Peroxynitrite: A Vicious Cycle of Cellular Damage:
Dr. Martin Pall’s NO/ONOO– (Peroxynitrite) hypothesis is probably the most comprehensive explanation of cellular dysregulation in CFIDS, ME/CFS, and other oxidative stress illnesses.
His model proposes that the chronic stage of CFS is driven by a vicious cycle of oxidative stress, in which the basic mechanisms that are meant to control pathogens don’t turn off. The result is free radicals (or “oxidants”) run amok, creating havoc in the cell’s energy cycles, and increasing inflammation.
The protocol described here was originally put together by Dr. Pall and by Dr. Grace Ziem. It is based on antioxidant treatments which break the vicious cycle of oxidative stress as well as other agents that act to lower other parts of the cycle, such as lowering inflammatory responses, improving mitochondrial function and lowering excessive NMDA activity. However, taking large quantities of single antioxidants can actually increase oxidative stress. Once antioxidants such as tocopherols (vitamin E), vitamin C, and flavonoids react with free radicals, these antioxidants are themselves converted into free radicals. Other antioxidants are then needed to neutralize those newly formed free radicals. Therefore, a wide variety of antioxidants is optimal.
Below is a list of Dr. Pall’s therapies. More detailed information follows.
1.Nebulized reduced glutathione
2.Nebulized inhaled hydroxocobalamin
3.Mixed natural tocopherols
5.Magnesium, as malate
6.Four flavonoids: gingko, cranberry extract, silymarin and bilberry
10.Carotenoids including lycopene, lutein and B carotene
11.Alpha lipoic acid
12.Zinc (modest dose), manganese (low dose), copper (low dose)
13.Vitamin B6, as pyridoxal phosphate
Detailed antioxidant protocol:
Vitamin C. Pall suggests doses on the order of 500 to 1000 mg/day, taken several times per day. Vitamin C can act to regenerate tetrahydrobiopterin (BH4) and, therefore, may act to lower nitric oxide synthase (NOS) uncoupling, and high doses of vitamin C can be useful in scavenging peroxynitrite (ONOO–), the most central element in his NO/ONOO– cycle hypothesis.
CoQ10. CoQ10 has been used in a number of diseases to improve mitochondrial function. It scavenges free radicals, protects against loss of mitochondrial respiratory function, increases energy metabolism, and down regulates NMDA activity. Take early in the day.
Magnesium. This mineral lowers NMDA activity, reducing excitotoxicity. Dr. Pall believes that “magnesium is one of the most promising agents for treatment of multisystem diseases, but, like other such agents, it produces modest responses and may best be used in a complex, combination therapy.”
Selenium. Selenium is considered an antioxidant because certain proteins that contain selenium have antioxidant properties. Selenium occurs in glutathione peroxidases, enzymes that eliminate peroxide in cells. Selenium is also essential in making T3, the most active form of thyroid hormone. The best form of selenium is selenomethionine, which is a selenium-grown yeast. (For those who are yeast-sensitive, there are non-yeast forms.)
Carotenoids. These are plant pigments which are quite active in scavenging free radicals. Lycopene is more active than beta-carotene as a peroxynitrite scavenger. Lutein and zeaxanthin, two carotenoids, may also have special roles as antioxidants because of the way they insert into biological membranes.
Flavonoids. Anthocyanidins, which are found in purple plants, lower inflammatory activity, act as potent chain-breaking antioxidants, and regenerate other chain-breaking antioxidants after they have been converted to free radicals. Flavonoids also act as chelators for free iron, protecting cells from oxidative damage. Many flavonoids are soluble in both water and lipids. Flavonoids from green tea, citrus, grape seed extract, gingko, soy, olive, hawthorn, blueberry, and purple rice are effective antioxidants. Silymarin scavenges peroxynitrite, and increases the synthesis of SOD (superoxide dismutase), which makes it especially important. Flavonoids are rapidly absorbed in foods, and are quickly excreted through the kidneys, so they need to be eaten (or taken) throughout the day.
Acetyl-L-carnitine. Carnitine transports fatty acids into mitochondria, and is therefore essential for providing cellular energy. Acetyl-L-carnitine is more effective than L-carnitine because most oral L-carnitine ends up being excreted by the kidneys before it can be transported through the blood-brain barrier. Acetyl-L-carnitine is transported more efficiently. Recently, it has been shown that acetyl-L-carnitine lowers excessive NMDA activity and this may well be more important than the effects on mitochondrial function for lowering the NO/ONOO– cycle.
Reductive Stress Agents. Reductive stress causes oxidative stress. Methyl groups – SAMe, betaine, and carnitine – act as protective agents. Dr. Pall’s preference for a methylated compound is betaine (TMG.) It is cheaper and more stable than SAMe.
Hydroxocobalamin form of B12. B12 is a potent nitric oxide scavenger, but it is difficult to absorb. Oral absorption of B12 is limited by intrinsic factor. [Independent of intrinsic factor, the absorption rate of B12 is less than 1% of the total amount ingested.] Hydroxocobalamin taken as a nasal spray or injection is more effective.
Folate (folic acid). Reduced folate decreases uncoupling of NOS activity. Reduced folate in the form of 5-methyltetrahydrofolate (5-MTHF) is a potent scavenger of peroxynitrite and may well turn out to be among the most useful agents for lowering the NO/ONOO– cycle. Optimal dosage may well vary among different individuals but, in general, it should be taken along with quite a bit of vitamin C (at least 500 mg and preferably perhaps twice this amount). The reaction between peroxynitrite and 5-MTHF is important not only because it can be used to lower peroxynitrite levels. It is also important because in NO/ONOO– diseases, elevated peroxynitrite will act to lower the levels of 5-MTHF, lowering methylation cycle activity, and will also act to lower all reduced folates in the body. In this way, lowered methylation activity may be caused by the NO/ONOO– cycle.
B6, as P5P. B6 minimizes neurotoxicity. The best form is pyridoxine phosphate (P5P).
Riboflavin. Riboflavin is important for the production of reduced glutathione. It is also useful in the treatment of migraine.
Alpha Lipoic Acid (ALA) scavenges free radicals. As an added benefit, it can regenerate other antioxidants by reducing oxidized and free radical forms of glutathione, tocopherols, vitamin C and flavonoids. It can maintain glutathione pools by turning oxidized glutathione into its active form, reduced glutathione. ALA can cross the blood-brain barrier, making it an effective tool for reducing damage due to oxidative stress in the brain.
Zinc, Manganese and Copper. These minerals are components of superoxide dismutases (SOD), the enzymes that convert the oxidant superoxide into hydrogen peroxide and oxygen. Zinc, copper and manganese deficiencies can produce oxidative stress, part of which may be due to the lowered ability to produce SODs. Doses of these metals can be tricky. Excessive levels of copper and manganese can themselves produce oxidative stress. Excessive zinc lowers copper levels. Dr. Pall suggests “modest levels.”
Taurine is an unusual amino acid, because it is an antioxidant as well as a neurotransmitter. Taurine acts to stimulate the synthesis of GABA, and is transported easily across the blood-brain barrier, allowing it to work in the brain. Taurine stimulates several inhibitory receptors, leading to lowered NMDA activity. It also acts to lower intracellular calcium levels, thus lowering NO synthesis.
Long-chain omega-3 fatty acids. Polyunsaturated fatty acids (PUFAs) are more susceptible to lipid peroxidation than are other fatty acids, and consequently they tend to be depleted whenever there is oxidative stress. Fish oil, borage oil and flaxseed oil are sources of long-chain omega-3 fatty acids.
Curcumin, honokiol (from magnolia), cat’s claw, vinpocetine and feverfew all reduce inflammation by lowering NF-kappaB activity, as do a number of conventional pharmaceuticals.
Vitamin E should not be taken as synthetic alpha-tocopherol, which is the most commonly taken form, Pall argues. Rather, it should be taken as relatively high doses of gamma-tocopherol and tocotrienols with modest amounts of natural alpha-tocopherol. These other forms of vitamin E have important functions, such as lowering inflammation, scavenging an important breakdown product of peroxynitrite, lowering excessive NMDA activity and improving mitochondrial function, all important for lowering NO/ONOO– cycle diseases.
Algal supplements. Both chlorella and blue-green algae are rich in antioxidants. Blue-green algae contain phycocyanin, which is a potent free radical scavenger.