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 can’t, 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 doesn’t 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.

Summary

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 scientific rationale.

Possible risk Factors That May Contribute to the Development of the Disease in an Individual Based on the Scientific Literature Review

• Lipid peroxidation
• High carbohydrate intake
• High polyunsaturated fat intake
• High estrogen levels
• Inadequate copper and zinc
• Viral infections
• Stress
• Toxins
• Caucasian
• Female gender
• Presence of these risk factors during adolescence
• Decreased melatonin production due to decreased direct sunlight exposure
  

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