BDNF, LRRK and Pink and Environment Play Role in Parkinson's Disease~!

"PD risk is modulated by both genetic factors including BDNF, PINK, and LRRK and environmental exposures."

Read more: CiteULike: Lrrk2 S1647T and BDNF V66M interact with environmental factors to increase risk of Parkinson's disease.:

Flavonoids May Modulate BDNF and Amyloid In Alzheimer's ~!

"stimulating BDNF and reducing Aβ toxicity by natural flavonols provide a therapeutic implication for treatment of AD."


Hou, Y. et al. Anti-depressant natural flavonols modulate BDNF and beta amyloid in neurons and hippocampus of double TgAD mice. Neuropharmacology 58, 911-920 (2010). URL http://dx.doi.org/10.1016/j.neuropharm.2009.11.002.


Related:
Health and Environmental Illness Blog: Solvents, PAHs and BDNF as a Modulator of TrkB, Anxiety and Nrf2~!

Nrf2's Regulation of NRF1 and Its Influence on NMDA Subunits and Environmental Illness - see comments.

BDNF and Other Neutrophic Factors May Prevent Seizures and Assoc. Inflammation!

Bovolenta, R. et al. Hippocampal FGF-2 and BDNF overexpression attenuates epileptogenesis-associated neuroinflammation and reduces spontaneous recurrent seizures. Journal of neuroinflammation 7, 81+ (2010). URL http://dx.doi.org/10.1186/1742-2094-7-81.

Solvents, PAHs and BDNF as a Modulator of TrkB, Anxiety and Nrf2~!

In other blogs, we have discussed how BDNF may play important roles for neuron health and therefore, may play an important role in environmental illnesses. This neutrophic factor is an important regulator in pathways of the cell. Older studies suggest it regulates the PI3K-Nrf2 pathway and Donovan explains that BDNF-TrkB are important for hippocampal regulation. This new studies further supports the role of BDNF in anxiety disorders and possibly others like PTSD. Other studies have shown that "chronic exposure to solvents has a number of health effects including abnormal EEG's, altered sense of smell, numbness or weakness in the extremities, emotional problems, including depressive tendencies, anxiety and social withdrawal. Also, frequent associations between the sense of well being and the cognitive functioning were reported by many authors. Hegazy et al suggests that some of the symptoms related to solvent exposure may be from downregulation of protein expression including BDNF and the activation of the AhR in response to some pollutants may influence BDNF expression as well. (Lin)  This has important implications overall, for the effects of solvent use and their hazards on the modulation of the antioxidant system in general. Taking these studies into account and others in recent months, it has been suggested that modulation through pharmacological or flavonoid therapy may provides benefits and correction of this pathway and be important for neurological disorders such as Parkinson's disease.

"11 base pair deletion in TrkB is significantly associated with increases in anxiety traits during childhood and the development of anxiety disorders in adulthood. We found that this deletion impaired transcription in some human cell lines"

Read more: CiteULike: A Deletion in Tropomyosin-Related Kinase B and the Development of Human Anxiety.:

Comment: In yesterdays blog, I noted how PAH may negatively effect autism genes and becomes an important consider also!


Related Tags: neurotrophins, BDNF, Nrf2


Ernst, C., Wanner, B., Brezo, J., Vitaro, F., Tremblay, R., and Turecki, G. (2010). A Deletion in Tropomyosin-Related Kinase B and the Development of Human Anxiety. Biological psychiatry.
http://www.citeulike.org/user/HEIRS/article/8364218
Nakaso, K., Nakamura, C., Sato, H., Imamura, K., Takeshima, T., and Nakashima, K. (2006). Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins. Biochemical and biophysical research communications, 339(3):915-922. http://www.citeulike.org/user/HEIRS/article/5770676?show_msg=already_posted
Donovan, M. H., Yamaguchi, M., and Eisch, A. J. (2008). Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus. Hippocampus, 18(5):435-439. http://www.citeulike.org/user/HEIRS/article/8364397
Hegazy, N. M., Abdel Gawad, N. B., Metwally, F. M., Ahmed, H. H., Abdel Raouf, E. R., Abrahim, K. S., and Sharaf, N. E. (2010). Neurotoxic effects of organic solvents in exposed workers: Altered expression of some biochemical markers. New York Science Journal, 3(11):171-176.
http://www.citeulike.org/user/HEIRS/article/8364905
Sheng, L., Ding, X., Ferguson, M., McCallister, M., Rhoades, R., Maguire, M., Ramesh, A., Aschner, M., Campbell, D., Levitt, P., and Hood, D. B. (2010). Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicological sciences : an official journal of the Society of Toxicology, 118(2):625-634. http://www.citeulike.org/group/6113/article/8357284

Lin, C.-H. H., Chen, C.-C. C., Chou, C.-M. M., Wang, C.-Y. Y., Hung, C.-C. C., Chen, J. Y., Chang, H.-W. W., Chen, Y.-C. C., Yeh, G. C. C., and Lee, Y.-H. H. (2009). Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons. Journal of neurochemistry, 111(3):777-789. http://www.citeulike.org/user/HEIRS/article/5817355?show_msg=already_posted
Jiang, X., Tian, F., Mearow, K., Okagaki, P., Lipsky, R. H., and Marini, A. M. (2005). The excitoprotective effect of N-methyl-D-aspartate receptors is mediated by a brain-derived neurotrophic factor autocrine loop in cultured hippocampal neurons. Journal of neurochemistry, 94(3):713-722.  http://www.citeulike.org/user/HEIRS/article/258195
Tuon, T., Valvassori, S. S., Lopes-Borges, J., Fries, G. R., Silva, L. A., Kapczinski, F., Quevedo, J., and Pinho, R. A. (2010). Effects of moderate exercise on cigarette smoke exposure-induced hippocampal oxidative stress values and neurological behaviors in mice. Neuroscience letters, 475(1):16-19. http://www.citeulike.org/user/HEIRS/article/6900487

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.

"These results suggest that, by recruiting cyclic GMP and PKG, nNOS-derived nitric oxide plays a novel and essential role in RAR signaling leading to ERK-dependent BDNF up-regulation in midbrain dopaminergic neurons."

Midbrain dopaminergic neurons utilize nitric oxide/cyclic GMP signaling to recruit ERK that links retinoic acid receptor stimulation to up-regulation of BDNF.:

Dr. Francis Lee on the BDNF molecule and anxiety disorder research- Watch!

"BDNF stands for brain derived neurotrophic factor. This molecule, found in the brain's fear hub could have a significant impact on the study of anxiety disorders including Post Traumatic Stress Disorder. Dr. Francis Lee of Weill-Cornell Medical College is a leading BDNF investigator and was a recent guest lecturer at the National Institute of Mental Health." Read more or watch...

NIMH · Speaking of Science - Dr. Francis Lee on the BDNF molecule and anxiety disorder research:






Read:
Article: Inducing a safety memory in the brain

For further reading: HEIRS Blog Tags: BDNF



****HEIRS Library: BDNF






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The BDNF Val66Met Polymorphism Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Hippocampus

"Consistent with the NMDA receptor-dependent synaptic plasticity impairment, we observed a significant decrease in NMDA receptor neurotransmission in the CA1 pyramidal neurons of BDNFMet/Met mice. Thus, these results show that the BDNF Val66Met polymorphism has a direct effect on NMDA receptor transmission, which may account for changes in synaptic plasticity in the hippocampus."

Link:CiteULike: The BDNF Val66Met Polymorphism Impairs NMDA Receptor-Dependent Synaptic Plasticity in the Hippocampus:

Caffeine Modulates Pathway That May Have Neurological Benefit!

Caffeine may have ability to enhance activity-dependent Bdnf expression may contribute to the neurological benefit observed in infants receiving caffeine treatment.

Note: BDNF has been implicated in conditions including chronic fatigue syndrome, PTSD and mood disorders.



CiteULike: Caffeine modulates CREB-dependent gene expression in developing cortical neurons.: "caffeine to enhance activity-dependent Bdnf expression may contribute to the neurological benefit observed in infants receiving caffeine treatment."

Boosting Brain Hormone May Have PTSD/Anxiety Implications

Boosting BDNF activity in hippocampal-infralimbic circuits may ameliorate disorders of learned fear.

CiteULike: Induction of fear extinction with hippocampal-infralimbic BDNF.: "Peters, J., Dieppa-Perea, L. M., Melendez, L. M., and Quirk, G. J. (2010). Induction of fear extinction with hippocampal-infralimbic bdnf. Science (New York, N.Y.), 328(5983):1288-1290."

Painful Memories may be Erased by Anti-Fear Drug

Painful Memories may be Erased by Anti-Fear Drug: "Scientists have said that it is possible to overcome bad memories of painful situations with the help of a chemical that works on the brain.....
The chemical, called brain-derived neurotrophic factor (BDNF), is naturally produced in the brain and is involved in learning and memory. When given to the rats, the drug caused them to re-learn a painful association so that the memory of it is extinguished - although not lost entirely."

Read more: Painful Memories may be Erased by Anti-Fear Drug

HEIRS Tag: Blog BDNF
Library BDNF

Postive Effects of Exercise on Memory from BDNF Resistance to Corticosterone.

Corticosterone is a main glucocorticoid  involved in regulation of fuel, immune reactions, and stress responses. (Corticosterone: Wipedia)

"This study suggests that the resistance of the hippocampal BDNF expression to suppression by corticosterone, as seen after water maze training, may contribute to an optimal memory performance." (Schaff)

Comment: It has been suggested that exercise exerts its influence by increasing a number of different hormones and cellular activators including BDNF and enhances memory and learning by activating the antioxidant system. (Ayoub) BDNF has been implicated as a factor in a number of mood disorders and altered levels in conditions including PTSD, fibromyagia and CFS and proteins such as GSK-3b may alter BDNF's downstream regulators. (Mai)
For more: HEIRS Library Tag: BDNF  
Related Blogs: BDNF 

Recommended:
















CiteULike: Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation.: "suggest that the resistance of the hippocampal BDNF expression to suppression by corticosterone, as seen after water maze training, may contribute to an optimal memory performance."
Schaaf, M. J., De Kloet, E. R., and Vreugdenhil, E. (2000). Corticosterone effects on bdnf expression in the hippocampus. implications for memory formation. Stress (Amsterdam, Netherlands), 3(3):201-208. http://www.citeulike.org/user/HEIRS/article/7224956




Other Sources:
Ayoub, R. S. (2009). Effect of exercise on spatial learning and memory in male diabetic rats. 18(3). http://www.citeulike.org/user/HEIRS/article/7224997
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















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Gene that changes the brain’s response to stress identified

You may recall I have written about the potential of the influence of this hormone on a number of illnesses....

HEIRS  Research Tag: BDNF


Gene that changes the brain’s response to stress identified

"Research identifies gene that changes the brain’s response to stress"

The Rockefeller University » Newswire: "Research identifies gene that changes the brain’s response to stress"

BDNF in Obsessive Compulsive Disorder.

Serum levels of brain-derived neurotrophic factor in drug-naïve obsessive–compulsive patients: A case–control study

BDNF Regulates Hedonic Feeding by Acting on the Dopamine System

"amperometric recordings in brain slices of mice depleted of central BDNF uncovered marked deficits in evoked release of dopamine in the nucleus accumbens (NAc) shell and dorsal striatum but normal secretion in the NAc core."

Brain-Derived Neurotrophic Factor Regulates Hedonic Feeding by Acting on the Mesolimbic Dopamine System -- Cordeira et al. 30 (7): 2533 -- Journal of Neuroscience:

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

Ammonia, ASIC Channels and Mental Health

We recently have been discussing how the biological accumulation of ammonia may be an important condition related to a number of environmental illnesses. In fact, several studies suggest that accumulation of ammonia may contribute to autism and others note it plays a very important role in hepatic failure. As we noted, elevated levels of homocysteinemia may impair the urea cycle - which helps the body get rid of excess ammonia and glutamine synthetase genes of the Wnt/Catenin pathway, also regulate  ammonia concentrations in the body. Interestingly, several "so-called therapies" for MCS also have the capacity to reduce ammonia. Also, it is well-known that psychological disturbances are co-morbid with a number of environmental conditions, in addition to those mental effects associated with autism and liver disease.

In light of the potential for elevated ammonia levels to influence the psychological and physical effects of environmental disease, I thought I would point out two interesting studies. The first is a study that suggests that ASIC channels contribute to the health consequences where hyperammonemia becomes an issue. As the author points out, this may include hepatic encephalopathy, cirrhosis and neuronal disorders. This study discusses how these types of channels have been implicated in neuronal death after their activation. Incidentally, nociceptive behavior is associated with acidic environments that develop from injury and inflammation and therefore could play a role in the pain generation in environmental illnesses including  MCS (Pall) and chronic fatigue syndrome (Light).  Pidoplichko provides evidence the involvement of these channels may contribute to the loss of dopamine neurons in Parkinson's disease because these channels are associated with those neurons and "ammonium sensitivity is a widely distributed ASIC characteristic in the CNS, including the hippocampus." The second study seems to suggest that these same channels have an important role in the development of depression-related behavior by demonstrating genetically altered -/- mice presented with anti-depressant-like behaviors even while put under experiemental stress. In addition, the dysruption of these channels interfered with an important "biomarker of depression" which is a decrease of levels of BDNF in the hippocampus. In past blogs, we have explained how BDNF is important for "olfactory neurogenesis" and may be important consideration in the development of MCS.  Coryell concludes by saying that his "findings of ASIC1 signaling in the amydala in mood regulation support others and that pharmaceutical approaches that target ASIC1 signaling may be therapeutic for this kind of depression. We might propose that investigating therapies that reduce ASIC signaling may be beneficial for a number of environmentally-related conditions may be of value.

Notes:

• A recent study shows that HO-1 activates bilirubin and CO to modulate BDNF/GDNF in neurons and astrocytes. This provides a protective effect on dopaminergic neurons.

Coryell, M. W., Wunsch, A. M., Haenfler, J. M., Allen, J. E., Schnizler, M., Ziemann, A. E., Cook, M. N., Dunning, J. P., Price, M. P., Rainier, J. D., Liu, Z., Light, A. R., Langbehn, D. R., and Wemmie, J. A. (2009). Acid-sensing ion channel-1a in the amygdala, a novel therapeutic target in depression-related behavior. J. Neurosci., 29(17):5381-5388. http://www.citeulike.org/user/HEIRS/article/6607146
Pidoplichko, V. I. and Dani, J. A. (2006). Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proceedings of the National Academy of Sciences of the United States of America, 103(30):11376-11380. http://www.citeulike.org/user/HEIRS/article/6607127
Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. http://www.citeulike.org/user/HEIRS/article/5370052
Ugawa, S., Ueda, T., Ishida, Y., Nishigaki, M., Shibata, Y., and Shimada, S. (2002). Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. The Journal of clinical investigation, 110(8):1185-1190. http://www.citeulike.org/user/HEIRS/article/2942104
Pall, Martin (2007). Explaining Ünexplained Illnesses": disease paradigm for chronic fatigue syndrome, multiple chemical sensitivity, fibromyalgia, post-traumatic syndrome, Gulf War syndrome, and others. Harrington Park Press:Hawthorne Press, 10 Alice Street Binghampton NY 13904. http://www.citeulike.org/user/HEIRS/article/3042479
Hung, S.-Y. Y., Liou, H.-C. C., and Fu, W.-M. M. (2010). The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression. Neuropharmacology, 58(2):321-329. http://www.citeulike.org/user/HEIRS/article/6196852

Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression.

CiteULike: Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microRNA-132 expression.:

"Kawashima, H., Numakawa, T., Kumamaru, E., Adachi, N., Mizuno, H., Ninomiya, M., Kunugi, H., and Hashido, K. (2009). Glucocorticoid attenuates brain-derived neurotrophic factor-dependent upregulation of glutamate receptors via the suppression of microrna-132 expression. Neuroscience."

LTP mechanisms in the dentate gyrus in vivo: BDNF signaling, translation control, and gene function

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: