Elevated Levels of Ammonia Impair the NO/cGMP Through Alterations of Cellular Transporters~!

In other blogs, I have suggested that alterations in the NO/cGMP pathway by environmental factors may influence environmental disease including CFS and MCS. Several recent studies have suggested a relationship between the NO/cGMP pathway and the activation of the Nrf2. Because the Nrf2 has a neuroprotective role on astrocytes and neurons, the failure of this pathway could contribute to neurological damage commonly associated with aging as well as, other neurological disorders. In this most recent study, the author provides more evidence that in cases of hyperammonemia, the No/cGMP pathway activity is decreased and therefore, may provide some explanation for damage resulting from high ammonia levels.

"reduced delivery of Arg due to enhanced y(+)LAT2-mediated exchange of extracellular Gln for intracellular Arg may contribute to the decrease of NO/cGMP pathway activity evoked in the brain by HA."

Zielińska, M., Ruszkiewicz, J., Hilgier, W., Fręśko, I., and Albrecht, J. (2010). Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y(+)LAT2 in rat cerebral cortex: implications for the nitric oxide/cGMP pathway. Neurochemistry international. http://www.citeulike.org/user/HEIRS/article/8341074
Sidoryk-Wegrzynowicz, M., Wegrzynowicz, M., Lee, E., Bowman, A., and Aschner, M. (2010). Role of Astrocytes in Brain Function and Disease. Toxicologic pathology.  http://www.citeulike.org/user/HEIRS/article/8341171

Ammonia and Hyperammonemia Increase the Extracellular Accumulation/ Degradation of Astroglia-Derived Glutathione.

These results suggest that in rats with HA or HE ammonia specifically promotes GSH synthesis and export from astrocytes and increases its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity.

CiteULike: Direct Exposure to Ammonia and Hyperammonemia Increase the Extracellular Accumulation and Degradation of Astroglia-Derived Glutathione in the Rat Prefrontal Cortex: "Hilgier, W., Wegrzynowicz, M., Ruszkiewicz, J., Oja, S. S., Saransaari, P., and Albrecht, J. (2010). Direct exposure to ammonia and hyperammonemia increase the extracellular accumulation and degradation of astroglia-derived glutathione in the rat prefrontal cortex. Toxicol. Sci., pages kfq171+."

Ammonia, Smoking,Insulin Resistance and Protein Dysfunction in MCS

Background: Manufacturers of cigarettes have admitted to adding ammonia since the 1960s to make them more addictive by boosting the absorption of nicotine significantly. This may make cigarette smoke more toxic to some including people that are more vulnerable such as young children with immature immune systems, the elderly or other individuals that have urinary impairments or genetic factors that alter excretory metabolism. Below are some examples of why adding ammonia to cigarettes may be indirectly responsible, at least in part, for the rise in cardiovascular and other diseases from smoking because of its toxic effects on genes and different tissues in the body.

In cells, chemical toxins effect metabolic pathways which may run parallel, are independant and/or interact, potentiate or possibly minimize the effects of each another.   For this reason, it is difficult to predict the severity and the consequences of them on the health of an organism. Exposure to cigarette smoke is no different and has been shown to act differently in different people and on more than one molecular pathway at the same time. Through the years, hundreds of studies have demonstrated the health hazards associated with the toxic effects of smoking and one of these effects includes the dysregulation of metabolism including altering blood sugar homeostasis. Personally, I have suspected this to be the case for some time. Over the past several years, scientists have discovered smoking not only increases the risk for diabetes which includes higher glucose levels, higher insulin levels and increased blood pressure it may also contribute to episodes of hypoglycemia in diabetes. As one article state, "this may be due to an effect of smoking on insulin clearance, leading to hyperinsulinemia, increasing hypoglycemia, and worsening metabolic control. In addition, smoking has been shown to increase the secretion of hormones (i.e., growth hormone, vasopressin, and cortisol) that counteract insulin action, leading to an increased insulin requirement. Smokers have been found to require more insulin than nonsmokers to achieve the same level of glycemic control in some, but not all, studies." (Hirai)

In addition to ammonia making cigarettes more addictive, ammonia can act on the cortico-releasing factor (CRF) system which regulates behavior including feeding and increases serotonin and dopamine levels. As a consequence, it can influence mood and alter homeostasis leading the conditions like the weight loss and weight gain from smoking and cessation, respectively.  Activation of this pathway, in fact, mediates  psychological effects of nicotine withdrawal.  (Grunberg) I recently mentioned that because ammonia activates the CRF pathway that regulates neuroendocrine, drug abuse responses and aversion one could relate MCS behaviors to a scewed form of addictive behavior. (Kreibich, Sahuque) More simply, its activation leads to changes in hormone production and alter behaviors, it is possible that abherrant signaling in this system may be responsible for some of the symptoms of MCS and similar to those from chemical withdrawal but modified into aversive response. It is also possible the addictive nature of smoking from ammonia or other volatiles on the CRF from smoke exposure could be a sensitizing factor, stimulate the immune system and also initiate a "loss of tolerance" which has been suggested as an explanation of multiple chemical sensitivity and sensitivities in autism. An interesting research study could be designed to determine wether a potential correlation of MCS sensitization and smoking could exist.

To support this idea further, researchers have demonstrated the addictive nature of smoking involves a cellular pathway called CREB that involves the relationship of reward to smoking behaviors and their association with environmental cues.  Also, recent research findings show a strong association of CREB and CRF in stress-induced drug reward behavior. It is not beyond reason to suggest that alterations in signals that lead to physical and psychological symptoms of drug withdrawal may also influence physical and emotional aversive behaviors of MCS and argues against the notion of that symptoms of MCS are "psychosomatic".  The high levels of cadmium may further disrupt the CREB pathway and normal cell functions.  Both of these discoveries provide an important mechanism to explain activation of MCS by environmental cues and suggests that insulin resistance may play a part in some of its reactions. "Previously,it has been shown the CREB pathway keeps blood sugar in balance under certain metabolic conditions and excessive CREB activity in diabetes contributes to high blood sugar and insulin resistance. New findings show CREB encourages insulin resistance by lowering adiponectin and the insulin-sensitive glucose transporter 4 (GLUT4)." (US Health News) CREB is a mediator of inflammation and both of these findings demonstrate that overactive CREB may contribute to endothelial dysfunction and impair cognitive function by mediating inflammation and insulin resistance. (Ishiki)  On the other hand, downregulation of the cGMP/NO/CREB by amyloid or hyperammonemia may contribute to neurodegenerative diseases and Alzheimer's. (Copper Mountain, CO, Puzzo) This has important implications not only for cigarette smoke but persistent organic pollutants considering they both may contribute to diabetes complications.Other environmental factors such as other exposures to heavy metals implicated in contributing to diabetes and altered methylation may also contribute to these conditions. (Pozharny)

Along those same lines, cigarette smoking also contributes to weight loss through activation of the aryl hydrocarbon and endoplasmic reticulum stress. In other blogs, I have suggested this process also is involved in MCS. A recent study agrees with findings that cigarette smoke and dioxin does lower adiponectin but also demonstrated that PPAR-gamma and c/EPB were also decreased. In another study, ornithine impairments in c/EPB knock-outs from hypoglycemia presented with significantly higher levels of ammonia. Further, it has been shown ornithine enzymes interact with C/EPB and is important for ammonia detoxification. Without it, you get impaired excretion of urea and gluconeogenesis. As one can see, metabolically cigarette smoke may cause severe alterations in metabolism. This may include alterations of ammonia which may potentially sensitize an individual towards development and contribute to multiple chemical sensitivity.




Citations and other documents available here.

Thought for the Day: Hyperammonemia and Environmental Illness...

Does anyone see these as being familiar symptoms? To me, they seem like some common symptoms in CFS or exposures????

The symptoms and blood ammonia values of mild to moderate chronic hyperammemia (CH) are similar to those observed during physical exhaustion with ‘exercise-induced hyperammonemia’ (EIH). These include confusion, hyperventilation, and muscular dysfunction.....Treatments for lowering CH and EIH are similar, and include: 1) restriction of dietary
protein, 2) increasing carbohydrate (%) intake, 3) administration of amino acids (AA’s)that enhance ammonia clearance into (the less toxic) urea, and 4) correction of the underlying metabolic etiology

HEIRS Library Tags: Hyperammonemia
Blog Tags: Hyperammonemia, ammonia

Edwards, W. ARM CRANK POWER AND HYPERAMMONEMIA IN RESPONSE TO L-ASPARTIC ACID SUPPLEMENTATION. PhD thesis, Louisiana State University.
http://www.citeulike.org/user/HEIRS/article/7111333

Chronic Elevated Ammonia Contributes to Neuroinflammation, Cognitive and Motor Dysfunction.

CiteULike: Hyperammonemia Induces Neuroinflammation that Contributes to Cognitive Impairment in Rats with Hepatic Encephalopathy.: "Chronic moderate hyperammonemia or BDL activated the microglia, especially in cerebellum; increased iNOS, IL-1beta, and prostaglandin E2 levels; and impaired cognitive and motor function, compared with controls"

Chronic hyperammonemia alters the circadian rhythm... [J Neurosci Res. 2010] - PubMed result

Chronic hyperammonemia alters the circadian rhythm... [J Neurosci Res. 2010] - PubMed result: "Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats."

NO-cGMP and Mitochondrial Biogenesis -- Mediator of PGC-1a

As we have noted, hyperammonia may impair the NO-cGMP pathway. Nisoli explains, "nitric oxide-cGMP-dependent pathway controls mitochondrial biogenesis and body energy balance."

Nisoli, E., Clementi, E., Paolucci, C., Cozzi, V., Tonello, C., Sciorati, C., Bracale, R., Valerio, A., Francolini, M., Moncada, S., and Carruba, M. O. (2003). Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science (New York, N.Y.), 299(5608):896-899. http://www.citeulike.org/user/HEIRS/article/7030900





HEIRS Environmental Illness Research Blog: Dysfunction of Methylation and Nrf2 in Environmental Illness - A Better Explanation than NO/ONOO- ?

Dysfunction of Methylation and Nrf2 in Environmental Illness - Is This A Better Explanation than NO/ONOO- ?

One of the most important themes of my research is that accumulation of ammonia may play a causal role in including in conditions such MCS and autism through alterations in the methionine and glutamine synthetase pathway and elevations of ammonia in general which may change the expression of a variety of genes that regulate cell function. Of course, this has been suggested by a number of experts. Further, I also have proposed that the dysfunction in Nrf2 and related genes contribute to the severity and elicits autoimmune-type responses and chemicals such as PFOS may influence it or "trigger" it in addition to other chemicals that are more commonly considered as more toxic. In support, in support it has been suggested that hyperammonemia may alter that nitric-oxide-cGMP pathway (Hermenegildo) and as a result this could alter NO funtioning and contribute to conditions such as fibrosis in some tissuesand endothelial dysfunction. Alterations in the ornithine pathway may contribute to this but it is worth mentioning that NO may alter this pathway on it own. (Bauer) Interestingly, recently it has been reported that one of the benefits of fish oil may be mediated through the eNOS-cGMP pathway. (Lopez)  Nrf2 also has an important role in regulating NO and CO through its interaction with the antioxidant HO-1 and plays a substantial neuroprotective role against diseases such as Parkinson's disease. The deficiency or lack of Nrf2 expression offers one explanation of why individuals with MCS are so sensitive to carbon monoxide, nitrous oxide and other greenhouse gases. Mainly, because of the dysregulation of their regulator HO-1 by Nrf2. Tinnitus is common with MCS and can be associated with over-exposure to nitrous oxide which may also indicate problems associated with vitamin B and methylation. (Wipedia) Genetic polymorphisms in HO-1 and metal toxicity may also contribute to this problem. (You can see how lead, mercury and aluminum alter function in different steps in the cycle....here but you have to look closely.) Other Nrf2 interactions include modulation of Il-6 which is elevated in neuroinflammatory responses in the brain and Il-10 which is an anti-inflammatory that modulates sickness syndrome. According to a new report, sickness syndrome may be implicated in causing some of the symptoms of Gulf War Syndrome.


In addition, conditions such as elevations of ammonia activate the CRF pathway in animals that display hyperanxious behavior and recently this pathway has been shown to regulate both anxiety and depression as a consequence of stress. (Biomedicine) Interestingly, the glutamine pathway is also altered during depression and as a result, one may suggest this pathway may be dysregulated from exposure to chemicals such as PFOS and cause mood changes such as depression and anxiety and endogenous elevations of ammonia may induce mood changes even more. In addition, dysfunction of Nrf2 may lead to neurotoxicity and other consequences including augmenting ammonia accumulation. Chemical sensitivity has been implied as important in autism and ammonia may contribute to this which is produced endogenously and exogenously and many therapies used for MCS have also been used to reduce ammonia levels in autism. An interesting suggestion is that in some form through the dysfunction of Nrf2, deficits in the ornithine pathway contribute to the cellular toxicity experienced in MCS and autism. Of course, there are a number of other genetic defects that may alter the urea-cycle, including minor ones that may not appear until adulthood or later because of compensation from other pathways lost with ageing. Ammonia production is higher correlated with inflammatory markers in liver injury and has a profound effect on the permeability of the blood-brain-barrier, providing access of more toxic agents to brain tissue. (Jalan)

Alterations in the methionine pathway have also been suggested to play an important role in autism and we suggest here, MCS and relies on the notion of abherrant methylation "tagging" that potentiate the problems or vice versa. Q10 and vitamin B12 has been used as a therapy for MCS but is also used to assist mitochondrial function and support the methionine cycle and reduce ammonia, respectively. In methyl cycle disfunction, BH4 is drained in ammonia detoxification (Yasko ?) in addition in contrast to its role for NOS production and peroxynitrite which is part of the NO/ONOO- hypothesis. (Pall) Here we see the dichotomy between the Methyl Pathway and the NO/ONOO- hypothesis where BH4 is concerned. In one BH4-dependant process, NOS is converted to nitric oxide and on the other hand it assists in ammonia detoxification in the methylation cycle. If you put alterations in Nrf2 function, which is activated by ONOO- into the mix it can alter expression of genes important for these processes. ONOO- is not the only pro-oxidant that activates the Nrf2, it has been suggested that H2O2 is a much stronger activator and numerous other conditions normally upregulate Nrf2 in normal circumstances. Marzec recently demonstrated that SNPs that exist in the Nrf2 may make on more or less susceptible to oxidative stress and therefore cellular injury and disfunction. The inheritability hypothesis of epigenetics also relies on methylation and helps to explain why environmental illnesses largely run in families and the relationships between gene expression help to explain why gender plays an important role too! Unfortunately, alterations in methylation and consequently, alteration of function has been demonstrated in Nrf2 and several other genes implicated in environmental illness including autism. (To get an idea of how complicated genetics in environmental illness is --click here. ) In addition, alterations in Nrf2 and PGC-1a may contribute to diabetes and insulin resistance and are associated with POP exposures. In addition, GSK-3b involvement from reduced expression of PGC-1a, elevations in dopamine and exposures to bacteria (endotoxin) are a few additional factors that may hamper Nrf2 detoxification system which can lead to more elevations of neuroinflammatory processes, mood changes and significantly increase the likelihood of more neurodegeneration; all associated with environmental illness. GSK-3b signalling also may involve alterations in dopamine-regulated behaviors such as twitching (Tourette's) and ADHD that are often co-morbid with environmental illnesses after exposure injury. Incidentally, a number of behavioral responses to drugs (ie cocaine) can be reduced by GSK-3b inhibitors.

Currently, the NO/ONOO- cycle hypothesis which implicates elevation in ONOO as an important cause for responses in the conditions and proposed by Martin Pall, PhD is one of the most commonly accepted hypothesis to explain many of the symptoms in many environmental illnesses including MCS, chronic fatigue syndrome, fibromyalgia and PTSD. While this hypothesis is an important one, I can not say that it accurately describes the multi-inflammatory processes that occur in all of these illnesses and fails to adequately describe the metabolic processes that lead to these conditions. For one, obesity and insulin resistance and diabetes are important in environmental disease and the complications of ageing augment most of these and others as well. Recent evidence is highly suggestive these conditions may influence the development of the more commonly accept EI conditions and for this reason, I have to include them under that umbrella as well. In addition, there is no mention of methylation or how dysregulation of the antioxidant system Nrf2 negatively impacts the expression of NO, CO, HO-1, Il-10 as well as, modulates inflammatory cytokine expression. HO-1 (again with interaction from Nrf2) and vitamin D are involved in the suppressive function of regulatory Tcells. Their absence has been implicated in autoimmune disease that provides an explanation for why environmental illnesses like CFS and GWS and others including diabetes have autoimmune-type behavior. A recent study has presented the hypothesis that exposure to environmental pollutants and high ammonia levels directly alters Treg behavior. In would suggest the inability of oxidants including peroxynitrite and H2O2 to activate Nrf2 is one explanation for failure of the Nrf2 antioxidant system in addition to impairments in activation and regulation of Keap1 and genetic expression of the many genes that regulate the system in different ways. Not only does Nrf2 regulate NO but so does SIRT1 through AMPK, all of which are indirectly or directly involved in activating PGC-1a upregulated by exercise which prevents activation of GSK-3b that turns off the antioxidant system which provide upregulation of nuclear factors including NRF1. In further support, pharmaceutical therapies such as those that elevate PGC-1a and reduce ammonia levels, electroacupuncture, food therapies that elevate Nrf2 through sauna or Waon therapy and nutrition and antioxidant support to reduce mitochondrial dysfunction may be a valuable "tool kit" for the treatment of MCS, autism, provide some relief in CFS and PTSD and help prevent endothelial damage that may be instrumental in causing a number of conditions in many of them.

HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2, dopamine, DAR, cocaine, encephelopathy, Il-6, neuropathy, B12, methionine


HEIRS Tags: ammonia, hyperammonemia, homocitrulline, diabetes, insulin resistance, GSK-3b, HO-1, Nrf2, PGC-1a, SIRT1, AMPK, NO/ONOO-, H2O2,

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Original Article and Citations:

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

Preliminary Study Shows Polymorphism in Different Loci of Autism/Aspberger's Gene in Chronic Fatigue Syndrome.

A preliminary study suggests that a polymorphism in the DISC1 gene is associated with chronic fatigue syndrome. These findings, if found to be true, have important implications for the conditon, as well as, may have an influence on research findings of other environmental illnesses. DISC1 is also known as Disrupted in Schizophrenia and has been associated with a number of mental health conditions including schizophrenia, bipolar disorder and major depression. Just recently the gene has also been implicated in playing a role, in addition to other genes, in autism. We have noted before that some experts believe that conditions such as ADHD and certain types of MCS are in fact, autism spectrum disorders. As one author points out, DISC1 is responsible for a number of physiological activities including the production of new neurons during brain development and adult neurogenesis. A defective DISC1 gene which has been demonstrated in schizophrenia could lead to a reduction in dendritic spines and also influence nerve cells to maintain weaker connections with neighboring neurons and for the purpose of simplification, reduce the "cross-talk" between neurons by influencing dopamine production. If similar disruptions through mutation in DISC1 were to occur, it does make sense it may be involved in the development of autism because of its effect on the central nervous system. (Tsai)


Of course, the idea that it plays a role in chronic fatigue syndrome is a novel finding. From my standpoint, the idea that DISC1 may play a role in CFS makes a lot of sense. As I have described in other blogs, a protein called GSK-3b is an on/off switch for Nrf2 which provides a protective role against endogenous threats that may negatively influence neurotransmission  in autism. Recently, it was demonstrated that the Wnt pathway is a pathway involved in ammonia and urea excretion that also involves the activities of GSK-3b. Biochemically, one researcher writes that DISC1 inhibits GSK-3b and therefore, this pathway has been suggested to play the important role in a number of mood disorders which we noted earlier. Like most anything in cell biology, too much activity or too little can have dramatic effects on function. In the case of GSK-3b, blocking its abherrant signaling has been associated with symptomatic benefits in MS, colitis, sepsis and arthritis and conditions involving inflammation. The latter implicates an inhibitory role of GSK-3b signaling on Nrf2. Elevations of GSK-3b activity are also present in patients with Parkinson's disease and Alzheimer's. A recent report from MIT demostrates that DISC1 knock-out present with behaviors including hyperactivity, a characteristic of schizophrenia and GSK-3b inhibitors reversed these behaviors. The author suggests that the scewed balance of neural cell development and alterations in signaling may lead to compromised cognition and behavior alterations. (Halber) A polymorphism in DISC1 that has been suggested in CFS could very well lead to abherrant signaling from GSK-3b, elevations in oxidative stress and uncontrolled expression of inflammatory proteins and changes in redox because of subsequent loss of Nrf2 signaling. Of course, other factors such as genetic SNPs in Nrf2 and suppression of gene expression should also be considered.

Citations and Original Document

Ammonia Enzymes, Immune Cells & X-Linked Mutations In Autoimmunity and Disease

Background: We have suggested that environmental illnesses may involve the loss of suppression of regulatory T cells and that several different proteins may be involved which changes the dynamics or "immunological footprint" of these conditions in each individual. Previously we mentioned how high ammonia levels may account for some of the symptoms associated with multiple chemical sensitivity. We also noted recently how alterations in ornithine enzymes may effect ammonia levels and the Nrf2 gene regulator has some control over its expression. The following article discusses findings related to how a mutation in ornithine transcarbamalase may influence the immune system and play a role in autoimmune type disease. Interestingly, the author points out the condition is X-linked which might account for higher number of females presenting with them because males usually die in utero and do not live but a few days after birth. There is usually a large sexual dimorphism in the prevalence of many environmental diseases. As Li explains, there may be a number of factors that contribute to autoimmune disease which may include estrogenic production as well as, vulnerable phenotypes may be more susceptible to metals exposure which may accelerate some individuals to reactive phenotypes. (Li)

The author writes, "Antigen expression in the thymus leads to the deletion of self-reactive T cells and generation of regulatory lymphocytes, including regulatory T cells(Treg) and NKT cells. We show an Ornithine transcarbamylase(OTC) mutation causes ineffective presentation of self antigens in the thymus. As such, deletion of self reactive T cells is compromised and production of Treg and NKT cells is reduced in the OTC mutant mice. More importantly the heterozygous mice have increased susceptibility to autoimmune diseases, including the generation of autoantibodies and more severe EAE." Further, "OTC mutant mice, the production of Treg in the thymus is reduced, which is correlated with the impaired antigen presentation due to hyperammonemia."


Comment: This article is a good representation of why only qualified medical professionals that understand the multitude of genetic conditions and environmental conditions that activate them should be treating them. There is no evidence thus far, that a "therapeutic recipe" is effective at treating all of them.


Chang, X. (2006). X linked foxp3 & otc in immune tolerance and autoimmunity. Ohio State University. http://www.citeulike.org/user/HEIRS/article/6650098
Li, J., Stein, T. D., and Johnson, J. A. (2004). Genetic dissection of systemic autoimmune disease in nrf2 deficient mice. Physiological Genomics.
http://www.citeulike.org/user/HEIRS/article/6604948

Mitochondrial MAO Enzyme May Contribute to Oxidative Stress in Hyperammonemia!

brain mitochondrial MAO-A is regulated by the function of NMDA receptors. The enzyme can contribute to the oxidative stress associated with hyperammonemic conditions such as encephalopathy and Alzheimer’s disease.

CiteULike: Brain monoamine oxidase A in hyperammonemia is regulated by NMDA receptors: "Kosenko, E. and Kaminsky, Y. (2009). Brain monoamine oxidase a in hyperammonemia is regulated by nmda receptors. Central European Journal of Biology, 4(3):321-326."

Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.

Hyperammonemia significantly alters the rhythm of spontaneous ambulatory activity, reducing strongly ambulatory counts and slightly average velocity during the night (the active phase) but not during the day, resulting in altered circadian rhythms. In contrast, hyperammonemia did not affect wheel running at all, indicating that it affects spontaneous but not voluntary activity. Vertical activity was affected only very slightly, indicating that hyperammonemia does not induce anxiety. Hyperammonemia abolished completely the circadian rhythm of corticosteroid hormones in plasma, completely eliminating the peaks of cortisol and corticosterone present in control rats at the start of the dark period

.

Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats.: "Ahabrach, H., Piedrafita, B., Ayad, A., El Mlili, N., Errami, M., Felipo, V., and Llansola, M. (2009). Chronic hyperammonemia alters the circadian rhythms of corticosteroid hormone levels and of motor activity in rats. Journal of neuroscience research."

Altered Metabolism, Toxicity, Glutamate Dehydrogenase and NRF-1 and Its Activator PGC-1

Background: NRF-1 binding sites include ornithine decarboxylase and glutamate dehydrogenase through ADP Ribose in humans. Since NRF-1 associates with PGC-1a and Nrf2 -- I think one could suggest it elevates its importance in conditions possibly for those known to fall under the umbrella of environmental illness.

Definition:
****PFC: Perfluorinated compounds (PFCs) refer to a class of organofluorine compounds that have all hydrogens replaced with fluorine on a carbon chain—but also contain at least one different atom or functional group and persist as persistent organic compounds.
The two most studied PFCs are:
    **********PFOA or perfluorooctanoic acid, used to make fluoropolymers such as Teflon,   among other applications.
   **********PFOS or perfluorooctanesulfonic acid, used in the semiconductor industry, 3M's former Scotchgard formulation, and 3M's former fire-fighting foam mixture.


In a recent report, PFC from blood samples from loggerhead turtles were high enough that suggested liver damage and suppression of at least one immune function. (ScienceDaily: 2/22/08)

Quote for the day: I may not be a turtle but I am human....

I mentioned the article above because interestingly, I found articles related to similar chemicals found in  products in human home environments including our textiles, upholstery, carpets etc including perfluorooctanoic acid (PFOA) and similar to those found in turtles like those mentioned above. Chemicals such as these may influence the regulation of genes for amino acid metabolism...including those that overlap for methionine and glumate including GLUD1 (glutamate dehydrogenase in rats) and GLUL (glutamate ammonia ligase). "PFOA alters genes in wild-type mouse liver through PPAR alpha and a subset of genes are regulated by CAR and possibly PPAR gamma in the PPAR alpha-null mouse." As Corton explains, nuclear receptors can regulate nutrient and xenobiotic transport and metabolism and stress resistance and that "PGC-1 and PGC-1ß regulate the ligand-dependent and -independent activation of a large number of nuclear receptors including PPAR and constitutive activated receptor (CAR)." This would suggest that conditions that alter the expression of PGC-1a/PGC-1b may synergistically influence or oppose expression of these genes. From this one could propose these interactions may contribute to symptoms associated with environmental illness such as behavioral and mood changes or possibly even chemical sensitivity. These are chemicals that have been found in newborns and past studies show that PFOA cause tumors and are associated with developmental toxicity at high doses although admittedly, the health effects of these chemicals are mostly unknown.(ScienceDaily)


Rosso, L., Marques, A. C., Reichert, A. S., and Kaessmann, H. (2008). Mitochondrial targeting adaptation of the hominoid-specific glutamate dehydroge nase driven by positive darwinian selection. PLoS genetics, 4(8).
http://www.citeulike.org/user/HEIRS/article/3108334
MacMullen, C., Fang, J., Hsu, B. Y., Kelly, A., de Lonlay-Debeney, P., Saudubray, J. M., Ganguly, A., Smith, T. J., Stanley, C. A., and Hyperinsulinism/hyperammonemia Contributing Investigators (2001). Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. The Journal of clinical endocrinology and metabolism, 86(4):1782-1787. http://www.citeulike.org/user/HEIRS/article/6623806
Virbasius, C.-m. A., Virbasius, J. V., and Scarpulla, R. C. (1993). Nrf-1, an activator involved in nuclearmitochondrial interactions, utilizes a new dna-binding domain conserved in a family of developmental regulators. Genes & Development. http://www.citeulike.org/user/HEIRS/article/6623819
Hossain, M. B., Ji, P., Anish, R., Jacobson, R. H., and Takada, S. (2009). Poly(adp-ribose) polymerase 1 interacts with nuclear respiratory factor 1 (nrf-1) and plays a role in nrf-1 transcriptional regulation. Journal of Biological Chemistry, 284(13):8621-8632. http://www.citeulike.org/user/HEIRS/article/6623948
Haigis, M. C., Mostoslavsky, R., Haigis, K. M., Fahie, K., Christodoulou, D. C., Murphy, A. J., Valenzuela, D. M., Yancopoulos, G. D., Karow, M., Blander, G., Wolberger, C., Prolla, T. A., Weindruch, R., Alt, F. W., and Guarente, L. (2006). Sirt4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell, 126(5):941-954.  http://www.citeulike.org/user/HEIRS/article/6623971
Rosen, M.B., Lee, J.S., Ren, H., Vallanat, B., Liu, J., Waalkes, M.P., Abbott, B.D., Lau, C., and Corton, J.C. (2008). Toxicogenomic dissection of the perfluorooctanoic acid transcript profile in mouse liver: Evidence for the involvement of nuclear receptors pparalpha and car. Toxicol. Sci., 103(1):46-56. http://www.citeulike.org/user/HEIRS/article/6608986
Corton, J. C. and Brown-Borg, H. M. (2005). Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. J Gerontol A Biol Sci Med Sci, 60(12):1494-1509. http://www.citeulike.org/user/HEIRS/article/2339648?show_msg=already_posted

Hyperammonemia, Subordination, Hypoxia Influence Stress Hormone CRF Production in Fish

"Comparison of the plasma cortisol levels in response to the diverse treatments showed that subordination was the most severe stressor followed by hyperammonemia, isolation, and hypoxia. In the POA, with the exception of subordination that had no effect on UI expression, all stressors resulted in increase in CRF and UI mRNA levels."

Comment: Basically, this says that in fish these stressors increase stress hormones. Other organisms are often used as experimental models to test psychological theories. These same hormonal pathways exist in humans and for this reason, one can suggest these stressors may elicit similar responses and these kinds of experiments are often performed on animals to analyze reactions before humans or where experimentation on humans would be "unethical" or "too difficult".


Bernier, N. J., Alderman, S. L., and Bristow, E. N. (2008). Heads or tails? stressor-specific expression of corticotropin-releasing factor and urotensin i in the preoptic area and caudal neurosecretory system of rainbow trout. The Journal of endocrinology, 196(3):637-648. http://www.citeulike.org/user/HEIRS/article/6611532
Kawabata, K., Kawai, Y., and Terao, J. (2009). Suppressive effect of quercetin on acute stress-induced hypothalamic-pituitary-adrenal axis response in wistar rats. The Journal of nutritional biochemistry. http://www.citeulike.org/user/HEIRS/article/4498837
Ortega, V. A., Renner, K. J., and Bernier, N. J. (2005). Appetite-suppressing effects of ammonia exposure in rainbow trout associated with regional and temporal activation of brain monoaminergic and crf systems. J Exp Biol, 208(10):1855-1866. http://www.citeulike.org/user/HEIRS/article/6594636
Land, B. B., Bruchas, M. R., Lemos, J. C., Xu, M., Melief, E. J., and Chavkin, C. (2008). The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J. Neurosci., 28(2):407-414. http://www.citeulike.org/user/HEIRS/article/2215488
Walsh, P. J., Veauvy, C. M., McDonald, M. D., Pamenter, M. E., Buck, L. T., and Wilkie, M. P. (2007). Piscine insights into comparisons of anoxia tolerance, ammonia toxicity, stroke and hepatic encephalopathy. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology, 147(2):332-343. http://www.citeulike.org/user/HEIRS/article/6611593

Elevated Ammonia and Endotoxin: Implications for Synergistic Toxicity in Environmental Illness

Background: I happened on an article this morning that no doubt has important health implications, at least for I and others with impairments of detoxification are concerned. I doubt it evoked much interest by the "Powers That Be" that study this stuff everyday but none-the-less, it seems important for me, not to dismiss it so readily. What I write here are my own thoughts and I by no means am or claim to be, an expert on autism and autistic behavior.

As you may recall, we recently discussed the similiarities of autism and other environmental illnesses including ADHD and multiple chemical sensitivity. Previous studies have shown that certain exposures may inhibit metabolic pathways such the one for production of methionine synthase important for DNA synthesis and repair and may increase concentrations of homocysteine, a potentially toxic byproduct of methionine metabolism. To demonstrate, the inhibition of this pathway by nitrous oxide causes lasting impairment in spatial working memory in aged rats via mitochondrial swelling and subsequent neuronal death.(Culley) In line with this thinking,severa; studies provide evidence that inhibiting or the presense of impairments in pathways such as the one for methionine synthase or others may contribute to a number of mental and physical health conditions including environmental illnesses such as mood disorders, Alzheimer's, autism and MCS.

In the past, I have noted several "remedies" including B12, Q10 and tetrahydrobiopterin recommended for chemical sensitivity which are also commonly used therapies for autism. Curiously, methylhydrofolate is a precursor of BH4 and often prescribed to reduce ammonia levels produced as a side-effect from different supplement treatments and also ammonia produced from gut-derived exogenous bacteria. In addition to hyperammonemia, excess ammonia may lead to elevations in production of nitric oxide synthase and enhanced nitric oxide, free radicals and oxidative stress.

Jalan and Bernuau propose that endotoxin may increase the severity of complications associated with hyperammonemia which of course may have important safety implications for a number of occupational and residential settings including farms and agricultural areas. In this article the authors explain, the "ammonia is detoxified by astrocyctes in the brain". Notably, the deficiency of protective pathways which protect astocytes such as Nrf2 should be an important concern. Jalan further explains that "during hyperammonemia, astrocytes swell from the effect of glutamine. In addition, recent studies show these cells are more swollen in animals exposed to endotoxin and interestingly, the swelling of the atrocytes occur in an environment of an intact blood brain barrier which indicates a functional abnormality. It is assumed that astrocytes are critical managers of blood flow and it may be that during hyperammonemia the astrocytes are sensitized to a "second hit" by LPS endotoxin. The author also proposes other mechanims may be involved in the astrocyte swelling in addition to the ammonia-glutamine hypothesis and one may suggest it includes the activation of P53 and its suppressive effects on Nrf2. (Panickar, Faraonion) The author also mentions pharmacological pre-treatment doses of amiloride, a diuretic used to treat congestive heart failure and hypertension, were required that were 200 fold higher in animals with hyperammonemia in association with exposure to endotoxin." This should demonstrate to anyone whether toxicologically inclined or not, that "something just ain't right",,,,!

He goes on to say, "several substances have been shown to cross the BBB under hepatoxic conditions such as acute liver failure. Incidently, he points out ammonia induces the expression of GLUT1, a transporter across the BBB and this report suggests a non-specific increase in permeability of the BBB and proposes hyperammonia could "unlock" the BBB." It has been shown that ammonia can "alter endothelial cell gene expression and transporter function." (Belanger Of course, this is an important issue to consider whenever a condition of hyperammonemiua occurs. It very well could contribute to the neuroinflammatory consequences in pathological conditions such as autism and conditions that where elevated homocysteine levels impair renal function and as this article suggests, exposures to endotoxin exacerbate related metabolic consequences.

Jalan, R. and Bernuau, J. (2007). Induction of cerebral hyperemia by ammonia plus endotoxin: Does hyperammonemia unlock the blood–brain barrier? Journal of Hepatology, 47(2):168-171. http://www.citeulike.org/user/HEIRS/article/6556614
Essa, M. M. and Subramanian, P. (2006). Hibiscus sabdariffa affects ammonium chloride-induced hyperammonemic rats. eCAM. http://www.citeulike.org/user/HEIRS/article/6556740
Panickar, K. S., Jayakumar, A. R., Rao, K. V. R., and Norenberg, M. D. (2009). Ammonia-induced activation of p53 in cultured astrocytes: Role in cell swelling and glutamate uptake. Neurochemistry International, 55(1-3):98-105. http://www.citeulike.org/user/HEIRS/article/4523207
Faraonio, R., Vergara, P., Di Marzo, D., Pierantoni, M. G. G., Napolitano, M., Russo, T., and Cimino, F. (2006). p53 suppresses the nrf2-dependent transcription of antioxidant response genes. The Journal of biological chemistry, 281(52):39776-39784. http://www.citeulike.org/user/HEIRS/article/4364516?show_msg=already_posted
Culley, D. J., Raghavan, S. V., Waly, M., Baxter, M. G., Yukhananov, R., Deth, R. C., and Crosby, G. (2007). Nitrous oxide decreases cortical methionine synthase transiently but produces lasting memory impairment in aged rats. Anesth Analg, 105(1):83-88. http://www.citeulike.org/user/HEIRS/article/6557028
Bélanger, M., Asashima, T., Ohtsuki, S., Yamaguchi, H., Ito, S., and Terasaki, T. (2007). Hyperammonemia induces transport of taurine and creatine and suppresses claudin-12 gene expression in brain capillary endothelial cells in vitro. Neurochemistry international, 50(1):95-101.
http://www.citeulike.org/group/7833/article/6557716