Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease.

Background: Nrf2 is a regulator of the antioxidant system including the production of HO-1 that provides protection against a number of toxic insults and GSK-3b acts as an on/off switch of that system. In addition, it has been shown that GSk-3b regulates the inflammatory response of LPS endotoxin through modulation of toll receptors. TLR4 has been shown to be instrumental in initializing and maintaining neuropathic pain.

Infante, J., García-Gorostiaga, I., Sánchez-Juan, P., Sierra, M., Martín-Gurpegui, J. L., Terrazas, J., Mateo, I., Rodríguez-Rodríguez, E., Berciano, J., and Combarros, O. (2009). Synergistic effect of two oxidative stress-related genes (heme oxygenase-1 and gsk3β) on the risk of parkinson's disease. European Journal of Neurology, 9999(9999). http://www.citeulike.org/user/HEIRS/article/6426071


HEIRS Library Tags: GSK-3b, HO-1

Supplemental citation: Martin, M., Rehani, K., Jope, R. S., and Michalek, S. M. (2005). Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nature immunology, 6(8):777-784. http://www.citeulike.org/user/HEIRS/article/2605
Hutchinson, M. R., Zhang, Y., Brown, K., Coats, B. D., Shridhar, M., Sholar, P. W., Patel, S. J., Crysdale, N. Y., Harrison, J. A., Maier, S. F., Rice, K. C., and Watkins, L. R. (2008). Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (tlr4). The European journal of neuroscience, 28(1):20-29. http://www.citeulike.org/user/HEIRS/article/2997140

Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat

Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat: "URL: Chronic treatment of silymarin improves hyperalgesia and motor nerve conduction velocity in diabetic neuropathic rat

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Glial inhibitors influence the mrna and protein levels of mglu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain

Glial inhibitors influence the mrna and protein levels of mglu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain.


Osikowicz, M., Skup, M., Mika, J., Makucha, W., Czarkowska-Bauch, J., and Przewlocka, B. (2009). Glial inhibitors influence the mrna and protein levels of mglu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. PAIN, (147):175-186. http://www.citeulike.org/user/HEIRS/article/6208092

U-M Receives $1.8 Million to Develop Therapy for Neuropathic Pain

Researchers from the University of Michigan Department of Neurology have received a $1.8 million grant to develop a novel therapy for neuropathic pain, a difficult to treat condition.

LINK

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.

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.

Copper and Magnetic Bracelets 'Useless' in Pain and Stiffness of Arthritis

Copper bracelets and magnetic wrist straps are useless for relieving pain in people with arthritis, say University of York researchers. Click here...

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:

 

Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis

Autoimmune Neuritis: Peripheral nerve inflammation caused by injury, poisoning, or disease, and accompanied by sensory and motor changes in the area of the affected nerve.

Title: Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis.

Summary: "is the first report to show iNOS- and TNF--immunoreactive cells in dorsal root ganglia during EAN, suggesting an underlying pathology for the neuropathic pain behavior in EAN. Our results suggest that the cells bearing iNOS and TNF- in the different parts of the peripheral nervous system are involved in the development of the clinical signs observed at each stage of EAN."

De La Hoza, C. L. R., Castrob, F. R., Santosc, L. M. B., and Langonec, F. (2010). Distribution of inducible nitric oxide synthase and tumor necrosis factor- in the peripheral nervous system of lewis rats during ascending paresis and spontaneous recovery from experimental autoimmune neuritis. Neuroimmunomodulation, 17(1). http://www.citeulike.org/user/HEIRS/article/5891598

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