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:

Neuroinflammation and Neurodegenerative Diseases: One Condition One Therapy

Does neuroinflammation fan the flame in neurodegenerative diseases?:

Microglial activation is the response to multiple traumatic insults whether triggered by infection, trauma or hypoxia. This common stress response can become self-feeding and can become chronic. The authors postulate that the particular presentation (PD, ALS, Huntingtons, etc) depends on genetic variation of environmental variability.

I believe and have so believed for more than a decade that all these conditions can be remitted by blocking the perpetuation of microglial activation by the use of dopamine and seotonin precursor therapy (PURSOR).

Summary

It is becoming increasingly evident that neuroinflammation plays a crucial role in the development and progression of many neurodegenerative diseases. Glia and in particular microglia are central to mediating the effects of neuroinflammation. While neuroinflammation and microglia provide an attractive therapeutic target in the treatment and prevention of neurodegenerative diseases investigators face several challenges ahead (Appendix 2) which must be overcome before one can advocate in favor of large-scale anti-inflammatory trials in the clinic. Some of these include developing approaches to improve the access of drugs to CNS tissue as well as developing therapies that maintain or optimize the beneficial effects of neuroinflammation while eliminating or minimizing its detrimental effects.

Key Observations

1. Neurodegenerative diseases are associated with signs of chronic neuroinflammation
2. A variety of initiating triggers (some as yet unknown) associated with the different neurodegenerative disorders converge at a common intersection point - activation of microglia.
3. While the initial neuroimmune response may be aimed at limiting the disease process, chronic neuroinflammation driven by persistent microglia activation is likely to aid in the progression of the disease and the hastening of neuronal demise.
4. How the inflammatory response affects specific neuronal and glial populations and contributes to specific neurodegenerative diseases remains a critical and unanswered question

Critical challenges involved in developing neuroprotective anti-inflammatory therapeutic strategies

1. Identify internal and external factors that trigger chronic neuroinflammatory responses, with a focus on how acute immune responses become chronic.
2. Identify inflammatory mediators that compromise survival of specific neuronal populations.
3. Develop therapeutic compounds that cross the blood brain barrier (BBB)
4. Selectively target destructive inflammatory mediators without compromising beneficial survival-promoting effects and overall immune function.
5. Develop inclusion and exclusion criteria for human subjects to be enrolled in clinical trials taking into account their immune status."

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.