-synuclein leading to pathological aggregation were brought by DHA (22:6 n-3; De Franceschi et al., 2009, 2011;Bousquet et al., 2011). 

Actions of Fatty Acids in the Peripheral Nerves 

A subset of peripheral sensory neurons expresses transient receptor potential cation channel-A1 (TRPA1), which is involved in pain and neurogenic inflammation. TRPA1 is a target for a variety of noxious and inflammatory irritant substances. In addition, it was found that n-3 PUFAs could act as a ligand for TRPA1 to excite sensory neurons and hence regulate their responses in vivo (Motter and Ahern, 2012). Transient receptor potential vanilloid cation channel-1 (TRPV1), which is another member of the family, is also found mainly in nociceptive neurons of the peripheral nervous system, where they are involved in transmission and modulation of pain. In this respect, it was shown that NPD1, which has anti-inflammatory properties, inhibited TRPV1 currents induced by capsaicin in dorsal root ganglion neurons, and modulated TRPV1/TNF-α-mediated synaptic plasticity in the spinal cord, suggesting a novel analgesic role (Park et al., 2011). The effects of fatty acids on sensory neurons go beyond receptor signaling. Both n-6 and n-3 PUFAs promoted neurite outgrowth in sensory neurons from dorsal root ganglia of embryos but also adult and aged animals (Robson et al., 2010). Enhanced levels of endogenously synthesized n-3 PUFAs also bestowed beneficial effects in various aspects. Thus, dorsal root ganglion neurons from Fat-1 expressing mice exhibited more resistance to hypoxia and mechanical injury as compared to neurons from wild-type littermates. Furthermore, Fat-1 expressing mice showed better functional recovery after sciatic nerve crush. The increased endogenous levels of n-3 PUFAs reduced the expression of the stress sensor activating transcription factor-3 in dorsal root ganglion neurons, and diminished muscle atrophy (Gladman et al., 2012). Similarly, our own studies also reported that the down-regulation of SCD1, which is in charge of the production of MUFAs such as oleic acid (18:1), triggered accelerated motor function recovery after sciatic nerve crush, providing evidence for a new role of this fatty acid desaturase in modulating the restorative potential of the neuromuscular axis (Hussain et al., 2013). 

The retina possesses a high concentration of n-3 PUFAs, particularly DHA (22:6 n-3). Many studies have shown that this fatty acid not only has a structural function but also protects visual neurons from trauma and disease. Recently, it was noticed that the retinal dysfunction induced by diabetes could be recovered to some extent by supplementing DHA (22:6 n-3) extraneously. In fact, diabetes resulted in reduced levels of n-3 PUFAs, by affecting n-3 fatty acid desaturase enzymatic activity, so that the provision of a DHA (22:6 n-3) enriched diet prevented dysfunction of rods and ameliorated vision (Yee et al., 2010). Also, n-3 PUFA derived NPD1, together with pigment epithelial-derived growth factor, promoted corneal nerve regeneration in a rat model of surgical injury (Cortina et al., 2010,2012; Kenchegowda et al., 2013). However, other studies rather obtained contradictory results. Therefore, augmented levels of DHA (22:6 n-3) bestowed no protection against retinal degeneration in mice carrying a disease-causing VPP rhodopsin mutation and expressing Fat-1 (Li et al., 2009, 2010). In the same way, it was also reported that high levels of DHA (22:6 n-3) in the retina could generate oxidative stress, instead of protection, and hence enhance the susceptibility to degeneration (Tanito et al., 2009). 

Conclusion

The biological functions of fatty acids have been investigated intensively during these last years, due to their active involvement in the physiology of both central and peripheral nervous system. They promote brain development, ameliorate cognitive functions in normal and diseased conditions, serve as anti-depressants and anti-convulsants, bestow protection against traumatic insults, and elevate repairing processes. At the cellular level, fatty acids stimulate gene expression and neuronal activity, and boost synaptogenesis and neurogenesis while preventing from neuroinflammatory toxicity and apoptosis (Figure 2). Although the demand for fatty acids in a healthy body applies to any of them, it can be said that, in general, excess of SFAs and, to some extent, n-6 PUFAs brings about negative consequences, whereas MUFAs and n-3 PUFAs are endowed with rather beneficial properties. In this respect, the ratio of n-6 to n-3 PUFAs is of special interest. It has been postulated that a relatively constant n-6:n-3 ratio of about 1:1 constituted a major breakthrough in the expansion of gray matter in the cerebral cortex of modern human beings (Bradbury, 2011). In the brain, the preservation of an optimal n-6:n-3 ratio is crucial to the maintenance of the variety of the cellular processes in which PUFAs participate (Luchtman and Song, 2013). During the last century, however, the n-6:n-3 ratio has dramatically increased up to 20–25:1, particularly in Western societies, because of a high consumption of n-6 PUFAs to the detriment of n-3 PUFA intake (Simopoulos, 2011). Once the equilibrium is broken, an excessively high n-6:n-3 ratio would impair normal brain function and, importantly, predispose to disease (Palacios-Pelaez et al., 2010). According to what we have exposed herein, a huge amount of studies have shown the good and the bad side of different fatty acids in many experimental models of trauma and disease. Nevertheless, the diversity in modeling any given physiopathological condition, together with differences in time, dose and type of fatty acid used to counteract the insult, certainly account for a number of conflicting results concerning the nature of the observed effects. In addition, it must be taken into consideration that particular fatty acids are assumed to foster neuroprotection but engender indeed a series of collateral deleterious actions, such as increasing oxidative stress susceptibility or favoring neurodegenerative protein aggregation, which may preclude the use of these fatty acids under certain (pathological) conditions (Figure 3). Finally, it is also noteworthy that, frequently, studies used nutritional approaches consisting in giving a specific fatty acid or its precursor mixed with others and forming part of foods relatively more complex than desired, since they also contain other substances with potential, uncontrolled positive or negative effects. Taken together, these drawbacks limit the translatability of successful results in terms of neuroprotection obtained in animal experiments into effective therapeutic interventions in humans. Numerous epidemiological studies have put fatty acids forward as key factors contributing to neuropathology but, in some cases, discrepant concentrations of fatty acids were reported in the corresponding diseased brain regions (Table 2). Despite these constraints, on the basis of these epidemiological studies and supported by experimental research, there is quite realistic evidence to envisage that nutritional therapies based on fatty acids can be of benefit to several neurodegenerative and neurological diseases, such as age-related macular degeneration, cognitive decline, depression, and some related behavioral disorders (Prior and Galduróz, 2012; Schleicher et al., 2013). More research is needed now for arriving at the final and conclusive result concerning the type of fatty acid, number of double bonds, origin, particular stage and proper concentration to achieve beneficial therapeutic potential against otherwise incurable diseases. 

Conflict of Interest Statement 

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 

Acknowledgments 

This work was supported by funds from European Community’s Health Seventh Framework Programme under grant agreement No. 259867, and Thierry Latran Foundation to Jean-Philippe Loeffler; and “Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres Maladies du Motoneurone” to Jose-Luis Gonzalez de Aguilar. Ghulam Hussain is supported by the Higher Education Commission of the Pakistani government and “Association pour la Recherche et le Développement de Moyens de Lutte contre les Maladies Neurodégénératives” (AREMANE). Florent Schmitt is granted by “Association Française contre les Myopathies” and AREMANE. Jose-Luis Gonzalez de Aguilar is recipient of a “Chaire d’Exellence INSERM/Université de Strasbourg.” 

References are available at the Frontiers site.

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