Alterations of BDNF, Behavior Hormones in PTSD, Fibromyalgia and Other Environmental Illnesses

Many experts believe that the functions of the hypothalamus are dysrupted in environmental illness. We recently blogged about how hypothalamus-stimulated signaling of  BDNF levels are altered in a number of environmental illnesses. In fibromyalgia they are increased while in other are they are lower. A more recent report has indeed supported the fact that BDNF levels are increased in fibromyalgia. Also, they have demonstrated that this hormone is elevated shortly after trauma in PTSD and evens out over time. Interestingly, these findings were independant of severity, psychiatric history and treatments with medication. Because BDNF has been implicated in learning and memory the higher levels of this protein may contribute to the pathology of PTSD and considering they are elevated in fibromyalgia, one may suspect they also contribute to the pathology of fibromyalgia also. Of course, further evidence is warranted but these findings are interesting none-the-less.

Note:

• Orexin is another signaling peptide of the hypothalamus and it has been demonstrated that altered levels are consistent with fibromyalgia, chronic fatigue syndrome, PTSD and panic attacks. We have discussed this hormone in other blogs and explained, it dictates a number of different animal behaviors and is sexually dimorphic and plays a role in sickness behavior.  In addition, there is an important connection between orexins and BDNF. Dopamine are regulators of orexins and low levels are also associated with Parkinson's disease.
• BDNF is mediated by GSk-3b which is implicated in a number of psychological disorders and can be activated by environmental exposures. (Mai)

For further Reading:

• Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

Reference Library Tags: orexin, narcolepsy, chronic fatigue syndrome, PTSD, BDNF
                HEIRS Blogs: orexins, BDNF, chronic fatigue syndrome, sickness syndrome, fibromyalgia,  PTSD,


Strawn, J. R., Pyne-Geithman, G. J., Ekhator, N. N., Horn, P. S., Uhde, T. W., Shutter, L. A., Baker, D. G., and Geracioti, T. D. (2010). Low cerebrospinal fluid and plasma orexin-a (hypocretin-1) concentrations in combat-related posttraumatic stress disorder. Psychoneuroendocrinology. http://www.citeulike.org/user/HEIRS/article/6644003
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today.  http://www.citeulike.org/user/HEIRS/article/6640584
Bubser, M., Fadel, J. R., Jackson, L. L., Meador-Woodruff, J. H., Jing, D., and Deutch, A. Y. (2005). Dopaminergic regulation of orexin neurons. The European journal of neuroscience, 21(11):2993-3001. http://www.citeulike.org/user/HEIRS/article/6463668
Gaykema, R. P. and Goehler, L. E. (2009). Lipopolysaccharide challenge-induced suppression of fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain, behavior, and immunity, 23(7):926-930. http://www.citeulike.org/user/HEIRS/article/4967509
Stanley, S., Wynne, K., McGowan, B., and Bloom, S. (2005). Hormonal regulation of food intake. Physiol. Rev., 85(4):1131-1158. http://physrev.physiology.org/cgi/content/full/85/4/1131/F2
Mai, L., Jope, R. S., and Li, X. (2002). Bdnf-mediated signal transduction is modulated by gsk3β and mood stabilizing agents. Journal of Neurochemistry, 82(1):75-83. http://www.citeulike.org/user/HEIRS/article/6621876

Sleepiness in CFS and Fibromyalgia May Be a Form of Narcolepsy!

In our recent blog discussed how orexin(hypocretin) effects sleep patterns and may have an important role in CFS and sickness syndrome. A new study using a pharmaceutical called sodium oxybate showed significant improvement in patients in fatigue with both chronic fatigue syndrome and fibromyalgia and point to the "real possibility" that sleep problems in these conditions are similar to narcolepsy. In addition, the study suggests, even though further study is warranted that both CFS and FM are similar or not the same condition because of the improvements seen in patients with them.  We have noted similarities to sickness syndrome in these conditions and have emphasized that sickness syndrome also occurs in animals and importantly, narcolepsy also is not exclusive to humans and in often seen in dogs. Some breeds more commonly than others.

Other recent discoveries indicate that the major pathophysiology of human narcolepsy "is the loss of lateral hypothalamic neurons that produce the neuropeptide hypocretin (orexin). Approximately 90% of people diagnosed as having narcolepsy with cataplexy are hypocretin ligand deficient." Narcolepsy is thought to be an autoimmune related disorder and can alter regulation of cortisol and influence steroid production which also may initiate panic.  In our recent blog, we wrote how streptococcus pneumoniae may be an important trigger of orexin-influenced narcoleptic sleep behavior. This is important because this pathogen effects the severity of H1N1 and may mean that patients with EI may be more susceptible to both. Parkinsonism is also associated with alterations in hypocretin and future therapies in PD may involve treatments involving orexin. Some suggest that narcolepsy and Parkinson's disease have a common and therefore, one must begin to hypothesize that CFS and fibromyalgia may have the same or similar causal factors as PD and and narcolepsy.

For Further Reading About Orexins in CFS, Sickness Syndrome and Fibromyalgia, see

• How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome. HEIRS, January 1, 2010.
• Hormone Linked to Panic Attacks Also Linked to Endotoxin and Sickness Behavior

Spitzer, A. R. and Broadman, M. (2010). Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Practice, 10(1):54-59. http://www.citeulike.org/user/HEIRS/article/6512085
Zeitzera, J. M., Nishinob, S., and Mignotc, E. (2006). The neurobiology of hypocretins (orexins), narcolepsy and related therapeutic interventions. Trends in Pharmacological Sciences, (27):368-374. http://www.citeulike.org/user/HEIRS/article/6512089
Thannickal, T. C., Lai, Y.-Y., and Siegel, J. M. (2007). Hypocretin (orexin) loss in parkinson's disease. Medscape Today. http://www.citeulike.org/user/HEIRS/article/6512132

Have Unexplained Pain? These Questions Could Lead to a Fibromyalgia Diagnosis - US News and World Report

"From back pain, headache and knee pain, to jaw and neck pain, chronic pain disrupts people's lives, resulting in doctor's visits and missed work or school days. One common cause of chronic pain is fibromyalgia, a condition that affects an estimated 5 million Americans. It causes widespread pain and fatigue and is often tied to other health problems, such as irritable bowel syndrome and depression. But the condition is controversial, partly because of the way it's been diagnosed until now—using a tender point exam, in which a doctor applies pressure to 18 points on the body and diagnoses fibromyalgia if the patient reports pain in at least 11 of those points."

Have Unexplained Pain? These Questions Could Lead to a Fibromyalgia Diagnosis - US News and World Report:

Why Endotoxin Can Increase Pain,Chemical and Mold Sensitivity and Causes Sickness Behavior!

Toll-like receptors: are a class of proteins that play a key role in the innate immune system. (Wipedia)

Background: Binding to toll-like receptors may initiate inflammatory responses including the production of chemokines. They mainly signal through NF-kappaB and increase transcription of inflammatory proteins Il-1b, Tnf-a, CCL2 (MCP-1) etc. (Devaraj) These are receptors that are highly expressed and are considered to be a link between diet and metabolism and are implicated as important factors in a number of health conditions including lupus, atherosclerosis and diabetes. (Dasu) We have noted in other blogs that they may play an important role in conditions that are most often considered "environmental illnesses" including chronic fatigue syndrome and/or contribute to symptoms of chemical sensitivity. To put it simply, toll-like receptors are considered signal transducers that initiate inflammatory processes and two common ligands are LPS endotoxin (which has been implicated in CFS) and saturated fatty acids. The ligands that bind TLR contain a "molecular pattern" the TLR recognizes and may be present in microbial and non-microbial agents or may be responsive to signals generated at the site of inflammation or from endogenously-produced proteins like heat shock proteins. Thus, their activites become a concern when ever pathogenic exposure or inflammation may be present.

The distribution of the toll-like receptors is different in different tissues but include epithelia and endothelia in the intestinal tract, the respiratory tract, the blood-brain barrier, etc. It is now believed that there is a commensal relationship that exists between the gut microbiota and TLR to maintain gut integrity (Hopkins) and may involve epigenetic influences and down-regulation of TLR gene transcription. (Takahashi)    It has been determined that TLR2 and TLR4 bind to gram positive and negative bacteria respectively. However, the production of one type of TL receptor may induce the induction of the other. Devaraj demonstrated that type-1 diabetes and increased levels of IL-1b and TNF-a is correlated with expression of TLR and also endotoxin "contribute to the inflammatory burden by activating TLR receptors" and suggests their instrumental in diabetes pathology. In addition, it has also been determined that high glucose levels can stimulate the expression of these receptors in monocytes. While toll-like cells are involved in cytokine production and cell activation, the inflammatory responses initiated by activation of receptors may last long after the initial stimulus is gone or may potentiate the inflammatory responses of other insults. It may seem beneficial to blunt the responses of TLR, but it may be more harmful by making the organism more susceptible to infection.(Hopkins) On the other hand, aberrant signaling from TLR can lead to autoimmune-type conditions as we noted above.

Other studies demonstrate that the expression of TLR are widespread are can activate microglia and astocytes and play a role in neuroinflammatory responses. Microglia are sensory-type cells that are the main source of inflammatory mediators in the nervous system.  Some studies show that TLR activation of microglia leads to an increase in NO, superoxide and other cytokines and that TLR-deficient microglia demonstrated a significant reduction in several types of inflammatory responses. Obata confirmed TLR3 has an important role in the development of tactile allodynia after nerve injury and blocking these receptors may provide effective treatment for neuropathic pain which has been linked to fibromyalgia. Recent findings are suggestive of the notion that fibromyalgia is a "disorder of central processing with neuroregulation/
transmission dysfunction" (NFA) and TLR4 may initiate an inflammatory profile through NF-kappaB at least in a subset of fibromyalgia patients. In one model of neuropathic pain, tactile allodynia was "abrogated" in CCR2 mice which is the receptor for CCL2 (MCP-1), the inflammatory cytokines activated by NF-kappaB and has been suggested as a possible marker for fibromyalgia. It also plays a very important role in the development of neuroinflammation via the TNF-a/CCL2/CCR2 pathway. From this, it has been suggested that activation of immune cells and microglia peripherally and in neurons may contribute to inflammatory and neuropathic pain states and (Abbadie) importantly, it is now understood that TLR agonists modulates CCR2 expression and CCL2 responsiveness. (Souto, Parker) Jo et al explains peripheral injuries that lead to neuropathic states causes pathology not only in the damaged nerves but also causes changes in the central processing of sensory information and glial activation may facilitate "noxious signal transduction" even after the initial injury has healed. Therefore, TLR may not only initiate neuropathic pain but also maintain it.  Experts believe nociceptive behavior may influence symptoms of MCS (Pall) and it has been demonstrated pain caused by bacterial infection may be generated through activation of nociceptors via the TLR in neurons. (Wabachi) In addition, TLR responses play a role in viral and parasitic infections, multiple sclerosis, exacerbate injury in ischemia (Kielian) and chronic activation of TLR is associated with anxiety, avoidance and sickness behavior (Hudson) and increased sensitivity to other toxicants (Pestka).

Other reports show in epithelial cells, TLR mediate immune cells production from exposure to particulate matter and contribute to airway hypersensitivity from exposure to ozone. (Williams) More recently, it has been shown that the aryl hydrocarbon receptor (AhR), which plays a role in the detoxification of polyaromatic hydrocarbons and halogenated hydrocarbons, negatively regulates TLR signaling. Animals that are deficient in the AhR exhibit exaggerated inflammatory responses including significant elevations in TNF-a and IL-6 and are highly susceptible to septic shock. (Ogawa, Kimura) We have expressed the belief that the abnormal functioning of the AhR may contribute to environmental illnesses including multiple chemical sensitivity because of its role in detoxification and its relationship to the antioxidant system regulator Nrf2. The Nrf2 protects neurons and other cells against oxidative and environmental insults in primary and secondary injury. TLR activates NF-kappaB through the universale adaptor protein MyD88 and it has been shown that Nrf2 has a "global influence" on MyD88-dependant and independant signaling. Deficiency of Nrf2 dysregulated expression of genes that encode molecular components of innate immunity (e.g., peptidoglycan-recognition proteins, proinflammatory cytokines, chemokines, and adhesion molecules and receptors." (Thimmulappa)

Study Highlight: Pestka provides evidence that the preexposure of a TLR agonist such as LPS endotoxin increases the inflammatory response of DON, a mycotoxin. This response which included production of IL-1b, Il-6, and TNF-a was at levels higher than either produced alone. During the study, preexposure to other TLR agonists, also increased the pro-inflammatory responses of DON in a similar manner as LPS. In addition, similar heightened responses occured from LPS preexposure of TLR and subsequent effects of microbial and non-microbial "agents" including satratoxin, Shiga toxin, zearalenone and toxicants such as nickel chloride, triphenyltin, dinitrochlorobenzene (a known irritant) and dioxin. It has been concluded from this study that prior exposure to TLR agonists (ie endotoxin, saturated fat and others) "might render macrophages highly sensitive to subsequent induction of proinflammatory gene expression by xenobiotics with diverse mechanisms of action." (Pestka)

Notes:

• An important source of bacterial and endotoxin contamination is from our drinking water. Find out more about the importance of healthy water with a clip from the Dr. Oz Show. Other main sources include from the air we breath.
• IRAK-1 is necessary for LPS-mediated suppression of PPARalpha and PGC-1alpha, nuclear factors essential for the expression of anti-oxidative enzymes such as GPX3 and catalase (Maitra) "ROS trafficking(NADPH oxidase) mediates LPS/TLR signals in neutraphils and downstream targets including IRAK-1. Deficiency of Nrf2 predisposes neutraphils to greater responsiveness to LPS which is mediated by increased ROS generation. (Thimmulappa)

Reference Resource:

• Toll-like receptor (TLR)-mediated biology (Hopkins)
  

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Original document and citations can be accessed here.

Study: What Makes Patients With Fibromyalgia Feel Better?

Title: What makes patients with fibromyalgia feel better? correlations between patient global impression of improvement and changes in clinical symptoms and function: A pooled analysis of 4 randomized placebo-controlled trials of duloxetine.

Summary: Factors that may make a patient with fibromyalgia feel better determined by the results of this study include reductions in pain, reduced fatigue, physical functioning, better mood and improved quality of life.


Citation: Hudson, J. I., Arnold, L. M., Bradley, L. A., Choy, E. H. S., Mease, P. J., Wang, F., Ahl, J., and Wohlreich, M. M. (2009). What makes patients with fibromyalgia feel better? correlations between patient global impression of improvement and changes in clinical symptoms and function: A pooled analysis of 4 randomized placebo-controlled trials of duloxetine. The Journal of Rheumatology, 36(10). http://www.citeulike.org/user/HEIRS/article/5952226

Elevated insular glutamate in fibromyalgia is associated with experimental pain.

Title: Elevated insular glutamate in fibromyalgia is associated with experimental pain.

Summary: The author concluded "enhanced glutamatergic neurotransmission resulting from higher concentrations of Glu within the posterior insula may play a role in the pathophysiology of FM and other central pain augmentation syndromes."



Harris, R. E., Sundgren, P. C., Craig, A. D., Kirshenbaum, E., Sen, A., Napadow, V., and Clauw, D. J. (2009). Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis & Rheumatism, 60(10):3146-3152.

Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia

Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia: "URL: Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia

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Pathophysiology and antioxidant status of patients with fibromyalgia

CiteULike: Pathophysiology and antioxidant status of patients with fibromyalgia: "Iqbal, R., Mughal, M., Arshad, N., and Arshad, M. (2010). Pathophysiology and antioxidant status of patients with fibromyalgia. Rheumatology International."

Dark Chocolate for Fibromyalgia & Chronic Fatigue Syndrome

Dark Chocolate for Fibromyalgia & Chronic Fatigue Syndrome: "Dark Chocolate for Fibromyalgia & Chronic Fatigue Syndrome"

Fibromyalgia, Endoplasmic Reticulum Stress, Neurotoxicity and CAMKII

Many experts now believe pain sensitivity in fibromyalgia is in part, neuropathic pain. "Martinez-Lavin notes that neuropathic pain is stimuli-independent and is accompanied by allodynia and paresthesia, which are also common features of fibromyalgia. He also points out that the most important characteristic of neuropathic pain is not the nerve lesion, but the resulting nerve dysfunction." (Kelly) Nociceptors (ie. TRPV1) can be upregulated in neuropathic conditions in addition to other inflammatory pain disorders. Also, a number of different agents activate nociceptors including those in food, fragrances and chemicals and other noxious stimuli like heat, cold and pH. Hormonals and neurochemical signals such as IGF and H2O2 and cytokines such as MCP-1 can increase the sensitivity of nociceptors which reduce their threshold for activation.
Upon activation of TRP channels, there is a flood of calcium inside the cell. Consistent and long-term activation and subsequent intracellular exposure to increased calcium may result in endoplasmic reticulum stress. Two consequences occur from ER stress 1) the activation of Nrf2 through PERK (Ho) which in endothelium includes Ho-1 binding to Nrf2 (Liu) and the 2) activation of CAMKII which may increase levels of cytokines and increase the likelihood of neuronal damage if not prevented. In cardiac cells, the inhibition of an isoform of CAMKII protects against intracellular levels of Ca+, H2O2 and acidosis in addition to protection from mitochondrial-induced apoptosis. Generally, H2O2 is generated through several mechanisms including from the mitochondrial respiratory chain and from activation of NADPH oxidases and can increase significantly during mitochondrial dysfunction. H2O2 signaling exerts prolonged signaling effects including those on dopamine release and down-regulation of CAMKII helps to prevent dopamine neurotoxicity(Cai, Bao). The activation of CAMKII from oxidative stress as noted by Xie, is responsible for "arrhythmia in diseased hearts and the heart's response to catecholamines in the "flight-fright" response (Cai). Also, CAMKII interacts with both TRPV1 and the NMDA receptor to alter their function. As for the latter, it may inhibit the downregulation of the NMDA receptor and increase the potential for pain generation and neurotoxicity.
Citations

Is This a Plausible Mechanism for Multiple Chemical Sensitivity Responses?

The results of this study suggest that "electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) evokes escape, defensive behavior that has been related to panic attacks and that serotonin signaling may influence the panic behavior."

"Considering the triggers, this seems like a very plausible explanation for the mechanism or something similar in multiple chemical sensitivity. This area seems to be influenced by stress signalling and also interacts with certain proteins including the CRH which reacts to environmental cues that leads to changes in neurotransmission. According to one source, "periaqueductal gray matter is responsible for inhibiting nociceptive activity (often leading to pain) though the release of certain proteins. Nociceptive signaling forms a platform for the "central sensitization" in fibromyalgia and other pain conditions and involves the enhancement of impulses and dysfunction in the pain system." For this reason, it very well could be an important component in the responses associated with chemical sensitivity.(Spaeth) As far as fibromyalgia, alterations in serotonin have been noted in past studies.


CiteULike: Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter.: "Miguel, T. L. B. L., Pobbe, R. L. H. L., Junior, A. S. S., and Junior, H. Z. Z. (2010). Dorsal raphe nucleus regulation of a panic-like defensive behavior evoked by chemical stimulation of the rat dorsal periaqueductal gray matter. Behavioural brain research."





Sources:
The Neurochemical Response Patterns to Acute Stress. Retrieved on May 13, 2010. http://focus.psychiatryonline.org/cgi/content/full/2/3/368/T1
Spaeth, M. (2006). Fibromyalgia syndrome: The role of neurochemicals. Primary Psychiatry, 13(9):72-75.
http://www.citeulike.org/user/HEIRS/article/7167665

Fibromyalgia pain severity not linked to psychological symptoms

"A new study finds that the pain of fibromyalgia is linked to reduced activity in the areas of the brain that inhibit sensation and dispells the myth that the illness and severity of pain reported is linked to psychological causes." According to researcher, "we've made careful measurements and have found no correlation at all between pain sensitivity in fibromyalgia patients and the degree of anxiety or depression they show." Click here to read more.

Aquatic Exercise Has Positive Effects on Cytokine Balance in Fibromyalgia.

CiteULike: Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients: "Ortega, E., Bote, M. E., Giraldo, E., and García, J. J. (2010). Aquatic exercise improves the monocyte pro- and anti-inflammatory cytokine production balance in fibromyalgia patients. Scandinavian Journal of Medicine & Science in Sports, 9999(9999)."

More Support for Brain Changes in Fibromyalgia, Says Study!

"fibromyalgia is associated with deficits in intracortical modulation involving both GABAergic and glutamatergic mechanisms, possibly related to certain aspects of the pathophysiology of this chronic pain syndrome"

CiteULike: Alteration of cortical excitability in patients with fibromyalgia.:

Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

A study that was published last year suggested that MCP-1/CCL2/CCr2 and eotaxin may be good biomarkers for fibromyalgia and identify a genetic component to the condition. (Zhang) Since then, researchers have noted that both chronic fatigue syndrome and fibromyalgia may be classified as inflammatory conditions when the exact cause of symptoms is not known. Interestingly, MCP-1 can cause inflammatory responses and therefore has the potential of contributing to sickness behavior syndrome which is a condition that results in behaviors often associated with people that are ill. Sickness behavior does not seem exclusive of human beings because similar behaviors have been observed in other animals. Maes concludes that oxidative and nitrosative stress contribute to the development of chronic fatigue which result in an increase inflammation, NF-kappaB, COX2, iNOS and damage to lipids and proteins. He further explains that triggers include strenuous exercise, LPS from gram negative bacteria, viruses and pshycological or physical stress. A few of the symtoms associated with sickness syndrome include fatigue, malaise, appetite changes, anxiety, depression, weight changes, sleep alterations and numerous others. (Maes) Previous studies show it can be stimulated by a variety of conditions including IGF-1, Tnf-a and Il-1b the latter two are produced as part of the stress response and modulated by the Nrf2 system that also stimulates induction of antioxidants. (Dantzer) Nrf2 has been shown to modulate metabolic homeostasis in adipocytes and is now linked with obesity. Nrf2 is responsible for detoxification of electrophiles and xenobiotics and the function of it can be altered by any number of environmental factors including but not limited to metals, nutrition, and other protein interactions such as the AhR which also may play a very important role in chemical sensitivity.

The severity of sickness syndrome has been demonstrated to be determined on the prevalence of the anti-inflammatory immune complex IL-10. When it is present the duration of sickness syndrome is less and the effects like memory and learning impairment are also decreased. (Richwine) Il-10 has been shown to reduce the levels of IFN-gamma and Tnf-a- induced production of superoxide and nadph oxidase 1 (NOX1) which would suggest prevention of ROS generation from it. (Kamizota) Il-10 also stimulates the induction of HO-1 and therefore may activate the Nrf2 pathway but HO-1 can act independantly. Inhibition of HO-1 significantly reduces the protective effects of Il-10 on Tnf-a by LPS. Lee et al shows that this relationship also involves carbon monoxide, a gasoneurotransmitter, on the protective effects of Il-10. Therefore this further suggests a possible involvement of Nrf2 considering that Nrf2 modulates the effects of carbon monoxide. (Lee) De Wilde demonstrated that production of Il-10 is completely abolished with inhibition of HO-1.

Nrf2 is now associated with protective effects in adipocytes. Eotaxin is a chemokine that is elevated in obesity because adipose tissue seems to be the predominant source of it. It is also an important inhibitor of MCP-1 and is a common factor in allergic reactions. Its presence at the site of allergic inflammation suggests coordinated cellular responses of allergic inflammation where both MCP-1 and eotaxin are present. (Olgilvie) Tnf-a is overexpressed in obesity (Uysal) and associated with insulin resistance and inhibition of the expression of numerous genes including PPAR-gamma and adiponectin. It is also an important inducer for prolonging the half-life of eotaxin.

Summary:

• Maes has suggested that a pathway to chronic fatigue syndrome is by LPS endotoxin and therefore because the production of Il-10 modulates the severity of sickness syndrome through HO-1. We can suggest that the alteration in signaling of Nrf2 could ultimately lead to CFS and sickness syndrome.
• Nrf2 is conserved in different organisms, the homolog in C elegans is skn-1. (An)
• Nrf2 can be ethnically derived and therefore some populations may be more susceptible to some of the triggers and have an increased risk for chronic fatigue syndrome. (Marzec, Dinos)
• EGCG has been shown to have positive effects on chronic fatigue syndrome in a mouse model of CFS. Studies have shown that EGCG increases induction of HO-1 through Nrf2.
  

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Source Citations

Nrf2 and Protease Inhibitors in COPD and Fibromyalgia....Their Link to Increased or Decreased Susceptibilty to S Pneumoniae and Influenza

I did not set out today to write about this topic but as I reviewed some of my recent blogline notices, the topic just kind of jumped out at me. I must note here that what I am about to write about probably will not seem important to you. However, it may be important to those who have a keen interest in current research on environmental illness. On this blog, we write, comment and note important research on all kinds of environmental illness, including those that are considered respiratory diseases such as emphysema and COPD. As we have noted before, the expression of Nrf2 has an important effect on the development of respiratory disease. A new study offers some more insight into the benefits of gene therapy on emphysema. As you will see, it also provides more evidence of how Nrf2 expression effects the disease.

Background: Activation of the Nrf2 pathway leads to expression of a number of different antioxidants which help to neutralize oxidative stress. Oxidative stress is produced from normal cellular metabolism but overly produced in dysfunctional cellular metabolism. Several research studies have demonstrated that in cells have an increase in oxidative stress that are deficient of Nrf2.

Late last month, it was announced that a new gene therapy may prevent the progression of emphysema. Medically speaking, this has important implications because it is estimated that 3 million suffer from emphysema which is a manifestation associated with COPD. It is characterized by accumulation of inflammatory cells in the airways and lungs. The World Health Organization expects COPD will be the 5th leading cause of illness and death by 2020 and therefore, any treatment that reduces the incidence of emphysema and COPD has important implications for public health. The researchers that developed this new type of gene therapy explain that mice lived for the duration of their life exhibiting the therapeutic effects of the gene in immune cells after the initial treatment. Generally, a genetic deficiency of a substance called A1 Anti-trypsin plays an important role in the most common form of emphysema seen in young people and this genetic deficiency not only increases the risk for early onset of lung disease but also liver cirrhosis and other health complications.

In 2005, Lizuka wrote an interesting paper that describes more about the relationship between cigarette-smoke induced emphysmena, Nrf2 and A1 anti-trypsin. As most people are aware, cigarette smoking is a major risk factor for the development of the disease and as the author notes, A1 antitrypsin deficiency is critical to its pathogenesis as it protects the body from a substance called neutrophil elastase.  In mice models, deletions of the gene for something called neutraphil elastase (NE) are protected from this type of emphysema. Neutraphil elastase is key to host immune defence and assists in decreasing pathogenic virulence by attacking a protein in the pathogen's cell wall. (Belaaouaj) Consequently, the very nature of its activity can cause damage to tissue. In addition oxidative stress plays an important role by inactivating A1 antitrypsin and activating inflammatory mediators including NF-kappab leading to the production of Il-8 and TNF-a. Interestingly, this author notes other similar compounds may provide similar protection as A1 anti-trypsin. He says, "because not all smokers develop emphysema and many smokers with emphysema have normal levels of A1 antitrypsin." His findings suggest that other anti-proteases called secretory leukoprotease inhibitors (SLPI) are effective at inhibiting neutrophil elastase (NE) and NE-induced emphysema and more effective at preventing neutrophil mediated lung damage.

What is interesting about this study and this author's work is that Nrf2 is an important activator of SLPI and his findings support numerous other reports that show Nrf2 deficiency increases the risk for CS-induced emphysema. Nrf2 -/- animals show severe inflammation when exposed to cigarette smoke. In addition, other findings include a lack of induction of anti-oxidant enzymes and significantly higher levels of oxidative stress in Nrf2-/- mice. He also points out that Nrf2 activates the gene CD36 which enhances phagocytosis of apoptotic neutraphils but in Nrf2 deficient animals the number of immune cells that phagocize neutraphils was much lower. This indicates that macrophage-medicated clearance of neutraphils may be impaired in Nrf2 animals. In relation to this possible mode of action for CD36, in November 2009, a potentially important study was published. During that study, the researchers investigated the bacterial clearances of COPD patients compared to others. They found that COPD patients showed reduced phagocytic response to the two pathogens tested, S pneumoniae and H. influenza. This suggests the presence of suppression of macrophage innate responses that may lead to bacterial colonization and increased incidence of bacterial infection which is commonly found in COPD patients. (Taylor) Lizuka goes on in his paper and describes that Nrf2 deficient animals had increased levels of NE increased after exposure to cigarette smoke compared to controls even though there was little difference in A1 anti-trypsin production after cigarette smoke. His other findings include the expression of SLPI was reduced in Nrf2 -/- mice compared to wild-type Nrf2 animals and he suggested this could account for increased levels of NE. Interestingly, the known activators such as sulforphane increased expression of SLPI whereas, the activators PPAR-gamma activators did not and therefore this confirmed that SLPI is under the regulation of Nrf2. SLPI is also produced by stimuli including LPS and proinflammatory cytokines, in addition to NE and has been shown to prevent activation of the NF-kappaB pathway. This not only may explain the susceptibility of Nrf-/- mice to emphysema but also may explain their susceptibility to others pathogenic stimuli that cause disease including inflammatory lung diseases. (Ishii)

In 2008, one study linked fibromyalgia with A1 anti-trypsin deficiency but a recent study of anti-trypsin 1 conflict on whether they include inflammatory processes. Albeit, this judgement was made from a very small study. It seems for now the jury is still out on whether it does or does not. Ishii does show in one study there is evidence that A1 anti-trypsin is regulated by Nrf2 but a similiar study by the same research failed to duplicate these findings. In spite of the contradictions in the results of these studies and with the recent evidence of the link between Nrf2 and SLPI, it is worth noting that thos with a1 antitypsin fibromyalgia and are Nrf2 deficient may experience symptoms more severely. As for those who are deficient in SLPI and elevated NE, the elevations in NE may identify Nrf2 deficient phenotypes.

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Activation of MCP-1/CCl2/CCR2 by TNF-a to cause microglial neuroinflammation and alterations in neurotransmission require the presence of the TNFR1. (D' Mello) The Nrf2 pathway has been shown to modulate inflammatory mediators including Tnf-a and the glutamate antiporter system. (Lewerenz) The TNFR1 receptor is important for preconditioning in ischemia to reduce injury from subsequent ischemia through interaction with the EAAT3. The EAAT3 transporter regulates glutamate and also is involved with glutathione synthesis and is present in cortical and striatal neurons. (Suchak) It works cooperatively with xCT to prevent depletion of glutathione caused by high glutamate levels and may be useful in eventual therapy for Parkinson's. (Lewerenz)

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Lewerenz, J., Albrecht, P., Tien, M.-L. T. L., Henke, N., Karumbayaram, S., Kornblum, H. I., Wiedau-Pazos, M., Schubert, D., Maher, P., and Methner, A. (2009). Induction of nrf2 and xct are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5627214
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http://www.citeulike.org/user/HEIRS/article/3401858