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The Role of Inflammation in Chronic Diseases

ACAM Medical Conference Report October 2000 Salt Lake City

February 2001

By Ivy Greenwell

Oxidative stress and chronic fatigue syndrome

Another speaker, Christian Renna, DO, presented an interesting thesis that without sufficient serotonin and antioxidant defenses, the brain decides that it's not safe to produce dopamine and norepinephrine—hence chronic fatigue and related neurosomatic disorders. A central feature of chronic fatigue-like disorders is a deficiency of norepinephrine. But simply increasing norepinephrine through pharmacological means is not appropriate, since the brain is already overwhelmed with stress, and thus with free radicals. In Renna's view, both stress reduction and antioxidant supplements are absolutely necessary to help the brain produce and maintain inhibitory and excitatory neurotransmitters in proper ratios. This applies not only to those diagnosed with chronic fatigue, but to all of us, especially as we age.

In the presence of excess free radicals, the brain seeks to protect itself by lowering its activity. This means lower production of excitatory neurotransmitters such as dopamine, and less energy production in the mitochondria. Every neuron has an excitatory threshold beyond which it will not fire, Renna explained. Instead, the overstimulated neuron shifts to an “escape pathway,” preventing the synthesis of dopamine and norepinephrine. In chronic fatigue, the neuroexcitatory threshold is set too low. Raising it requires increasing the brain's safety mechanisms: serotonin and antioxidants. “If the cell doesn't need to fear oxidative stress, the mitochondria light up like Las Vegas,” Renna said.

He also pointed out that many chronic fatigue patients responded well to fen/phen, which was a combination of a serotonin-raising drug and an amphetamine analogue. “Overcoming serotonin deficiency allows the brain to tolerate more norepinephrine,” Renna said. He didn't favor long-term use of antidepressants, however. He felt such use prevented the patient from achieving a more complete recovery. The point is to help the brain produce more of its own serotonin. Thus, we need to address the necessity of lowering stress—not only emotional stress, but also stress coming from chronic low-grade infections, toxins (including endotoxins [toxins produced within the body] originating in the gut under conditions of dysbiosis, meaning an overgrowth of harmful intestinal flora), excess calories, insufficient sleep or any other source. “The more gentle the stimulation, the better,” Renna said. “So don't rush.”

In addition, we must make sure the patient's antioxidant defenses are adequate before we use any kind of stimulant. “If a person is not energetic, maybe it's not safe for them to be energetic,” Renna said, again reinforcing the point about low serotonin and depleted antioxidant defenses. Both need to be corrected through stress reduction, diet, the right exercise and supplements. The brain will produce more dopamine when it becomes safe to do so.

Dopamine is a very energizing, feel-good neurotransmitter; in addition, dopamine stimulates the release of nerve growth factors. But dopamine has its dark side. “Dopamine is the most dangerous of all neurotransmitters because the brain needs to defend itself against overstimulation,” Renna explained. When serotonin is low, the threshold for what constitutes overstimulation is also set low. Low serotonin, low dopamine, and low energy production in cerebral mitochondria all lead to a cascade of harmful consequences. Since the brain is in constant chemical communication with the rest of the body, including the endocrine system and the immune system (in fact Renna calls the immune system “morcelized brain”), the whole body suffers. We see this not only in the chronic fatigue syndrome, but above all in aging.

Image with Caption
Tofu has recently come under
suspicion as deleterious to the
brain. In an ironic reversal of
our previous beliefs, coffee
and tea are now seen as
neuroprotective, while tofu is
increasingly under attack.

Renna also discussed neuroprotective supplements. His special emphasis was on flavonoids as particularly effective antioxidants and neuroprotectants. Flavonoids (such as those present in blueberries and bilberries, green tea, grape seed extract, and various fruits and vegetables) not only raise glutathione levels, but also help prevent inflammation by inhibiting the enzymes in the lipoxygenase family (LOX), which NSAIDs and COX-2 inhibitors cannot do. Renna added folic acid, SAMe and acetyl-l-carnitine to the list of essential neuroprotective supplements. As for the so-called smart drugs, such as deprenyl and piracetam, these too are worth looking into, according to Renna. They increase energy production while reducing oxidative stress (acetyl-l-carnitine works the same way).

Tofu has recently come under suspicion as deleterious to the brain. In an ironic reversal of our previous beliefs, coffee and tea are now seen as neuroprotective, while tofu is increasingly under attack. Renna takes his patients off tofu, at least until there is some solid new evidence of its safety.

Both Perlmutter and Renna covered a huge territory, at times overwhelming the audience. Permutter focused on the “anti-inflammatory breakthrough”: preventing and fighting inflammation in the prevention and treatment of Alzheimer's disease, as well as on the use of intravenous glutathione, the body's chief detoxifying compound, as a new and potentially revolutionary treatment for Parkinson's disease. Perlmutter also touched on the production of energy in the cerebral mitochondria, a subject developed more fully by Renna. The main message was clear: we already know a great deal about preventing and treating brain diseases and age-related cognitive and motor dysfunction. Relatively simple measures such as reducing caloric intake and taking fish oil, NSAIDs, lipoic acid and CoQ10 could save millions from terrible brain diseases. It is high time to start implementing this knowledge on a much broader scale.

Antioxidants against vitamins: lipoic acid and selenium improve the survival of AIDS patients

The excitement over the new anti-retroviral drugs designed to fight the AIDS virus is yielding to a sober assessment of their limitations. By now it has been shown that these drugs do not fully restore immune function. They are not the long-awaited cure. Their side effects are so severe that many AIDS patients drop out of treatment. In addition, the majority of the virus is in the latent stage in the nuclei of T cells, and antiviral drugs cannot affect latent viruses.

Are there effective alternative treatments? An affirmative answer was compellingly presented by two speakers: Raxit Jariwalla, PhD, a research scientist at California Institute for Medical Research in San Jose, and Lynn Patrick, ND, medical director of HIV Wellness Program in Tucson, Arizona. The speakers cited study after study showing improved survival rate for AIDS patients who used certain critical supplements known to reduce oxidative stress (a major factor in the progression of the disease) and, in some cases, to significantly suppress viral reproduction.

Both presenters singled out lipoic acid as particularly important. All antioxidants are also anti-inflammatory agents, but lipoic acid is regarded as an especially effective anti-inflammatory.

It has been known for almost a decade that lipoic acid effectively inhibits the replication of the AIDS virus in vitro. This is not surprising in view of our knowledge that lipoic acid inhibits the activation of Nuclear Factor kappa B (NFkB), which is believed to play an important role in the activation of the HIV virus. Essentially, the latent virus is activated by certain inflammatory cytokines that result from the activation of NFkB. These cytokines include Tumor Necrosis Factor alpha (TNF alpha)—hence the goal of reducing TNF alpha, and the similarity between alternative treatments against AIDS and hepatitis, Dr. Patrick pointed out. Both protocols emphasize lipoic acid, selenium and a combination of various other antioxidants. In addition, many AIDS patients are co-infected with Hepatitis C. “All AIDS patients need liver support,” Patrick said. In addition to 500 mg of lipoic acid/day, she also uses silymarin, shown to be remarkably effective in restoring liver health.

Lyn Patrick largely confirmed Dr. Jariwalla's primary emphasis on lipoic acid, stating that “lipoic acid is of extreme importance for HIV patients.” She reinforced this with some added details. Studies have found that lipoic acid inhibits reverse transcriptase (a viral enzyme needed for replication), and makes AZT significantly more effective.

Another obvious reason for the importance of lipoic acid for HIV patients is its ability to raise glutathione, our chief detoxifier and a crucial endogenous antioxidant. Glutathione is low in all serious illnesses. When the levels of glutathione rise, the result is reduced oxidative stress. The role of oxidative stress has been neglected in the discussion of AIDS, with the public getting the impression that the sole factor in the progression of this disease is the presence of AIDS virus, commonly referred to as HIV. Yet oxidative stress and consequent inflammation play a major role in whether symptoms of AIDS will appear at all, and in the rate of progression. Some people who are HIV positive do not show any symptoms of AIDS. Interestingly, this group tends to have a higher intake of antioxidants, from diet or supplements or both. Even merely taking a multivitamin turned out to reduce the risk of developing the symptoms of AIDS by 33% in HIV-positive individuals.

While lipoic acid plays a starring role in the alternative treatment for HIV patients, another thiol (i.e. sulfur-containing) antioxidant, the acetylated form of cysteine known as NAC, appears to be somewhat helpful as well. NAC too helps raise the levels of glutathione, but by itself it is not likely to have enough effect in AIDS patients; lipoic acid is far more efficient at raising glutathione and blocking NFkB. The special effectiveness of lipoic acid may derive from the fact that it's a dithiol (it has two sulfur groups), while NAC is a monothiol.

NAC is more effective when used with other antioxidants. In particular, it synergizes with high-dose ascorbate. High-dose ascorbate, Dr. Jariwalla stated, is unique in that it recycles itself to the reduced state. It also produces “dramatic dose-dependent suppression of viral reproduction.” It is believed that high-dose ascorbate suppresses viral replication through a different mechanism than thiol antioxidants (lipoic acid and NAC) and selenium. Some participants suggested that intravenous delivery of ascorbate would be most effective, due to the large dose required (6 to 12 grams if taken orally).

Selenium also plays a starring role in anti-viral regimens. It too inhibits NFkB. But the main reason that selenium is known as “birth control for viruses” derives from the fact that many viruses, including HIV, need selenium to replicate. Interestingly, in a selenium-rich milieu the viral genes that control replication stay turned off. In addition, selenium is required by T cells, and potentiates the action of interleukin-2. An AIDS patient is ten times more likely to die if s/he is selenium-deficient, according to Dr. Patrick. She uses the dose of 400 mcg per day.

Vitamin E is known to play an important part in bolstering immunity and reducing inflammation. Like lipoic acid, vitamin E also inhibits NFkB, essential for viral replication. Dr. Patrick stressed that only the succinate form of vitamin E inhibits both the activation of NFkB and the binding of activated NFkB to DNA, as shown by the research of Dr. Lester Packer in the early nineties. Vitamin E has also been shown to enhance the action of AZT. Thus, the form of vitamin E known as alpha-tocopheryl-succinate (“dry E” in popular parlance) is of crucial importance for HIV patients. It is possible, however, that gamma-tocopherol, being a COX-2 inhibitor, is also of value.

Vitamin A and beta carotene have been found helpful, as has zinc—but only in small doses. Zinc supplements in excess of 10 to 15 mg appear to increase disease progression. We don't know very much about zinc and HIV, but we do know that zinc is important for the immune system. Zinc activates the thymus hormone thymulin, which plays a part in the differentiation of T cells. Zinc is also involved in protease and integrase enzymes. It seems that supplementing with 12 mg of elemental zinc works best, according to Patrick.

HIV infection has also been linked to deficiencies in B6, B12 and folate—the methylating factors. There is a “rampant deficiency” of B12 among AIDS patients, according to Dr. Patrick. Such nutritional deficiencies in patients with full-blown AIDS result mainly from their poor absorption of nutrients due to gut problems, Patrick explained. Thus doses need to be especially large.

Most HIV patients are also glutamine-deficient, Patrick said. This is true of anyone under chronic severe stress, even though glutamine is abundant in any protein-rich diet (interestingly, the immune dysfunction seen in AIDS resembles the symptoms of protein-calorie malnutrition). Glutamine helps stop diarrhea and prevents muscle wasting. Large doses are needed (Patrick uses 40 g/day in four divided doses), but the cost is only $31 per week versus $1000 a week it would take for growth hormone treatment, another therapy aimed at preventing wasting.

Patrick mentioned yet another supplement: acetyl-l-carnitine. AZT is a mitochondrial toxin. It turns out that the combination of acetyl-l-carnitine and lipoic acid can reverse this toxicity.

After learning about the effectiveness of lipoic acid, NAC, Vitamin E, high-dose ascorbate and other supplements in fighting the HIV virus and improving the survival rate of AIDS patients, it was sad to hear that AIDS activists have largely lost interest in alternative therapies and are mostly waiting for the next “miracle drug.” So far, the drugs have proven highly toxic and not effective in many patients. We need to seriously consider the preventive and therapeutic use of supplements such as lipoic acid. In Dr. Jariwalla's words, “nutrients are compelling candidates for treatment of immune dysfunction underlying AIDS.”

Much is to be gained from paying attention to the developments in the alternative treatment for AIDS. Cellular immunity decreases not only in the course of AIDS, but also during aging. It is of utmost importance that we learn how to sustain a healthy immune system that can fight viruses and bacteria. Thus, the results presented in the lectures on AIDS are of special interest for anti-aging medicine. Antioxidants, with special emphasis on lipoic acid and selenium, once again show their amazing potential.