phosphate acts as a histamine2 agonist (H2) when compounded and maintained
in a specific pH, protected from hydrolysis and oxidation. H2 is a
potent neurotransmitter and neuromodulator in the central nervous
system (Nowak, 1994). H2 receptor sites are located in the central
nervous system (CNS), the hepatic oxidase system, peripheral lymphocytes,
and the parietal cells in the intestinal lining (Baer & Williams,
Research shows that MS patients have an impaired histamine metabolism
that results in the inadequate production of the H2 agonist (Tuomisto
et al, 1983). This results in deficient H2 receptor stimulation
throughout the CNS, the hepatic system, the immune system, the gastric/digestive
system, and the endocrine system. Deficient H2 receptor stimulation
in the CNS results in atrophy of the pineal gland. Atrophy and calcification
of the pineal gland has been found in MS patients studied during
an exacerbation or chronic progression of the disease (Sandyk &
Awerbuch, 1991). The pineal gland produces melatonin and cyclic
AMP. Melatonin is essential in fatty acid metabolism. The pineal
gland is the only region of the brain capable of metabolizing polyunsaturated
fatty acids via lipoxygenation, which does not produce toxic lipid
peroxides. All other regions of the brain are only capable of metabolizing
polyunsaturated fats by lipid peroxidation, which is toxic to the
myelin and nerve cell membranes (Kim et al, 1999; Sawazaki et al,
1994). Furthermore, the metabolism of histamine in the brain is
inhibited by lipid peroxidation up to 60% (Rafalowska & Walajtys-Rode,
1991). Research shows that MS patients have a high level of polyunsaturated
fatty acids in the CNS and depleted levels of antioxidants (Syburra
& Passi, PubMed). The reactive oxidative stress from the lipid
peroxidation depletes the antioxidants and contributes to the myelin
destruction. The myelin and nerve cell membranes are very vulnerable
to the cytotoxic effects of lipid peroxidation (Smith et al, 1999;
Mazierre et al, 1999; Berry et al, 1991; de Kok et al, 1994; Fang
et al, 1996; Fernstrom 1999). This increased oxidative stress and
depletion of antioxidants may account for the high incidence of
hypercholesteremia in MS patients (Sandyk & Awerbuch, 1994).
The body will increase the production of cholesterol with stress
and inadequate levels of antioxidants, because cholesterol can act
as an antioxidant for the body.
Melatonin is also involved in the circadian rhythm. Melatonin
regulates the activity of serotonin neurons in the brainstem. Inhibition
of melatonin results in the cease firing of the serotonergic neurons
during REM (rapid eye movement) sleep which results in sleep atonia
associated with REM sleep. MS patients experience cataplexy, which
is physiologically and pharmacologically similar to sleep atonia
during REM sleep (Sandyk, 1995). Sleep disturbance is a common symptom
in MS patients and research shows that MS patients often fail to
go into the REM stage of sleep. Low levels of melatonin result in
an inadequate swing from a high level to a low level of melatonin,
which is necessary for the initiation of REM sleep (Sandyk, 1995).
Melatonin is also necessary for the absorption of zinc from the
intestinal tract. A research study by Palm & Hallmans (1982)
found that MS patients had lower serum zinc levels compared to age
and sex matched controls. Low levels of zinc debilitate the CuZn
superoxide dimutase enzyme and this results in the increase in production
of lipid peroxides (Johnson, 2000). Furthermore, the demyelinated
pathological areas in the CNS of MS patients showed a decreased
zinc level (Yasui et al, October 1991). A study by Smith et al (1989,
July) showed that there is altered copper and zinc homeostasis in
MS patients. The RBC copper concentration was significantly lower
in MS patients after receiving steroid therapy. This copper deficiency
may correlate with the high levels of cortisol noted with the hyperactivity
of the HPA axis in MS patients that increases with disease progression
(Then Bergh et al, September 1999; Michelson et al, September 1994).
Exogenous histamine greatly increases endogenous cyclic AMP production
and moderately increases melatonin secretion. The CNS has H2 receptors
that when stimulated increase cyclic AMP production as evidenced
by the Nowak and Sek (1994) study that showed histamine to be a
powerful stimulator of cyclic AMP production in the chick pineal
gland. Cyclic AMP is produced throughout the CNS as well as by the
pineal gland. Cyclic AMP stimulates the synthesis of myelin components
by oligodendrocytes and Schwann cells (Anderson & Miskimins,
1994; Lyons, Morell, & McCarthy, 1994). The sclerotic lesions
of the myelin sheath are found exclusively in the CNS in MS patients
and not in the peripheral nervous system (PNS). This phenomenon
may be explained by the fact that studies have shown that oligodendrocytes,
the myelin producing cells of the CNS, will undergo self-induced
degeneration in the absence of cyclic AMP. These degenerating cells
will again become viable myelin producing cells if treated with
cyclic AMP. These same studies show that the Schwann cells, the
myelin producing cells of the PNS, do not undergo self-degeneration
in the absence of cyclic AMP, but rather become dormant (Nowak &
Sek, 1994). This self-induced degeneration of the oligodendrocytes
may explain the presence of macrophages around the myelin lesion
sites. (Macrophages are summoned to the site of tissue destruction
to clean up the debris.)
Cyclic AMP is involved in the function of all cells not just the
myelin producing cells. It is the second messenger for cells, carrying
the message from the first messenger receptors located on the surface
of the cell membrane to the mitochondria, mRNA, and mDNA (Cecil
Textbook of Medicine, 2000). Research shows that a deficiency in
cyclic AMP results in a desensitization of the first messenger receptors
being, steroid hormone receptors, vitamin D receptors, and peptide
hormone receptors (Waki et al, 2001). Research shows that these
cell surface receptors are important in modulating and execution
of cell death particularly in the nervous system (Deigner et al,
2000). Thus, a deficiency of cyclic AMP may potentially hinder the
ability of these cell surface receptors in modulating apoptosis.
The desensitization of the surface cell receptors due to a deficiency
of cyclic AMP may also explain why increases in the progesterone
level such as in pregnancy and exogenous glucocoriticoids have shown
benefit in lessening symptoms of MS.
The effect of H2 to stimulate the increase in the production of
cyclic AMP is enhanced by the presence of a phosphodiesterase inhibitor
(Nowak & Sek, 1994). Methylxanthine agents, such as theophylline,
theophylline derivatives, and caffeine inhibit phosphodiesterase,
the enzyme that breaks down cyclic AMP. Caffeine is the medication
of choice because it has a longer half-life, less untoward side
effects, and a wider therapeutic index (Baer & Williams, 1992).
Cyclic AMP is also produced from ATP with the catalyst adenylate
cyclase (Wescott et al, 1979; Wyngaarden et al, 1992). Perhaps an
abnormally low level of cyclic AMP in MS patients secondary to the
lack of H2 receptor stimulation results in the energy molecule,
ATP, to be catabolized to produce cyclic AMP resulting in the disabling
fatigue associated with MS. As mentioned previously, fatigue accounts
for 65% of the disability in MS patients.
Histamine is involved in the Na+ - K+ pump and action potential
for nerve conduction. Histamine can directly stimulate the activity
of the Na+ - K+ pump that changes the axon membrane ion gradient
resulting in nerve impulse conduction. Histamine increases the amplitude
of the action potential (Yang et al, 1993). The histamine at the
postsynaptic cleft enters the neuronal reuptake system to be retransported
into storage vesicles or deaminated (Cecil Textbook of Medicine,
2000). This may explain why it is common that MS patients can perform
an activity for a few repetitions and then cant, but then
after a brief period of rest, they can perform the activity again.
Histamine via the H2 receptors modulates many other neurotransmitters
such as serotonin and dopamine (Nowak, 1994). H2 either alone or
in combination with serotonin and cyclic AMP maintains the integrity
of the blood-brain-barrier (Sharma et al, 1992). Interestingly,
recent research has revealed that the integrity of the blood-brain-barrier
is impaired in MS patients (Huber et al, 2001).
Histamine is a major heat and stress regulator for the body. H2
receptors are desensitized with an increase in the core body temperature
(Fernandez et al, 1994). Normally this desensitization of the H2
receptors with heat stress stimulates increased production of the
H2 agonist. The resultant increase in the level of H2 stimulates
the pineal gland to secrete melatonin, which causes the body to
sweat and lower the core temperature. The increased H2 receptor
stimulation also dilates the small diameter peripheral arteries,
thus allowing a person to perspire (Fernandez et al, 1994). H2 receptor
stimulation increases the brain water content that in turn cools
the brain during heat stress and prevents dehydration of the brain
(Sharma et al, 1991). Thus, the deficiency of H2 receptor stimulation
in MS explains why heat is a classic stressor shown to worsen symptoms
and why it is very common that MS patients have decreased sweating
as the disease progresses. Also decreased H2 receptor stimulation
results in constriction of the small diameter peripheral arteries,
which may explain the cause of the cold hands and feet in MS patients,
the peripheral non-pitting edema, poor skin color, and dry skin.
The small diameter arterial constriction may also explain the common
occurrence of optic neuritis possibly caused by ischemia-induced
inflammation and swelling around the optic nerve.
Histamine via the H2 receptors also modulates stress. The production
of histamine is increased with stress (Ghi et al, 1992). Histamine
stimulates the increase of serum corticosterone levels, especially
adrenocorticotropin hormone (ACTH) following mild stress (Ghi et
al, 1992). The increase in cortisol increases the activity of enzyme;
MAO-A 1.5-2.5 fold by progesterone, hydrocortisone, and dexamethasone
(Youdim et al, 1989) but this increase is time-dependent as shown
in the study by (Edelstein & Breakefield, 1986). MAO-A is involved
in the metabolic pathway of histamine in the neurons (Ganong, 1973).
Perhaps there is a correlation between these findings and the fact
that episodes of relapses in MS patients is often precipitated by
stress, such as pregnancy, infection, emotional stress, or physical
injury (Ozuna, 1992). This may also explain why steroid IV treatments
have shown some immediate relief in symptoms associated with acute
exacerbations of MS, but this beneficial effect doesnt last
or necessarily reduce the long term neurological deficits of MS
(Ozuna, 1992; Kelley & Smeltzer, 1994). Stress stimulates the
endogenous inhibition of MAO-A and inhibition of MAO-A stimulates
the activity of the hypothalamus-pituitary-adrenal (HPA) axis, which
results in increased cortisol (Clow et al, 2000). The cortisol then
increases activity of the MAO-A (Youdim et al, 1989). The increased
activity of the MAO-A then decreases the stimulation of the (HPA)
axis and balance is achieved. In MS this regulation of the HPA axis
is impaired resulting in hyperactivity of the HPA axis (Michelson
et al, 1994 September) explaining the high level of cortisol in
MS patients. Possibly the inhibition of the MAO-A is too great due
to the presence of other factors that inhibit the MAO-A such as
lipid peroxidation, low copper levels, high estrogen levels, and
stress causing the stimulatory effect of increased cortisol on the
MAO-A activity to be inadequate to overcome the inhibitory effect
of all the other factors present on the MAO-A activity. The hyperactivity
of the HPA axis noted in MS contradicts an inflammatory or autoimmune
mediated etiology for MS. This was demonstrated in the LEW/N rat
model, where a decreased HPA axis response to inflammatory and immune
mediators resulted in the development of experimental allergic encephalomyelitis
(the animal model of MS) (Michelson et al, 1994 September).
H2 receptor regulation maintains the balance of the Th1 and Th2
of the immune cytokines, thus it is integral in the regulation of
the immune system particularly in the regulation of the T and B
cells (Gillson et al, 2000). Beta-adrenergic receptor density on
lymphocytes is inversely proportionate to the availability of histamine.
Studies show that an increase in histamine results in a decrease
in the density of beta-adrenergic receptors on lymphocytes (Galant
& Britt, 1984; Mita, Yui, & Shida, 1983). The significance
of these findings to MS is that beta-adrenergic receptor density
is two to three times greater that normal values in patients with
progressive MS or in an exacerbation. The beta-adrenergic receptor
density was within normal values in MS patients who were in remission
(Karaszewski et al, 1990; Zoukos et al, 1992). Yarosh & Kanevskaya
(1992) also established a high level of blood histamine in those
MS patients whose disease length was less than five years, and a
low level of blood histamine in those whose disease length was greater
than five years. Curiously, in the majority of MS cases the onset
of the disease is characterized by attacks and remissions during
the first five to ten years. Generally after ten to twenty years,
some degree of chronic disability is present (Bjork, 1978). Furthermore,
a study by Dziuba, Frolov, & Peresadin (1993) indicated that
during an exacerbation of MS, patients had marked T-lymphopenia.
This contradicts the autoimmune theory that the T-cells are attacking
the myelin, which is as yet not a proven hypothesis (National Multiple
Sclerosis Society website, 2002).
H2 receptor sites are also located in the hepatic oxidase system
and the parietal cells of the gastric mucosa. Histamine at the H2
receptors in the gastric system stimulates the secretion of hydrochloric
acid and intrinsic factor. Thus, the stimulation of the H2 receptors
is necessary for the absorption of vitamin B12 from the intestinal
tract (Baer & Williams, 1992). Numerous studies cited that macrocytosis
is common in patients with MS (Crellin, Bottiglieri, & Reynolds,
1990; Reynolds et al, 1992; Goodkin et al, 1994). The binding of
histamine to H2 receptors in the intestinal lining also stimulates
the secretion of gastrin and pepsin (Baer & Williams, 1992).
Thus, H2 is directly involved with the digestion of protein, fats,
and carbohydrates. A study by Gupta et al (1977) revealed microscopic
fat in 41.6 % of MS patients whose stools had been randomly screened
using Sudan III stain. Also, 40.9% of the MS subjects showed undigested
meat fibers in the stools. This study also identified the presence
of a measles viral antigen in the nuclei of the epithelial cells
in all of the jejunal biopsies performed in 40 MS patients. These
findings by Gupta et al (1977) were supported by Yarosh & Kanevskaya
(1992) study in which histological abnormalities were identified
in all the gastric mucosa biopsies of 32 MS patients.
Histamine via the H2 receptor stimulation is involved in numerous
cellular functions such as:
- The production and maintenance of the myelin.
- Nerve impulse conduction.
- Thermal regulation.
- Stress modulation.
- Cyclic AMP production.
- Immune system regulation.
- Hepatic oxidase system.
- Gastric acid and digestive enzyme production.
- Fatty acid metabolism.
- Small diameter artery vasodilatation.
- Maintenance of the integrity of the blood-brain-barrier
The symptoms associated with MS are manifested as a result of impairment
in these cellular functions. These facts and findings are the scientific
rationale for the use of Prokarin as an off-label
prescription medication in MS. The results of the double blind study
of the effect of Prokarin on fatigue in MS patients published
in the Multiple Sclerosis Journal Volume 8, Issue 1 supports this
Possible risk Factors That May Contribute to the Development of
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- High polyunsaturated fat intake
- High estrogen levels
- Inadequate copper and zinc
- Viral infections
- Female gender
- Presence of these risk factors during adolescence
- Decreased melatonin production due to decreased direct sunlight
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