Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells

Glucocorticoids differ from serotonin. The latter suppresses the inflammatory response (T_h1 driven) but augments T_h2. Glucocorticoids suppress either or both responses. Therefore, if you wish to manage an immune condition, the use of PURSOR^TM is far more specific than using the GLU sledgehammer. This is an extremely well-written article and, therefore, deserves a Frank McLynn award.

"Glucocorticoids exert profound and diverse physiological effects on a wide range of cell types. Produced and released from the adrenal cortex in response to stress, levels of glucocorticoids are under the control of the hypothalamic–pituitary–adrenal axis.

Glucocorticoids participate in numerous physiological processes such as glucose homeostasis; protein, lipid, and carbohydrate metabolism; development; neuorobiology; and programmed cell death. Glucocorticoids exert potent immunosuppressive and anti-inflammatory actions in a cell type–specific manner largely through the interruption of cytokine-mediated pathways. These anti-inflammatory actions are also complemented by the ability of glucocorticoids to induce apoptosis in many cells including thymocytes, blood monocytes, and peripheral T cells.

As a class of drugs, glucocorticoids are among the most widely prescribed in the world for the treatment of immune and inflammatory diseases, including asthma, rheumatoid arthritis, ulcerative colitis, and allergic rhinitis. They are also a component of many chemotherapy regimens for the treatment of leukemias, lymphomas, and myelomas because of their role in the induction of apoptosis. However, long-term use of glucocorticoids has been limited by adverse side effects ranging from suppression of the hypothalamic–pituitary axis and growth retardation to osteoporosis, in addition to the development of glucocorticoid resistance. These undesired side effects of glucocorticoids are hypothesized to occur mainly through activation of gene transcription, whereas the beneficial anti-inflammatory effects of glucocorticoids involve mainly mechanisms of gene repression.

Understanding the molecular basis of glucocorticoid-induced side effects requires an understanding of their actions on homeostatic signaling processes in all cell types. In this review, we discuss the basic cellular and molecular signaling mechanisms of glucocorticoid action during noninflammatory and inflammatory situations."

Mechanisms of Glucocorticoid Receptor Action in Noninflammatory and Inflammatory Cells -- Necela and Cidlowski 1 (3): 239 -- Proceedings of the American Thoracic Society:

A cute introduction to the immune system from Vimeo

Does neuroinflammation fan the flame in neurodegenerative diseases and autism?

The following quotation comes from a review article that is being published this month.

"While peripheral immune access to the central nervous system (CNS) is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia) resulting in ... the release of inflammatory mediators such as cytokines and chemokines. Chronic neuroinflammation is a long-standing and often self-perpetuating  response that persists long after an initial injury or insult. ... The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors.

Neurodegenerative CNS disorders discussed are multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS)."(REF/ FULL TEXT)

Researchers are becoming aware that  autism is another neuroinflammatory condition that can be triggered in animal experiments. Terbutaline, a bronchodilator also used to arrest preterm labor, has been associated with the development of human autism. In animal experiments, terbutaline given early, also induce a condition that appears to be like autism. Neuroinflammation, mostly associated with innate immunity, characterized by activation of microglia and astroglia, as well as increased cytokines and chemokines, has recently been documented in post mortem studies of autism brains and in the animal damaged by neuroinflammation.(REF/FULL TEXT)

Another 2009 article that reinforces the suggestion that autism and neurodegenerative diseases are central nervous system autoimmune diseases skewed towards a proinflammatory bias :

Elevated immune response in the brain of autistic patients

This study determined immune activities in the brain of ASD patients and matched normal subjects by examining cytokines in the brain tissue. Our results showed that proinflammatory cytokines (TNF-alpha, IL-6 and GM-CSF), Th1 cytokine (IFN-gamma) and chemokine (IL-8) were significantly increased in the brains of ASD patients compared with the controls. However the Th2 cytokines (IL-4, IL-5 and IL-10) showed no significant difference. The Th1/Th2 ratio was also significantly increased in ASD patients. Conclusion: ASD patients displayed an increased innate and adaptive immune response through the Th1 pathway, suggesting that localized brain inflammation and autoimmune disorder may be involved in the pathogenesis of ASD.

Finally, Paul Ashwood writes this. I would highly recommend you read the full text of his article:

Autism spectrum disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders known as pervasive developmental disorders, which occur in childhood. They are characterized by impairments in social interaction, verbal and nonverbal communication and the presence of restricted and repetitive stereotyped behaviors. At the present time, the etiology of ASD is largely unknown, but genetic, environmental, immunological, and neurological factors are thought to play a role in the development of ASD. Recently, increasing research has focused on the connections between the immune system and the nervous system, including its possible role in the development of ASD. These neuroimmune interactions begin early during embryogenesis and persist throughout an individual's lifetime, with successful neurodevelopment contingent upon a normal balanced immune response. Immune aberrations consistent with a dysregulated immune response, which so far, have been reported in autistic children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2 cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels. In addition, autism has been linked with autoimmunity and an association with immune-based genes including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles described. There is potential that such aberrant immune activity during vulnerable and critical periods of neurodevelopment could participate in the generation of neurological dysfunction characteristic of ASD.

Damage or Disruption?

The PURSOR protocol has been extremely effective in ALS. It may be that irreversible changes occur in the child with autism. However, if the changes are not permanent, neuroinflammation and the autistic behavioral abnormalities may very well be remitted with PURSOR.

Common Pathways of Abused Substances; All Lead to Dopamine

There is an excellent diagram in Nature Neuroscience that shows how the various drugs of abuse share a common pathway, usually starting in the ventral tegmental area and progressing to the dopamine neurons in the nucleus accumbens.

This highly technical article accentuates the point that all substances of abuse increase dopamine, remove pain and promote pleasure. The PURSOR protocol also increases dopamine but rather than increasing it very rapidly, does it relatively slowly, seconds vs. milliseconds. PURSOR relieves the psychic pains of low dopamine but provides no rush of pleasure. It therefore is not addictive.

Lyme Arthritis: Current Concepts and a Change in Paradigm

The ability of B. burgdorferi, the spirochete responsible for Lyme Arthritis, to avoid clearance by the immune system may be attributed in part to an inadequate innate immune response upon infection. However, innate cells such as monocytes, macrophages, and dendritic cells display a vigorous response against borrelial infection and play a major role in the activation of the adaptive immune response against the spirochete. Despite these efforts, though, arthritis still develops in a significant number of patients infected with B. burgdorferi. It appears that the robust response elicited by monocytes, macrophages, and dendritic cells against the spirochete may be viewed as insufficient in early infection but excessive in the later stages. Paradoxically, in mounting such a strong defense against the organism, these cells may inadvertently be contributing to the induction of Lyme arthritis.

Lyme disease is associated with a chronic inflammatory bias with excessive T helper 1 cytokines. This condition has responded to PURSOR therapy in a Rhode Island lady who had not responded to antibiotic treatment at Yale under the care of my medical school classmate Allen Steere who has deservedly earned a reputation in this field.

Lyme Arthritis: Current Concepts and a Change in Paradigm

A Wide Specrum of Maladies are Associated with Immune Imbalance

I have a strong belief that the PURSOR protocol can correct the basic imbalance in both the innate and adaptive immune systems. I have compiled a list of just some of the many conditions whose symptoms and signs are directly associated with this imbalance. You can find at this site a new type of bibliography that I have created at the National Library of Medicine. One can retrieve all the references and then select whether you wish to select all the review articles or those articles with free full texts

Many investigators have postulated that were we to correct this underlying imbalance, commonly referred to as biased Th1/Th2 cytokine dysregulation, the chance of a remission would be likely I offer here two relevant and well-written articles. Moss, R.B. et al (2004) and Lucey, Clerici, & Shearer (1996).

Psychoneuroimmunology and the Renaissance of "Balance is Health; Imbalance is Illness and Pain"

For more than two millennia, the concept that imbalance was basic to most disease processes was accepted in both Eastern and Western medicine.

• The Hippocratic school held that all illness was the result of an imbalance in the body of the four humours, fluids which in health were naturally equal in proportion (pepsis).^[25] When the four humours, blood, black bile, yellow bile and phlegm, were not in balance (dyscrasia, meaning "bad mixture"), a person would become sick and remain that way until the balance was somehow restored. Hippocratic therapy was directed towards restoring this balance. For instance, using citrus was thought to be beneficial when phlegm was overabundant (Wiki),

• Traditional Chinese medicine is largely based on the philosophical concept that the human body is a small universe with a set of complete and sophisticated interconnected systems, and that those systems usually work in balance to maintain the healthy function of the human body(Wiki)

As Western medicine matured, it gained tools such as the microscope, petri dish and many more and just as Linneau at the peak of the enlightenment classified plants,so did other classify the various illnesses. This was all to the good. But as knowledge progressed and amazing leaps in medical therapy  were made, a new medical paradigm was developing.

When I was in high school  in the late '50s, I was an avid reader and regularly reviewed Scientific American. I witnessed in the field of nuclear physics an explosion of particles that were derived from the atom. When the number surpassed 35 I gave up reading any more. Just as Italian politics at that time, when prime minister were coming and going nearly on a weekly basis. Too many prime ministers and too many particles told me even in my adolescence that something was wrong in theoretical physics and in Rome. Murray Gell-Mann and George Zweig introduced the quark and brought some order, Bellasconi still proves that Italy can not govern itself. Western medicine has evolved  Although Descartes supported mind-body duality and saw the body as an automaton run by the brain, he did recognize that the body could influence the brain. Unfortunately, while most physicians pay lip service to Hans Selye's concept of stress, most continue to practice medicine as if the unitary link between mind and body did not exist.

The following are landmarks in the development of psychoneuroimmunology:

Homeostasis (from Greek: ὅμοιος, homoios, "similar"; and ἵστημι, histēmi, "standing still"; defined by Walter Bradford Cannon in 1929 + 1932 is the property of a system, either open or closed, that regulates its internal environment and tends to maintain a stable, constant condition. Typically used to refer to a living organism, the concept came from that of milieu interieur that was created by Claude Bernard and published in 1865 (Wiki)

Hans Selye's inspiration for the general adaptation syndrome (GAS, a theory of stress) came from an endocrinological experiment in which he injected mice with extracts of various organs. He at first believed he had discovered a new hormone, but was proved wrong when every irritating substance he injected produced the same symptoms (swelling of the adrenal cortex, atrophy of the thymus, gastric and duodenal ulcers). This, paired with his observation that people with different diseases exhibit similar symptoms, led to his description of the effects of "noxious agents" as he at first called it. He later coined the term "stress", which has been accepted into the lexicon of various other languages.(Wiki)

In 1964, George F. Solomon, published "Immunity, emotions and stress. With special reference to the mechanisms of stress effects on the immune system" and birthed the field of psychoneuroimmunology. In the next thirty years multiple articles proving that stress, modifying the immune system was directly linked to  illness not only psychologic but also physical. No longer could the various infirmities that plague us exist in their solitary splendor or decay but could be linked into a common structure resulting from an imbalanced immune system. Diseases are not to be classified like plants but are intimately linked with each other.

In the near future, I plan to write a section that shows how diseases are linked by the bias of the cytokines that are associated with them. I will show that the development of T helper cell (Th) imbalances of the subsets Th1 and Th2 reciprocal systems are the not markers for disease but the causative factor.

Finally, I would suggest that you review RB Moss's fine article that reviews the multiple conditions that are associated with imbalances of Th1 and Th2 cells. Moss suggests a couple of methods to restore this imbalance and his approach, especially with DNA  vaccinations, may prove to be invaluable.My contention in this unpublished article that the PURSOR protocol can achieve a similar balance needs to be proven, but if it can, WOW.

Why 5-HTP and the PURSOR Protocol May Improve Parkinson's Disease Rx

Summary

The inevitable progression of Parkinson’s Disease (PD) is unresponsive to treatment. Dopamine (DA) agonists may promote the underlying neurodegenerative process. Combined 5‑hydroxytryoptophan (5-HTP), the immediate precursor of serotonin (5-HT), and levodopa therapy should block DA induced PD progression because DA and 5­­-HT have countervailing actions in the immune system. While DA promotes inflammatory Th1 cytokines, neurotoxicity and neural apoptosis (programmed cell death), 5-HT promotes anti-inflammatory Th2 cytokines, acts as a neuroprotectant, and is antiapoptotic. Combined DA and 5-HT precursor therapy (PURSOR) with levodopa and 5-HTP suspensions titrated by taste, already associated with unprecedented partial remissions in another neurodegenerative disorder, amyotrophic lateral sclerosis, should markedly improve symptomatic Parkinson’s treatment, decrease the incidence of levodopa toxicity, and, by restoring Th1/Th2 balance and putatively decreasing QUIN induced excitatory neurotoxicity, alleviate or even halt the progression of PD.

Seven Reasons:

A.      The buccal mucosal route permits both precursors to pass through the blood-brain barrier directly without first passing through the general circulation. Since this markedly diminishes the decarboxylation of either precursor prior to its entering the CNS, carbidopa is no longer necessary.
B.       Maximum therapeutic levodopa doses to assuage nigrostriatal DA deficiency should now be realized promptly and safely. Prior to the proprietary PURSOR protocol, the responsible clinician, concerned that increasing the levodopa dose could at any time induce severe adverse effects, knowing that the only clinical endpoints were the onset of levodopa toxicity or PD clinical improvement, recognizing there was no procedure to ameliorate levodopa toxicity except the passage of time, increased levodopa dosage slowly and gingerly. One can assume that many a PD patient never achieves maximal levodopa intervention because of this understandable concern. The PURSOR protocol permits one to increase levodopa more acutely since the administration of 5-HTP reverses the toxic symptoms of levodopa excess
C.      The neurotoxicity associated with PD and increased by levodopa administration presumptively can be reversed by the increase of 5-HT, a glutamate antagonist and a neuroprotectant with the ability to diminish excessive QUIN toxicity and cellular apoptosis associated with hyperstimulation.
D.      The PURSOR protocol, by promoting CNS 5-HT levels, should decrease or ablate the Th1>Th2 imbalances associated with autoimmune disorders and suppress or halt the underlying neurodegenerative PD process.
E.       The unprecedented and rapid partial remissions noted by patients with ALS treated with the PURSOR protocol strongly suggests that 5-HT is modulating the EAA-associated neurotoxicity endemic in neurodegenerative disorders.
F.      Approximately 15% of DA treated PD patients develop obsessive/compulsive disorders. The addition of 5-HT to the regimen potentially ablates this as a problem.
G.       PD destroys both dopaminergic and serotoninergic cells. If for no other reason, the joint administration of both 5-HT and DA precursors makes empiric sense.

(Full text) More Formal Presentation

Combined dopamine and serotonin precursor protocol remits addictive craving & immune disorders

Introduction

I have found that the contemporaneous administration of the precursors for dopamine and serotonin has widespread therapeutic applications. Using sequential suspensions of levodopa and 5-HTP when administered according to what I call the PURSOR (patent applied for) protocol, one can remit addictive craving, mood disorders and correct certain immune disorders. If interested, you can review my thoughts on PURSOR and the immune system and my thoughts on why this approach for Parkinson's disease may be most rewarding.

The PURSOR protocol employs a serendipitous finding. Both of these precursors in suspension with flavoring agents are at the onset initially pleasant. Continued administration and each suspension becomes bland to taste and then unpleasant. The loss of pleasant taste appears to correlate with repair of the inherent CNS deficiency. Incidentally, you can also produce this phenomenon at home by mixing a 0.5 tablespoon or so of MSG. (sold as Accent in the USA) with a third of a packet of an artificial sweetener. Dip a wetted finger in the powder and it is sweet. Continue to do so and it becomes salty and not pleasant. Why this happens I do not know.

PURSOR Procedure and Protocol

I leave the exact formulation for PURSOR with the formulating pharmacy in California, but this is the general idea.

• For the 5-HTP admixture one combines powdered 5-HTP with an oil. A simple sugar syrup is added, it has an inherent pleasant taste. Other inert materials suggested by the formulating pharmacist are added. This is placed in a 30cc. bottle
  
• For the levodopa, same thing. Also added is an artificial sweetener and tangerine flavoring, etc. This is placed in a 30 cc. opaque bottle and refrigerated. Levodopa oxidizes readily.
  

Prior to use, each bottle is shaken. 3 drops or so at a time of the 5-HTP suspension is dropped on a spoon and licked off. Back of the hand also works. Usually, this suspension is pleasant at first. Rarely, the first aliquot is mean and nasty. Continue with further aliquots until taste changes to bland. If you continue it becomes unpleasant. Should you ignore this change with either precursor, nausea and vomiting follows. The addition of a bitter substance seems to make the endpoint more noticeable.

After the 5-HTP endpoint is achieved, do the same with the levodopa suspension. The whole sequence takes about 3 minutes Were the patient craving alcohol or cocaine, severely depressed and anxious and suffering from asthma, in a moment all these disorders remit. When craving or the other conditions return, they can be effectively managed by repeating the procedure. 2-3 times a day usually suffices. The response rate for craving alcohol, methamphetamine and cocaine is nearly 100% and nearly the same for affective disorders and immediate hypersensitivity. The preliminary results with opiates is promising.

Some patients find only one suspension pleasant. I have interpreted this to mean that there is no inherent CNS deficit for this particular neurotransmitter. Control patients rarely have found both to be unpleasant from the start.

You urge the patient to swish the suspensions around in the mouth as long as possible. Since they don't spit, they swallow the residual.

Were you to immediately swallow, the respective precursors would be absorbed in the alimentary tract, pass first through the liver and be there decaboxylated to either DA or 5-HT. Absorption through the buccal and lingual mucosa permits the first pass to the brain. No need for a decarboxylase inhibitor such as carbidopa.

Addictive Craving

In 1993, I introduced Dr. Richard Rothman, director of NIDA's Intramural Research Program in Baltimore, to the idea that combined dopamine and serotonin agonists (CODAS) could treat addiction and other disorders. I have gone on and used levodopa and 5-HTP (PURSOR) as the best way to manage same. Richard has gone in another direction. In this recent article, he reviews the rationale behind CODAS and discusses his recent work.

Sample Results

Recently, in a two week period, practitioners in Colorado and Sacramento started PURSOR on seven new patients. All but one of them were craving either alcohol, cocaine or methamphetamine. All but two of them were suffering from anxiety and/or depression. In every case, the patients enjoyed total relief of craving and their mood disorders in minutes. The return of any of their symptoms (craving or dysphoria) signals the need for the next treatment. One patient is enjoying total relief from his chronic rhinitis. He is letting his stuffy nose tell him when he should take the next dose.

• You may wish to review a brief PowerPoint Presentation).
  

• This is the Google site hyperlink.
  

Pietr Hitzig, M.D.
Baltimore, MD
phitz96@gmail.com
Google Site: http://foxyurl.com/7Bh
PowerPoint: http://bit.ly/2UbPrN
443 231-6240

The YIN YANG (DA/5-HT) duality

the Monoamines Dopamine and Serotonin are Antipodal in Nature.

Yin (陰 or 阴 "shady place, north slope, south bank (river); cloudy, overcast"; Japanese: in or on; Korean: 음, Vietnamese: âm) qualities are characterized as soft, slow, substantial, water, cold, conserving, tranquil, gentle, and corresponds to the night.

Yang (陽 or 阳 "sunny place, south slope, north bank (river), sunshine"; Japanese: yō; Korean: 양, Vietnamese: dương) qualities are characterized as hot, fire, restless, hard, dry, excitement, non-substantial, rapidity, and corresponds to the day.

Dopamine is Yang while Serotonin is Yin

DA and 5-HT have been antipodal in their activities for more than a billion years. Here, for example, the prostostomes, who according to Dawkins, went their particular way and parted from us 500M years ago are using the monoamines to decide whether to move or not.

The effect of dopamine on [snail] command neurons is significantly reduced in the presence of serotonin. In the presence of dopamine, the efficacy of serotonin action on the size of the response elicited in command neurons is reduced. Based on the data obtained, it was concluded that the interrelation of dopamine and serotonin concentrations could be the basis for the formation of behavioral choice in snails

Dopamine is the Reward Neurotransmitter

When the cortex has received and processed a sensory stimulus indicating a reward, it sends a signal announcing this reward to a particular part of the midbrain–the ventral tegmental area (VTA)–whose activity then increases. The VTA then releases dopamine not only into the nucleus accumbens, but also into the septum, the amygdala, and the prefrontal cortex.The nucleus accumbens then activates the individual’s motor functions, while the prefrontal cortex focuses his or her attention.
These regions are connected by what is called the pleasure or reward bundle. In neuroanatomical terms, this bundle is part of the medial forebrain bundle (MFB), whose activation leads to the repetition of the gratifying action to strengthen the associated pathways in the brain.
First described by James Olds and Peter Milner in the early 1960s, the MFB is a bundle of axons that originates in the reticular formation, crosses the ventral tegmental area, passes through the lateral hypothalamus, and continues into the nucleus accumbens as well as the amygdala, the septum, and the prefrontal cortex.
The MFB is composed of ascending and descending pathways, including most of the pathways that use monoamines as a neurotransmitter. The mesocorticolimbic dopaminergic system is one of its main components.

But Serotonin inhibits Reward and Stops Excessive Behavior

Serotonin plays a major role in the behavioural inhibition system (BIS).

This system was identified by Henri Laborit in the early 1970s. It is associated with the septo-hippocampal system, the amygdala, and the basal nuclei. It receives inputs from the prefrontal cortex and transmits its outputs via the noradrenergic fibres of the locus coeruleus and the serotininergic fibres of the medial Raphe nuclei.
The BIS is activated when both fight and flight seem impossible and the only remaining behavioural option is to submit passively. The pathological consequences of this behavioural inhibition have provided an understanding of how destructive chronic stress can be to people’s health.

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT(2C) receptor subtypes. Serotonin within the nucleus accumbens may play an important role in mediating incentive motivation by modulating dopaminergic neurotransmission.

Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones.

The blockade of serotonin receptors potentiates behavioral effects of dopamine agonists. It is concluded that central serotonin may play an inhibitory role, antagonistic to that of catecholamines

Increasing 5-HT activity in the nucleus accumbens inhibits dopamine-dependent behaviour, and further indicate that activation of 5-HT(1B) receptors is particularly important in this regard

T helper cell I and II Duality of the Immune System are under the Control of Dopamine and Serotonin

Devoino wrote seminal articles in the early 1980s that dealt with the monoamines regulation of the immune system. She wrote prior to the discovery of the T helper cell and its differentiation into Th1 and Th2 subsets. However, interpolating her articles forward she was clearly stating that DA promotes Th1 and suppresses Th2 cytokines and serotonin does the converse. She wrote in 1984:

The monoamine systems take part in the mechanisms of immunomodulation: the dopaminergic one accelerates and the serotoninergic system inhibits the development of immune response, the final result being determined by their interaction.

The combined use of a combined dopamine and serotonin agonist protocol (CODAS) such as PURSOR can titrate DA and serotonin into sufficiency and balance and remit addictive craving and immune disorders.