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.
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)
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)
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