Existence and distinction of acid-evoked currents in rat astrocytes.

"This study demonstrates that there are two kinds of acid-evoked currents in rat astrocytes, which may provide a new understanding about the functions of ligand-gated ion channels in astrocytes."

Read more: CiteULike: Existence and distinction of acid-evoked currents in rat astrocytes.:

Female Hormones May Contribute to Sexual Dimorphism in TMJ~!

Comment: I suspect this is going to has implications on other pain conditions as well, especially those under the environmental illness umbrella like CFS and fibromyalgia....

"hippocampal TRPV1 can modulate central pain processing and estradiol may contribute to the sexual dimorphism of TMD pain sensitivity through upregulation of TRPV1 expression in the hippocampus"

Link:CiteULike: 17-beta-Estradiol Enhanced Allodynia of Inflammatory Temporomandibular Joint through Upregulation of Hippocampal TRPV1 in Ovariectomized Rats:

How Changes in Neurons May Lead to Altered Cortisol in CFS/ME & Sickness Syndrome.

Background: Many research experts believe that endotoxin is a causal factor in the development of chronic fatigue syndrome. (Maes) In addition and as we have discussed on this blog, many of the symptoms may be attributed to sickness behavior or sickness syndrome. Generally, this is regarded as a reflection of immune responses that alter normal functions of hormones, neurotransmitters, etc. resulting in changes in behavior in humans and other animals.

We recently discussed how dysregulation of the hormone, ghrelin, may effect sickness behavior. A study just published provides more details about how another hormone may contribute to sickness syndrome and related alterations in behavior. According to the study, LPS endotoxin suppresses the neuronal circuitry in orexin and histamine neurons. As the abstract describes, the orexin neurons in the brain are important for behaviors including waking, feeding and reward-related behaviors and can be regulated by dopamine (Bubser), provide antinociceptive protection (Mobarakeh) and may reduce gastrointestinal injury through several mechanisms including injury from TLR signaling. In other blogs, we describe in detail how LPS from gram-negative bacteria and other environmental contaminants such as ozone can initiate inflammatory effects through TLR signaling and that genetic or environmental dysruption of the Nrf2 system will enhance the inflammatory effects.

Outside the brain, orexin neurons stimulate the production of cortisol in the adrenal glands and another studies shows orexin can time-dependantly raise cortisol levels as well as, influence steroidogenesis. Orexin studies have also revealed it regulates histamine release in the brain. Interestingly, narcolepsy which is suspected to be an autoimmune-related condition is associated with orexin deficiency. Aran proposes that streptococcus is an environmental trigger of narcolepsy. For this reason, the results of these studies in combination suggest that both gram-negative and gram-positive bacteria may contribute to sickness syndrome by altering orexin levels. In addition, orexin is a sexually-dimorphically expressed hormone which may help to explain the gender differences in the rates of environmental illness. (Johren)

Click to view original document and citations.

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Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells

Title: Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells.

Summary: "This is the first evidence that capsaicin-sensitive afferents exert a protective role in endotoxin-induced airway inflammation, but contribute to increased bronchoconstriction."


Umannova, L., Zatloukalova, J., Machala, M., Krcmar, P., Majkova, Z., Hennig, B., Kozubik, A., and Vondracek, J. (2007). Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome p450 enzymes in rat liver ßtem-like" cells. Toxicol. Sci., 99(1):79-89.

Infection/Endotoxin in Chronic Fatigue, Fibromyalgia and Multiple Chemical Sensitivity.

Definition: Endotoxin: a toxic component of bacteria not excreted by live bacteria but induces the inflammatory cascade and production of NO. (Endotoxin)

 An increasing number of scientific publications support the hypothesis that endotoxin infection and sickness syndrome may be important factors in environmental illnesses including fibromyalgia, chronic fatigue syndrome and quite possibly MCS. In fact, sickness syndrome would be a reasonable and holistic approach for explaining many of the behavioral, physical and emotional complications that are common in environmental illness. Sickness syndrome is described as the presence of a variety of symptoms including malaise, fatigue, sleep disturbances, appetite changes, brain inflammation, mood changes such as anxiety and depression and a host of other symptoms that occur as a reponse to injury or infection.  These responses occur both in humans and animals and some propose it is in part, adapative responses that are generated to alter the responses of the host and their social network. Over the past several years, there has been an significant amount of research on sickness syndrome. The occurence of which can be attributed to inflammatory cytokines that alter neurotransmission and genetic expression. There have been studies that show altered gene expression in environmental illnesses; the consequences of which can be quite severe and unexpected. Il-10 is an anti-inflammatory cytokine that has been shown to modulate the severity of sickness syndrome through interaction with HO-1. HO-1 is also a cytokine that is induced by activation of Nrf2, although there are other pathways that can induce this antioxidant. Recently, it has been demonstrated that the protective effect of an endogenous peptide thryotropin, against the damaging effect on the dopamine system from paraquat, is due to the chemicals ability to activate Nrf2 to reduce reactive species and increase the antioxidant glutathione. Other studies have demonstrated that thyrotropin is able to reverse hyperglycemia by increasing beta cell function and reducing programmed cell death. (Luo) Insulin resistance and diabetes are suspected to be important consequences of the sustained presence of inflammation and inflammatory cyokines that are characteristic of environmental illnesses.

A recent published study showed that there is brain disfunction in multiple chemical sensitivity (Orriols) and last week I suggested that some of the cognitive effects could be from an altered expression of BDNF. Of course, there are any number of factors such as malnutrition and inflammation that can influence cognitive function. Neurotransmitter regulate and can alter cognition and are modulated by factors that produce "sickness syndrome".  According to the author of the recent MCS study, SPECT scans showed alterations in the regions of the brain including the cingulus, striatum and the hippocampus in addition to others. Pekary et al explains that a common environmental toxin LPS has the potential to alter the expression of thyrotropin which may have an impact on LPS toxicity. The study showed elevations of cytokines and corticosterone after LPS with a transient drop in T3. Other results showed a decrease in thyrotropin-releasing hormone in certain areas of the brain while increasing it in others. Thyrotropin has been shown to improve recovery after neurological dysfunctions such as brain trauma and epilepsy in humans and animals and be neuroprotective against NMDA neurotoxicity. (Pizzi) These regions the author noted are areas that are associated with the neuroimmunomodulatory effects of sickness and injury and danger and appear to be similar to those effected in MCS SPECT scans. Also, a sustained elevation in TRH was present in b-cells accompanied by LPS-impaired insulin secretion. From these findings, the author concluded that thyrotropins can mediate and moderate the behavioral and toxic effects of LPS. In addition, LPS elevates inflammatory cytokines including Tnf-a, Il-6 and Il-1b and also increases expression of TLR receptors 2 and 4 and causes a prolonged sickness behavior in aged animals. Taking these findings into account and the fact that thryotropin mediate their positive effects through Nrf2, then one can assume that alterations in the antioxidant system may exacerbate the toxic effects generated by LPS endotoxin  It is also important to mention that Nrf2 levels drop as a consequence of the aging process(Godbout). This could lead one to propose that Nrf2 alterations from aging and other impairments and LPS may at least in part, mediate the effects in MCS. There has been evidence that hyperglycemia (which can be reversed with thyrotropin) sensitizes TRPV1 receptors which is implicated in MCS (Pall) and diabetes complications and TRPV1 may have direct or indirect effect on the release of neurotransmitters. (Pabbidi) Neuropeptides releases from capsaicin-sensitive efferents provide a protective mechanism against LPS but also increase bronchoconstriction which can increase airway hyperresponse. (Elekes) From these results and other studies, I have suggested that insulin resistance and hyperglycemia from chemical exposures may contribute to some of the inflammatory responses in MCS.

Endotoxin or LPS has been implicated as a possible pathway to the development of chronic fatigue syndrome. Above we noted that LPS increases the expression of toll-like receptors 2 and 4. Toll receptors recognize certain components on bacteria and transduces bacterial invasion through this recognition and has important relevance in preventing infection (Light) and expressed on a variety of cells including dendritic cells, B cells, neutraphils and macrophages. Defects in TLR expression can lead to an increase in susceptibility to infection from a number of pathogens while aberrant signaling of TLR such as from LPS are implicated in causing sepsis or even inflammatory or autoimmune-type conditions. (Harding) Activation of TLRs can lead to initiation of the the inflammatory pathway NF-kappaB and LPS endotoxins are ligand of TL4. Interestingly, saturated fats (bad fat) can induce inflammatory markers through TLR4 and therefore, saturated fats can alter gene expression through TLR4 interaction. For instance, the main component of coconut oil, lauric acid, has been demonstrated to potentiate the inflammatory effects of LPS COX-2. (Lee)  The just published Light study on chronic fatigue syndrome shows an increase in TLR4 after exercise and Light suggests this is due to "lesser fitness" in CFS patients. Light goes on to further explain that Il-10 is upregulated in CFS patients after exercise and one of its roles is to inhibit the production of Tnf-a which is also consistent with recent reports of an anti-inflammatory profile in FM. This and other studies of CFS revealed symptom flares may be related to cytokine activity postexercise. Notably, Tnf-a was elevated in muscle and Light explains that fatigue and muscle pain in CFS might be from the enhanced activation of "fatigue" and "nociceptive" afferents supplying muscle. Other supporting evidence of muscle involvement included elevations of ASIC3 channels that are often increased by muscle and joint inflammation. The elevation of Il-10 in the Light study was correlated to those patients with prolonged fatigue and pain but who also had elevations in pro-inflammatory cytokines and evidence of overall enhanced immune response. LPS has been shown to have a close relationship with sensory nerves and TLR4 receptors have been found on sensory nerves. The interaction between LPS and TLR4 may enhance the complications of TRPV1 activation. (Clark) In addition, Suter demonstrated that TLR2 and TLR4 are necessary for nerve-induced microglia activation and pain sensitization. (Suter)The presence of nociceptors on trigeminal nerves that suggests they recognize bacterial products and contribute to pain during infection. (Ball)

Citations and Original Document

Multiple Chemical Sensitivity, Altered Brain Responses and Ups and Downs Of BDNF

 Multiple Chemical Sensitivity, Altered Brain Responses

and Up and Down Regulation of Proteins

 

Multiple chemical sensitivity is characterized by a heightened physical and emotional sensitivity to "agents" such as fragrance and chemicals in the environment.  A recent study that was posted on The Canary Report documents new research that supports the fact that MCS has neurogenic origins. While the idea is not new, this study provides SPECT imaging results that show abnormalities in MCS patients.  According to the author, the findings show neurocognitive impairment and disfunction in the areas of odor-processing. (Orriols) A past study showed similar alterations in odor processing without neural sensitization and suggests MCS hypersensitivity is a result of alterations in the top-down regulation of the odor-response. (Hillert) I suggest that some of the effects of MCS may be a consequence of alterations in the production of BDNF which plays a role in the regulation of olfactory bulb neurogenesis.
 

In past blogs, we have mentioned a neuropeptide brain-derived neutrophic factor. BDNF is important for long-term survival of neurons including those involved with learning and memory and control of downstream targets including neurotransmitters such as dopamine and glutamate. (Paredes) It also is important for olfactory neurogenesis and fine odor discrimination and function and its functions suggests critical importance for detecting and processing of changes in the environment, ie. odors. (Yuan) In recent years, research had identified certain functions of BDNF although there is still much to be learned. These findings include important roles in glucose and cognitive function regulation. More importantly it increases NAD+ levels which would suggests it elevates SIRT1 and protects against excitoxicity. (Liu) SIRT1 is an important regulating protein that upregulates regulatory proteins and acts through PGC-1a which is necessary for  mitochondrial biogenesis. In addition, it interacts with Nrf2 and other proteins to maintain cellular homeostasis. One study showed women with impaired insulin function such as insulin resistance and diabetes had lower BDNF levels than controls. Women with higher BDNF has poorer explicit memory and this suggests higher levels of BDNF may not always be indicative of good health but is probably a mechanism to respond to damage. (Arentoft) Markham shows that neutrophins like BDNF can not only modify neuronal plasticity but also modifies brain metabolism and increases mitochondrial function which can have both positive and negative tissue-specific effects.

 

Parkinson's disease is neurodegenerative condition that has been linked to environmental toxin exposure and in one study it was demonstrated that carnosis acid (CA) in rosemary can reduce the down-regulation of BDNF from the pesticide dieldrin which is no longer used but may be present in the environment and tissue because it is bioaccumulative.  This author explains that CA "safeguards dopaminergic neuronal cells from environmental neurotoxins by enhancing brain-derived neurotrophic factor and repressing apoptotic molecules."  Many have noted that pesticides can mediate the development of MCS and alteractions in gene regulation, such as BDNF, provides one explanation of why these exposures have a long-term impact on cognitive function. (Park) This study demonstrates that BDNF protects dopamine cells and might suggest  lower levels of BDNF may produce aberrant behaviors controlled by dopamine including changes in mood and addictive behavior. A just published study has also implicated a decrease in glutaminergic neurotransmission may also be a factor in learning and memory deficits from dieldrin.  Other environmental factors such as high-fat diets significantly reduces BDNF levels enough to alter cognitive function regulation and aggravates effects of brain injury. (Wu) One author is quoted as saying, "when you have adquate levels of BDNF, then memories do not come back to haunt you...which
seems reminiscent of the more behavior-influencing effects of PTSD.
 

In addition, it has been demonstrated the stress response including the secretion of cortisone has an impact on the production of BDNF and if stress persists for too long this can lead to atrophy of the hippocampus. Zhou proposes cortisone inhibits long-term potentiation. This, he says, is mediated by a presynaptic mechanism and this mechanism may involve the decrease in BDNF expression. BDNF has been implicated as a factor in a number of mental health conditions including depression and schizophrenia. Behavioral factors such as exercise, calorie restriction and antidepressants increase levels of BDNF and as numerous studies have demonstrated, these factors can also reduce mental health symptoms including those for depression. (Daney)
 

For several years, researchers have studied drugs in a class of AMPAkines for treating a variety of conditions such as schizophrenia, problems with attention span and alertness and memory problems associated with dementia and Alzheimer's. Interestingly, this class of drugs also significantly elevate BDNF and also LTP which is an indicator for memory formation. (Daney) Alterations in BDNF levels have been associated with fear-induced olfactory learning which suggests a possible connection to MCS and the behavioral changes that may occur when a person with MCS is confronted with an offending "odor". However, Jones argues that a stressor and odor exposure must occur together for fear-induced olfactory learning and one might suggest that the stressor may come from the immune response itself. In any case, it again provides proof that BDNF influences the olfactory system and very well could intensify the behavioral aspects of MCS.  In other blogs, I have mentioned odors activate the TRP receptors and consistent and long-term activation can lead to endoplasmic reticulum stress, cellular dysfunction and possible alterations of the "adaptive pathway" Nrf2 through PERK and subsequently negatively impact subsequent immune responses to offensive and hazardous stimuli. Activation of Nrf2 can be dependant or independant of oxidative stress. (Ho)      
 

Imbalances in cellular homeostasis can lead to overexpression of BDNF and pain generation. Norman explains neuropathic pain and depression are often co-morbid and demonstrated how nerve injury produces inflammation resulting in both allodynia and depression-like symptoms and Il-1b. (This of course sounds a lot like sickness syndrome even though the author does not mention it.) The study also demonstrated that chronic stress exacerbated the levels of neuropathic pain, depression, Il-1b and elevated BDNF levels may be compensatory like it was suggested in the paragraph above. Application of a corticosteroid inhibitor prevented the effects of the stress and an inhibitor of Il-1 prevented the depression and the neuropathic pain. (Norman)

Numerous studies have suggested environmental illnesses may be due to the dysregulation of insulin and glucose homeostasis on specific receptors that regulate inflammation and cellular function and it is my belief this is true of MCS.  Several studies have shown that cyokines can influence the regulation of gene expression and there is no reason this is not also true of MCS. As the author suggests, MCS may be the result of abnormal odor processing after chemical exposure and the effects include cognitive impairments. TRPV1 has been implicated as an important factor in the development of MCS (Pall) and also in neuropathic pain (Wipedia) and recently, it has been demonstrated altered TRPV1 function may play a role in diabetes. (Pabiddi) BDNF have been shown to be elevated in fibromyalgia and as Martin-Lavin explains it has been suggested fibromyalgia is in part, neuropathic pain and suspected to be a consequence of abnormal summation of pain and spinal-cord reflexes. (Martinez-Lavin) Other studies have demonstrated that insulin and IGF-1 potentiates the activity of TRPV1 through PKC (Van Burnen)  and several reports suggest chemical exposure causes inflammatory responses that induce insulin resistance and hyperglycemia which can impair mitochondrial function. In addition, a growing body of evidence links obesity and diabetes and the "removal" of TRPV1 fibers improve pain decreases weight gain and improves glucose tolerance both in high-fat diets and diabetic models. As we have noted, chemical bioaccumulation mimic the effects and are exacerbated by high-fat diet models and therefore, these findings are of importance to studies of the impact toxic injury on metabolism.  Experiments changing TRPV1 function prevents pancreatic beta cell destruction and autoimmune diabetes and (Suri) hyperglycemia can elevate reactive species which activates TRPV1 expression and at higher levels cause cell death. Earlier we mentioned that insulin function can regulate BDNF and alterations in levels are associated with insulin resistance and diabetes. Exercise increases levels of BDNF but excess energy production from exercise or a high-calorie diet can increase ROS and cause cellular overload and reductions in BDNF and cognitive function. (Go'mez-Pinilla) Recent findings have shown that both BDNF and GDNF (another neural factor) can regulate the expression of TRPV1 and TRPA1 (in a slightly different manner) leading to enhanced neuronal sensitivity to stimuli and elevations in other receptors.  (Ciobanu)

 

Next Research Blog:

• What the Light Study on Chronic Fatigue Syndrome Says and What It Does Not Say!

Library Resources:

• BDNF

Citations and References:

 

Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet

Title:Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet.

Summary: "dietary capsaicin may reduce obesity-induced glucose intolerance by not only suppressing inflammatory responses but also enhancing fatty acid oxidation in adipose tissue and/or liver, both of which are important peripheral tissues affecting insulin resistance. The effects of capsaicin in adipose tissue and liver are related to its dual action on PPARalpha and TRPV-1 expression/activation."

Citation: Kang, J.-H. H., Tsuyoshi, G., Han, I.-S. S., Kawada, T., Kim, Y. M. M., and Yu, R. (2009). Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity (Silver Spring, Md.). http://www.citeulike.org/user/HEIRS/article/5898628

Hydrogen Sulfide, Cigarette Smoke, Endotoxin and Particulate Matter -- The Toxic Effects They Have In Common!

Different chemicals have different modes of toxicity which can reduce, be additive or potentiate the effects of the others and alter other metabolic processes such as insulin release and activities of Nrf2 cell signaling.  Take four example, the four toxicants endotoxin, hydrogen sulfide (H2S), cigarette smoke and particulate matter. These pollutants are all common in the environment and can cause negative health effects in those that are susceptible, have certain chronic illnesses and/or multiple chemical sensitivity. Interestingly, one will note that all four are found in tobacco smoke and therefore, this probably makes cigarette more toxic at lower levels than each of the different agents on their own.

First of all, lets review a few important details about each of these toxicants. Cigarette smoke contains acrolein which is an aldehyde that has been implicated in the development of neurogenic inflammation. Cigarette smoke also has hundreds of chemicals. Some that have been identified and some that have not. The toxicity of many of the toxicants that have been identified are still unknown. Particulate matter (PM)are particles that are present in air pollution and reduce air quality. Their presence at higher levels are an irritant to almost anyone but at lower levels they may become irritants to individuals with special health conditions such as those patients with asthma and COPD. For PM, size matters! Finer particles are better able to travel down the windpipe and absorb into the lower lung tissue's protective layer and induce inflammation. Ultra-fine particles also have more surface area to bind chemicals which can elevate inflammatory responses even further. Exposures to hydrogen sulfide can be from endogenous sources such as intestinal bacteria or from production in the different cells. As we have noted, major sources of exogenous sources of H2S are from bacteria in contaminated drinking water from wells and groundwater and the waste of large animals feeding operations (CAFOS) that end up in rivers and streams. Of course, the source of endotoxin can be from those same sources but other sources include bacteria on food, smoke from wood and tobacco smoke, water-damaged buildings, animals, and from indoor contaminants like dust in the home and commercial and occupational settings. Contrary to popular belief, endotoxin is one of the most common pollutants in the environments because it can be found almost anywhere especially where there is water and is so small, that there is little, if any technology that is available to get rid of it. For instance, very few models of air filtration units have the ability to filter gram-negative bacteria which is the source of most endotoxin. 

Hydrogen sulfide has the ability to cause any number of health effects including death at high levels. As we noted above, it is produced endogenously by bacteria in the gut in addition to other cellulars sources including adipocytes (Fang) and the pancreas (Harrison). It has been shown that long-term exposure to endogenous hydrogen sulfide can impair the function of beta cells in the pancreas which may lead to insulin resistance and diabetes. Researcher's now believe that one way this occurs is through the generation of inflammatory processes from Il-1b that is produced by the liver may drive the inflammatory processes that effect the beta cells. Endotoxin has been associated with liver inflammation and inflammation in the liver has been associated with activation of neuroinflammation and sickness syndrome. Changes in Nrf2 signaling have been associated with insulin resistance and may be due to reductions in insulin secretion by damaged beta cells (Harrison) from H2S produced by pancreatic cells altering KATP channels and also from Il-1 production in the liver exerting a peripheral effect on pancreatic beta cells. Insulin has been shown to be an important signaler for HO-1 and Nrf2 under normal conditions. Harrison describes a five-fold increase in heme oxygenase -1 mRNA and a 4-fold increase expression in kidney epithelial cells by insulin induction. Long-term exposure to intestinal bacteria or other processes that produce copious amounts of H2S that activate cellular signal like nociceptors when detoxification is overwhelmed and cause pain, alter the microbiota and interact immunologically to cause inflammation that may contribute to autoimmune-type reactions. Also, the initiation of inflammatory processes in the liver and impaired insulin and Nrf2/HO-1 signaling and diabetes can generate long-lasting inflammatory processes in the brain and other peripheral complications may even be more detrimental. (Ehses)

It is interesting to note that both high levels and low levels of H2S are associated with diabetes. Dr. Whiteman from the Northcott Devon Medical Foundation reports reduced levels of H2S in the blood of patients with diabetes. Lower levels of H2S were found to be important clinical markers for microvessel functioning which is an important complication of diabetes (ScienceDaily). Considering that Nrf2 modulates the effects of H2S from HO-1,this has important implications for the role of Nrf2. Maybe homeostasis becomes unbalanced at both high and low H2S levels which may be a consequence of impaired Nrf2 signaling. Oh describes that H2S and Ho-1 can inhibit the damaging effects of NO and NF-kappaB from LPS endotoxin and that down-regulation of H2S/CSE in lung injury pathology includes down-regulation of NO/iNOS and upregulation of CO/HO-1 (Zhou). (Jee whiz, I feel like I am on a roller coaster ride - up, down, up, down! Just kidding!) The point here is how we see the modulation of two neurogasotransmitters.

Recently it has been reported that antagonizing TRPA1 channels for a prolonged period reduces some of the symptoms associated with diabetic hypersensitivity (Wei). Hyperglycemia is an important consequence of insulin resistance and diabetes which produces alterations in mitochondrial function and as Bonnard shows from his findings the mitochondrial dysfunction is a consequence of insulin resistance and result of ROS generation in diet-induced diabetic mice. Diet is an important source for the ingestion and propagation of intestinal bacteria in the intestinal tract. Mitochondrial dysfunction generates reactive species especially H2O2 from NADPH which can alter cell signaling and cause further damage to cells.

Fibromyalgia is suspected to be at least in part, a condition associated with neuropathic pain in which nociception plays an important role. Ro presents evidence that both TRPV1 and TRPA1 contribute to muscle nociception and hyperalgesia and elevations inflammatory mediators, H2O2 and other ROS increase their expression as well as, sensitize them. In addtion, chronic and consistent activation of TRP channels may lead to endoplasmic reticulum stress and the effects of ER stress are usually attenuated through HO-1 (Liu) but Fallahi shows in his presentation that Nrf2 signal decline following activation of the ER stress response. Andre explains aldehydes, which acrolein is one in cigarette smoke and also present in cooking oil and combustive products, are the main cause of neurogenic inflammation mediated through TRPA1 and suggests this channel may add to smoking pathologies. Acrolein also triggers endoplasmic reticulum stress. Haberzetti writes acrolein is also produced from the metabolism of numerous drugs, in addition to be a major irritant in cigarette smoke and through his observations, he determined that exposure to acrolein induces ER stress including the unfolding response and implicates NF-kappaB and production of cytokines as important factors in the process. Zhang demonstrated that acrolein up-regulates HO-1 through the gene promoter Nrf2 and silencing Nrf2 attenuated significantly the response of HO-1 to acrolein. The result of which could include an increase in the toxic effects of smoking. From this study one can see that Nrf2 knock-out would increase sensitivity in the respiratory tract to cigarette smoke.  Roy reveals further details in showing that acrolein can either lead to an adaptive response at low doses, presumably through the up-regulation of HO-1 through Nrf2 or lead to death processes. At higher doses, mitochondrial-induced apoptotic processes are more apt to ensue. This is also the case if the adaptive process can not mitigate the effects of the toxicant.

Nociceptive behavior seems to be an important part of many of the environmental illnesses including fibromyalgia, airway hypersensitivity and other lung disease, degenerative diseases and multiple chemical sensitivity(MCS), just to name a few. One symptom often reported by those who suffer from MCS is a chronic and annoying cough from cigarette smoke and air pollution. Birrell recently showed that activation of TRPA1 by its agonists can lead to chronic cough and incidentally the "agent" he used in his experiment was acrolein which activated both TRPA1 and vagal nerves. The author points out that current cold remedy treatments are usually not effective for this kind of cough and there a number of TRPA1 ligands, and therefore are number of TRPA1 triggers that can generate a cough. This study might help to explain the persistant cough in many MCS patients. Of course, many chemicals can bind to particulate matter and therefore activate TRPA1 receptor and stimulate chronic cough. Caterina notes that TRPA1 can be activated in a different manner than just binding and this is achieved by TRPA1 ligands attaching themselves to cysteine residues on the channel which may change the structure and lengthen the time of activation. Bang explains that activators of TRPA1 are reactive eletrophile species. Meaning they are all able to effect gene expression by reacting with nucleic acids, proteins and other small molecules (Farmer) and include acrolein, mustard oil, iodoacetamide etc.  In addition, there are also non-electrophile activators which include menthol, THC, camphor and others. (Bang) TRPA1 also reacts to the ROS, H2O2. In addition, these compounds induce the expression of the enzymes of the Nrf2 detoxification system. Caterina explains, "there may be a so-far unexplained mechanism of cooperation between Nrf2 and TRPA1 that has not been identified". He could be referring to the now understood role of nociception and the ER stress response which involves PERK/Nrf2 or may be referring to some other mechanism. Madeira demonstrates that H2S is protective against gastic damage and in a similar study this is achieved by the down-regulation of NO and the up-regulation of CO/HO-1. He also suggests that TRPV1, at least in this case, plays some part in this protection. The similarities between Caterina's and Madiera's study are worth noting and may suggest interaction between TRP receptors and Nrf2 is important for the protective benefits of the gasoneurotransmitters.

The aryl hydrocarbon (AhR) may be another important factor in multiple chemical sensitivity. In addition to smoke mediated COX-2 and prostaglandin production and contributing to inflammation induced lung disease, the AhR is involved in the detoxification of polyaromatic and polyhalogenic hydrocarbons. Both classes include a number of chemicals that are present in the environment and used in manufacturing and agriculture. Also, abherrant functioning of the AhR is believed to be responsible for mediating the toxicity of dioxins which is also in cigarette smoke. In addition, to the ER stress response activation from cigarette smoke. Cigarette smokes also activates the AhR and also alters adipocyte differentiation and down-regulated the expression of adiponectin, PPAR-gamma and other markers and elevated MCP-1(Shimada) . There may be some negative control of the Nrf2/HO-1 pathway by cigarette smoke which can elevate levels of adiponectin and suppress levels cytokine levels (Kim). The absence of the aryl hydrocarbon is responsible for toxicities of other chemicals as well. It was reported last week that endotoxin which has been shown to be a trigger for chronic fatigue syndrome, is detoxified by the activities of the aryl hydrocarbon. Any dysfunction in this protein could lead to unexpected consequences and an increased sensitivity to endotoxin. It is important to remember here that Nrf2 is both modulated and modulates the AhR. Abnormal signaling by either one could lead to consequences related to toxicity. In addition, the beneficial activities of the AhR are inhibited by Tnf-a. Impaired Nrf2 which modulates the inflammatory mediator will only add to toxic effects in a negative way. Recent studies show endotoxin  causes endoplasmic reticulum failure "possibly by actions of the mitochondria" which would lead again, to reduction of Nrf2 (Koslov).   Endotoxin is extremely common in the environment in air and water pollution and therefore, it should be of particular concern for those with multiple chemical sensitivities as well as other conditions including those with dysfunction in immune regulation.

Related Reference:

• Slide Presentation: Loss of nrf2 dependant signaling following induction of endoplasmic reticulum stress.

Citations and Original Document

TNFR1, TRPV1 and Inflammation.

Title: Reactive oxygen species mediate tnfr1 increase after trpv1 activation in mouse drg neurons.

Summary: It has been demonstrated the TNFR1 receptor is important for neuroinflammatory responses by MCP-1 and TNFR2 and Nf-kappaB signaling are important to antagonize TNFR1 signal-induced apoptosis. (Marchetti) Ma et al explains how Tnf-a causes nociceptive responses through TNFR1 activation. This study shows TNFR1 and ROS is absent in mice deficient of TRPV1. The conclusions from this study were that TRPV1 activation increases the TNFR1 receptor in culture DRG neurons through a ROS signaling pathway that can lead to pain generation during inflammation.

Notes:

• Foxo3a controls the increased expression of TNFR2 which prevents Tnf-mediated apoptosis (programmed cell death). (Ding)   
• Foxo3a is decreased in Nrf2 null mice. (Hu)

Related Posts:

• Antioxidant System Regulates Aging Genes and Loss Can Lead To Cell Death! 

Citations: Ma, F., Zhang, L., and Westlund, K. N. (2009). Reactive oxygen species mediate tnfr1 increase after trpv1 activation in mouse drg neurons. Molecular pain, 5(1):31+. http://www.citeulike.org/user/HEIRS/article/4934284
Ding, B., Kirkiles-Smith, N. C., and Pober, J. S. (2009). Foxo3a regulates oxygen-responsive expression of tumor necrosis factor receptor 2 in human dermal microvascular endothelial cells. J. Biol. Chem., 284(29):19331-19339. http://www.citeulike.org/user/HEIRS/article/5725120
Pradillo, J., Hurtado, O., Romera, C., Cardenas, A., Fernandeztome, P., Alonsoescolano, D., Lorenzo, P., Moro, M., and Lizasoain, I. (2006). Tnfr1 mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 138(4):1171-1178. http://www.citeulike.org/user/HEIRS/article/5699676
Marchetti, L., Klein, M., Schlett, K., Pfizenmaier, K., and Eisel, U. L. (2004). Tumor necrosis factor (tnf)-mediated neuroprotection against glutamate-induced excitotoxicity is enhanced by n-methyl-d-aspartate receptor activation: Essential role of a tnf receptor 2-mediated phosphatidylinositol 3-kinase-dependent nf-kappab pathway. J. Biol. Chem., 279(31):32869-32881. http://www.citeulike.org/user/HEIRS/article/4080104
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TRPV1 and Endoplasmic Reticulum Stress

Activation of TRPV1 can cause endoplasmic reticulum stress which follows a pathway that leads to Nrf2 and unfolded protein response. Diabetes can lead to the unfolded protein response. In addition, chronic diabetic neuropathy can lead to nerve degeneration. DRG from diabetic rats show increased oxidative stress and cell injury. TRPV1 may be an early characteristic of diabetic sensory neuropathy.

• Note: Vitamin D has some preventative characteristics on endoplasmic reticulum stress.
  

Hong, S., Agresta, L., Guo, C., and Wiley, J. W. (2008). The trpv1 receptor is associated with preferential stress in large dorsal root ganglion neurons in early diabetic sensory neuropathy. Journal of Neurochemistry, 105(4):1212-1222.http://www.citeulike.org/user/HEIRS/article/2733060Civelek, M., Manduchi, E., Riley, R. J., Stoeckert, C. J., and Davies, P. F. (2009). Chronic endoplasmic reticulum stress activates unfolded protein response in arterial endothelium in regions of susceptibility to atherosclerosis. Circ Res, pages CIRCRESAHA.109.203711+. http://www.citeulike.org/user/HEIRS/article/5432618

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.
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