Nitric Oxide Cycle & Therapy

[Guest guest]

Sources:

http://molecular.biosciences.wsu.edu/faculty/pall/pall_main.htm

http://www.haworthpress.com/store/find.asp

L. Pall, Professor of Biochemistry and Basic Medical

Sciences;

Washington State University

martin_pall@...

In his new book: *Explaining " Unexplained Illnesses " : Disease

Paradigm for Chronic Fatigue Syndrome, Multiple Chemical

Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf

War Syndrome and Others, Haworth Medical Press*, Prof.

L. Pall mentions a list of agents predicted to

down-regulate NO/ONOO cycle biochemistry

~jvr

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Therapy

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The fifth principle of the NO/ONOO- cycle is that therapy should

focus on down-regulating NO/ONOO- cycle biochemistry. In

other words, lower the cause of illness. Let me state at the outset

that I am a Ph.D., not an M.D. and nothing here should be

viewed as medical advice.

There are several challenges to therapies aimed at lowering

NO/ONOO- cycle biochemistry.

* The first of these is that we need to stop doing things that

up-regulate this biochemistry and there are various stressors

that up-regulate this biochemistry therefore are of obvious

concern.

* The second is that the complexity of the NO/ONOO- cycle

makes it difficult to down-regulate and makes it likely that we will

need to use multiple agents in order to be effective in such

down-regulation. We don't have a magic bullet to treat these

illnesses and may have to rely, therefore, on complex

combinations of agents each of which may produce an

incremental improvement by lowering aspects of the cycle

mechanism.

* The third is that peroxynitrite, the most central element in the

NO/ONOO- cycle is difficult to effectively scavenge in vivo and

therefore approaches based solely on scavenging peroxynitrite

may not be expected to be effective.

Let's consider the first of these challenges. Such stressors as

chemical exposure in MCS, excessive exercise in CFS and

psychological stress, especially in PTSD, should be avoided to

have any expectation of effective therapy. Each of these

stressors are expected to up-regulated NO/ONOO- cycle activity

in these individual illnesses. Foods to which individuals have

developed food allergies should be avoided, as antibody-

antigen reactions cause tissues to increase nitric oxide

synthesis. Excitotoxins can stimulate NMDA activity and

up-regulate NO/ONOO- cycle biochemistry and should therefore

be avoided. Excitoxins include monosodium glutamate,

aspartame and possibly certain other flavorings such as

hydrolyzed vegetable proteins.

In Chapter 15 of my book, I consider 30 different agents or

classes of agents that are available today and are predicted to

down-regulate NO/ONOO- cycle biochemistry and are predicted,

therefore, to be potentially useful therapeutic agents. I will add a

31 st such agent that was suggested to me by Dr.

Teitelbaum. Each of these are listed in the long table that

follows.

Table 3 Agents Predicted to Down-Regulate NO/ONOO Cycle

Biochemistry

Agent (or class) Mechanism(s) Evidence

Tocopherols/

tocotrienols

Chain breaking antioxidants. Gamma-tocopherol may have

special role in peroxynitrite scavenging and tocotrienols are

reported to have special roles in protecting from excitoxicity

Ascorbate

Chain breaking antioxidant; may also scavenge peroxynitrite;

helps to regenerate other antixoxidants

CT

Coenzyme Q10

Stimulates mitochondrial function, scavenges peroxynitrite,

lowers NMDA activity

CT

selenium

Antioxidant properties, selenium compounds are peroxynitrite

scavengers, replete deficiencies

carotenoids

Scavenge peroxynitrite in membranes

flavonoids

Complex group of phenolic antioxidants with multiple and

variable functions; chain breaking antioxidants, lower NF- kB

activity, scavenge peroxynitrite, superoxide and nitric oxide,

allow regeneration of other antioxidants

CT

TMG, choline, SAMe, others

Compounds with methyl groups attached to positively charged

nitrogens or sulfurs act to relieve reductive stress

CT

Carnitine/ acetyl carnitine

Improved transport of fatty acids into mitochondrion for energy

metabolism and regeneration of mitochondrial inner membrane;

others?

CT

phospholipids

May allow regeneration of oxidized mitochondrial inner

membrane lipids; phosphatidyl choline may act to lower

reductive stress

CT?

Hydroxocobalamin (B 12)

Potent nitric oxide scavenger; limited uptake when taken orally;

other forms of B 12 may act as precursor but with probable

lower efficacy.

CT

Vitamin B 6; pyridoxal phosphate

Lowers excitoxicity by improving balance between glutamate

and GABA

CO/A

Riboflavin and also 5'-phosphate

May increase glutathione reductase activity and thus increase

reduction of oxidized glutathione

Other B vitamins

Improve energy metabolism, replete deficiencies

Reduced glutathione and precursors

Reduced glutathione not effective taken orally; precursors

should probably be limited in dosage used. Most important

antioxidant synthesized in body, many functions.

CO/A

a-lipoic acid

Helps restore reduced glutathione, antioxidant activity,

regenerate other antioxidants, lowers NF- kB activity ; quality of

supplements seems to be quite variable

Mg 2+

Magnesium acts to lower NMDA activity, improve energy

metabolism, replete deficiencies

CT

Zn 2+, Mn 2+, Cu 2+

Precursors of superoxide dismutases, antioxidant activity,

replete deficiencies; doses should be modest

riluzole

Lowers glutamate release, excitoxicity

taurine

Lowers excitoxicity, NF- kB activity, iNOS induction, Ca 2+

NMDA antagonists; gabapentin

Lower excessive NMDA activity, lower response to chemical

exposure in MCS

CT

Inosine

Increases uric acid pools which scavenges, in turn, peroxynitrite

breakdown products; may also act to speed recovery of ATP

pools; possible down-side may include increased mast cell

activity

Long chain omega-3 fatty acids

Lower iNOS induction, lower NF- kB activity, replete

deficiencies

CT

Agents that lower NF- kB activity

Lower NF- kB activity

CO/A?

Curcumin

Similar of flavonoids in actions

Algal supplements

Rich in antioxidants

CT

Hyperbaric O 2 treatment

May act via hydrogen peroxide to induce synthesis of

tetrahydrobiopterin and therefore decrease NOS uncoupling

CT

Minocycline/ tetracyclines

Lowers iNOS induction, NMDA activity

creatine

Lowers excitotoxicity

Lowers vanilloid activity, Panax ginseng? Guaifenesin?

Expected to lower vanilloid activity

CO/A?

carnosine

Reported peroxynitrite scavenger, unusual antioxidant

TRH

Lowers NMDA activity

D-ribose

Increases recovery of ATP pools after energy metabolism

dysfunction; may increase reduction of oxidized glutathione

CO/A

Evidence is listed as being clinical trial evidence (CT) or clinical

observations/anecdotal evidence (CO/A) or none, based solely

on studies of CFS, MCS, FM or closely related illnesses.

It can be seen from Table 3 that there are many different agents

that are promising candidates for therapy. Most of them are

nutritional supplements. There is some evidence for efficacy of

individual agents based on clinical trials (CT) or from clinical

observations and/or anecdotal evidence (CO/A) but in most

cases, the individual agents where they seem to be effective,

have relatively modest effectiveness. The suggestion is that

combinations of these agents may be much more effective than

individual agents. This combination therapy has been the

approach taken by five different physicians in developing their

treatment protocols and such combination therapy approaches

appear to be the most promising of all therapeutic approaches

for treatment of these illnesses.

Five physicians have developed complex treatment protocols for

these multisystem illnesses. Three of these have focused on the

treatment of chronic fatigue syndrome or closely related fatiguing

illness, one on both chronic fatigue syndrome and fibromyalgia

and one on chemically sensitive patients. Each of these

protocols uses from 14 to 18 different agents or classes of

agents that are predicted to down-regulate NO/ONOO- cycle

biochemistry! While two of these protocols (Teitelbaum's and

Cheney's) contain substantial numbers of agents not obviously

related to the NO/ONOO- cycle, each contains many agents

predicted to down-regulate the cycle. The treatment protocols

are outlined in the lists that follow:

Dr. Cheney has developed his treatment protocol based on

clinical observations and has honed it over the past two

decades of treatment of chronic fatigue syndrome patients. He

advises trying to avoid things that exacerbate the NO/ONOO-

cycle mechanism, some of the same things that I discussed

above. Specifically he suggests attenuating GI tract problems by

such strategies as going on a low food allergen diet, minimizing

environmental chemical exposure and also minimizing

inflammatory diseases, such as around the teeth. The agents

that I list are followed, in some cases, by comments on how they

may act-those comments are mine, not Cheney's.

* High dose hydroxocobalamin (B12) injections- potent nitric

oxide scavenger

* Whey protein-glutathione precursor

* Guaifenesin-vanilloid antagonist?

* NMDA blockers

* Magnesium-lowers NMDA activity

* Taurine-antioxidant and acts to lower excitotoxicity including

NMDA activity

* GABA agonists-GABA acts as an inhibitory neurotransmitter

to lower NMDA activity-these include the drug neurontin

(gabapentin)

* Histamine blockers-mast cells which release histamine are

activated by both nitric oxide and vanilloid stimulation

(Chapter 7) and may therefore be part of the cycle mechanism

* Betaine hydrochloride (HCl)-Betaine lowers reductive

stress, the hydrochloride form should only be used in those

with low stomach acid. Betaine (trimethylglycine) is also listed

separately in the protocol description

Antioxidants listed as follows:

* Flavonoids, including " bioflavonoids, " olive leaf extract,

organic botanicals, hawthorn extract

* Vitamin E (forms not listed)

* Coenzyme Q10-acts both as antioxidant and to stimulate

mitochondrial function

* a-lipoic acid

* Selenium

* Omega-3 and –6 fatty acids

* Melatonin-as an antioxidant that may act in the brain

* Pyridoxal phosphate-improves glutamate/GABA ratio

* Folic acid-lowers uncoupling of nitric oxide synthases

Cheney prescribes for his patients a total of 18 distinct agents or

classes of agents, each of which can be viewed as

down-regulating aspects of the NO/ONOO- cycle. I would argue

that this in not just coincidental, that it argues in support of the

NO/ONOO- cycle mechanism.

Dr. Teitelbaum has published placebo-controlled trial

data supporting the efficacy of one version of his protocol

(29,30), something none of these other physicians has done. It

seems to be effective on both chronic fatigue syndrome and

fibromyalgia patients. I am going to describe a recent version of

his complex protocol, focusing on what may be the central parts

of the protocol, the parts described as " nutritional treatments "

and " mitochondrial energy treatments. " The last agent in the list,

D-ribose, was added to the protocol recently (personal

communication).

* Daily energy B-complex-B vitamins including high dose B 6,

riboflavin, thiamine, niacin and also folic acid. These fall into

four categories that I have listed earlier in the chapter

* Betaine hydrochloride (HCl)-lowers reductive stress,

hydrochloride form should only be taken by those deficient in

stomach acid

* Magnesium as magnesium glycinate and magnesium

malate-lowers NMDA activity-often uses magnesium

injections

* a-Lipoic acid-important antioxidant helps regenerate

reduced glutathione

* Vitamin B 12 IM injections, 3 mg injections (does not state

whether this is hydroxocobalamin)-may act as potent nitric

oxide scavenger

* Eskimo fish oil-excellent source of long chain omega-3 fatty

acids. Lowers iNOS induction, anti-inflammatory

* Vitamin C

* Grape seed extract (flavonoid)

* Vitamin E, natural-does not state whether this includes

g-tocopherol or tocotrienols

* Physician's protein formula, used as glutathione precursor

* Zinc-antioxidant properties and copper/zinc superoxide

dysmutase precursor

* Acetyl-L-carnitine-important for restoring mitochondrial

function

* Coenzyme Q10-both important antioxidant properties and

stimulates mitochondrial function

* D-ribose-acts to increase rate of ATP and reduced

glutathione regeneration

If you consider that the oral B vitamins fall into four categories

listed earlier in the chapter, Teitelbaum uses a total of 18 agents

or classes of agents that are predicted to down-regulate the

NO/ONOO- cycle, in the core part of his treatment protocol.

Dr. Garth Nicolson started his scientific career developing the

famous Singer/Nicolson, fluid mosaic model of biological

membranes, a model that is described in essentially all of the

standard biochemistry textbooks. He and his colleagues have

published on open label trials of a complex proprietary mixture

known as NT factor TM, apparently designed to improve

mitochondrial and thus energy metabolism function. The trials

have been on a group of older patients with unexplained chronic

fatigue, and consequently there is some question whether these

patients have CFS. Nevertheless, Nicolson and coworkers

(31-33) report statistically significant improvements in fatigue

and in several other changes often found in multisystem disease

patients, affective/meaning, sensory and cognitive/mood. Many

of the NT factor components are predicted to lower much of the

NO/ONOO- cycle biochemistry. Unfortunately, there is no

detailed description of the concentrations of the components of

the NT factor proprietary mixture. The mixture contains the

following components that are predicted to lower NO/ONOO-

cycle biochemistry:

* Polyunsaturated phosphatidyl choline-predicted to lower

reductive stress

* Other phosphatidyl polyunsaturated lipids-this and the

phosphatidyl choline are predicted to help restore the

oxidatively damaged mitochondrial inner membrane

* Magnesium-lowers NMDA activity, may aid in energy

metabolism

* Taurine-antioxidant activity and lowers excitoxicity including

NMDA activity

* Artichoke extract-as flavonoid source?

* Spirulina-blue-green alga is a highly concentrated

antioxidant source

* Natural vitamin E-does not tell us whether this includes g

-tocopherol or tocotrienols

* Calcium ascorbate-vitamin C

* a -Lipoic acid-important antioxidant, key role in regeneration

of reduced glutathione, but also has role in energy metabolism

* Vitamin B 6-balance glutamate and GABA levels, lowers

excitotoxicity

* Niacin-role in energy metabolism

* Riboflavin-important in reduction of oxidized glutathione back

to reduced glutathione; also has important role in mitochondrial

function

* Thiamin-role in energy metabolism

* Vitamin B 12-as nitric oxide scavenger?

* Folic acid-lowers nitric oxide synthase uncoupling

The way I have categorized these earlier on this site and in

Chapter 15 of my book, these agents fall into 15 distinct classes

of agents expected to lower NO/ONOO- cycle biochemistry.

Dr. Neboysa (Nash) Petrovic is a South African physician who, I

believe, also has a clinic in England. His CFS treatment protocol

(34) has been described as follows (I am unsure how current this

is):

* Valine and isoleucine-branched chain amino acids known to

be involved in energy metabolism in mitochondria, and may be

expected,therefore, to stimulate energy metabolism; modest

levels may also lower excitotoxicity

* Pyridoxine (B 6)-improves balance between glutamate and

* GABA, lowers excitotoxicity

* Vitamin B 12 in the form of cyanocobalamin-cyanocobalamin

is converted to hydroxocobalamin in the human body but the

latter form will be more active as a nitric oxide scavenger,

since it does not require such conversion

* Riboflavin-helps reduce oxidized glutathione back to

reduced glutathione

* Carotenoids (alpha-carotene, bixin, zeaxanthin and lutein)-lipid

(fat) soluble peroxynitrite scavengers

* Flavonoids (flavones, rutin, hesperetin and others)

* Ascorbic acid (vitamin C)

* Tocotrienols-forms of vitamin E reported to have special

roles in lowering effects of excitotoxicity

* Thiamine (aneurin)-B vitamin involved in energy metabolism

* Magnesium

* Zinc

* Betaine hydrochloride (HCl)-lowers reductive stress,

hydrochloride form should only be used by those deficient in

stomach acid

* Essential fatty acids including long chain omega-3 fatty acids

* Phosphatidyl serine-reported to lower iNOS induction

(35,36)

According to the way I have listed these agents, his protocol

contains 14 agents or classes of agents predicted to

down-regulate NO/ONOO- cycle biochemistry.