A brain MRI study of chronic fatigue syndrome: Evidence of brainstem dysfunction and altered homeostasis [preview] – Source: NMR in Biomedicine, March 2011

New study suggests that astrocyte dysfunction may play a role in chronic fatigue issue.

A brain MRI study of chronic fatigue syndrome: Evidence of brainstem dysfunction and altered homeostasis [preview] – Source: NMR in Biomedicine, March 2011: "A brain MRI study of chronic fatigue syndrome: Evidence of brainstem dysfunction and altered homeostasis [preview] – Source: NMR in Biomedicine, March 2011"

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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

Astrocyte Oxidative Metabolism and Metabolite Trafficking after Fluid Percussion Brain Injury in Adult Rats

"integral protective role for astrocytes in maintaining metabolic function following TBI-induced impairments in glucose metabolism"

Read more: Mary Ann Liebert, Inc. - Journal of Neurotrauma - 0(0)::

Characterization of Developmental neurotoxicity of As, Cd and Pb mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions — Toxicol Sci

: "together, these observations are the first to show that mixture of As, Cd and Pb has the capacity to induce synergistic toxicity in astrocytes that may compromise the BBB, and may cause behaviroal dysfunction in developing rats."


Read more: Characterization of Developmental neurotoxicity of As, Cd and Pb mixture: Synergistic Action of Metal Mixture in Glial and Neuronal Functions — Toxicol Sci

NPR-C Attenuates Accumulation of ROS and NOS In Ammonia-Treated Astrocytes!

STIMULATION OF NATRIURETIC PEPTIDE RECEPTOR C (NPR... [J Neurochem. 2010] - PubMed result: "STIMULATION OF NATRIURETIC PEPTIDE RECEPTOR C (NPR-C) ATTENUATES ACCUMULATION OF REACTIVE OXYGEN SPECIES AND NITRIC OXIDE SYNTHESIS IN AMMONIA-TREATED ASTROCYTES."

Comments: Sulphoraphane, Ammonia and ALS Drug....

I find this interesting ................................... As we have already established there is potential for the Nrf2 to protect astrocytes from damage. Excitotoxicity from glutamate has been implicated in a number of neurodegenerative conditions. As a new report suggests, sulphoraphane and riluzole,a ALS drug, may be more effective combined that each alone to  minimize excitotoxicity.  The former has been shown to act through Nrf2 while the latter is is presumed at least to improve transport by regulating glutamate transporters. The former I get but as to the latter I do not have a lot of information here....Is caveolin responsible for urea and ammonia leakiness? Do conditions that elevate ammonia...alter proteins that coregulate that influence muscle weakness? Can this be a factor in weakness associated with old age or other illness where excitoxity becomes a factor.? Is this drug, only used for ALS? Just askin? Understanding animal behavior sometimes is alot easier...and wonder why is it that this stuff fascinates me.....? Even if it hard to understand when I do not have a lot to go on.....! Too much to learn, so little time and too little time before I will forget...or not!


 Geng Chang, Yansu Guo, Yaqiong Jia, Weisong Duan, Bin Li, Jixu Yu and Chunyan Li, “Protective Effect of Combination of Sulforaphane and Riluzole on Glutamate-Mediated Excitotoxicity”, Biol. Pharm. Bull., Vol. 33, 1477-1483 (2010) .  http://www.ncbi.nlm.nih.gov/pubmed/20823560

Mark J Hernandez, Tina M Roberts and Christopher D Hardin. Caveolin-1 and the Organization of Glycolysis in Astrocytes: Modulation by Ammonia. FASEB Journal 2007. 21:748.9   http://www.fasebj.org/cgi/content/meeting_abstract/21/6/A872-c

Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation

Seems to me that the findings from this author are pretty important....:)

"up-regulation of HO-1 in astrocytes is associated with down-regulation of iNOS expression and thereby NO production, an effect that involves the p38 MAPK signaling pathway, which suggests that this glial cell response could play an important protective role against oxidative stress in the brain."

"Sheng, W., Hu, S., Nettles, A., Lokensgard, J., Vercellotti, G., and Rock, R. (2010). Hemin inhibits no production by il-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 mapk activation. Journal of Neuroinflammation, 7(1):51+."

Read more: CiteULike: Hemin inhibits NO production by IL-1beta-stimulated human astrocytes through induction of heme oxygenase-1 and reduction of p38 MAPK activation:

Meth Labs, Wood Treatments, Pesticides and Ammonia Toxicity on Astrocytes~!

Astrocytes: (astroglia) : are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical support of endothelial cells which form the blood-brain barrier, provision of nutrients to the nervous tissue, maintenance of extracellular ion balance, and a principal role in the repair and scarring process of the brain and spinal cord following traumatic injuries. (Wipedia: Astrocytes)

This study would suggest that any condition that impairs the antioxidant system which has a primary role in protecting astrocytes against damage (ie Nrf2)  would augment the toxicity of ammonia whether it be produced endogenously or from exogenous exposures. Young children, the elderly and those with impaired immune systems would also be more at risk. Products that contain ammonia or have it as an "inert" ingredient or exposures from hazardous environments such as methamphetamine labs pose an elevated risk for the above populations because they would be more susceptible to ammonia toxicity.

"This study demonstrated that in rats with HA or HE ammonia specifically promote GSH synthesis and export from astrocytes and increase its extracellular degradation, which may improve the availability of precursors for GSH synthesis in neurons and their resistance to ammonia toxicity."

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. Toxicological sciences : an official journal of the Society of Toxicology, 117(1):163-168. http://www.citeulike.org/user/HEIRS/article/7292948?show_msg=already_posted
 
 

Resveratrol differentially modulates inflam responses of microglia & astrocytes

Comment: An extremely useful read for those interested in this kind of stuff. Full text available.

"the first report of a difference between microglial cell and astrocyte in response to LPS, and of a difference in the capacity of resveratrol to protect microglia and astrocytes from inflammatory insults."


Lu, X., Ma, L., Ruan, L., Kong, Y., Mou, H., Zhang, Z., Wang, Z., Wang, J. M., and Le, Y. (2010). Resveratrol differentially modulates inflammatory responses of microglia and astrocytes. Journal of Neuroinflammation, 7(1):46+.  http://www.citeulike.org/user/HEIRS/article/7694580

Nair, S., Barve, A., Khor, T.-O. O., Shen, G.-X. X., Lin, W., Chan, J. Y., Cai, L., and Kong, A.-N. N. (2010). Regulation of nrf2- and ap-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of nrf2-knockout or c57bl/6j mice and pc-3 ap-1 human prostate cancer cells. Acta pharmacologica Sinica. http://www.citeulike.org/user/HEIRS/article/7694509

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

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

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

GSK-3 Knock-down Allows for Endotoxin Tolerance in Astrocytes~!

"GSK3 inhibitors or knocking down GSK3 levels promoted LPS-tolerance and astrocytes expressing constitutively active GSK3 did not develop LPS-tolerance. These findings identify the critical role of GSK3 in counteracting IL-6 inflammatory tolerance in cells of the CNS, supporting the therapeutic potential of GSK3 inhibitors to reduce neuroinflammation by promoting tolerance"

Link: CiteULike: Glycogen synthase kinase-3 regulates inflammatory tolerance in astrocytes.:

Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination

"Demyelination and oligodendrocyte degeneration in this model follows astrocyte pathology. Similar structural abnormalities were also seen in a subset of active lesions in multiple sclerosis. Our studies suggest that astrocyte injury may be an important early step in the cascade of lesion formation in brain inflammation."

CiteULike: Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination:

Astroglial Amino Acid Shuttle Involved in Nociceptive Pain Sensitization!

"This study has demonstrated that the central sensitization induced in functionally identified nociceptive neurons in trigeminal subnucleus caudalis (the medullary dorsal horn) by application of an inflammatory irritant to the rat's tooth pulp can be significantly attenuated by continuous intrathecal superfusion of methionine sulfoximine, an inhibitor of the astroglial enzyme glutamine synthetase that is involved in the glutamate–glutamine shuttle......Further, the lack of any observed significant effects of MSO alone, in contrast to our findings that it significantly attenuates MO-induced central sensitization, suggests that its action on astroglial GS is not evident in basal conditions but is apparent in hyperexcitable states, consistent with findings by ourselves and others that glia may not affect basal nociceptive processing but rather participate in exaggerated pain states. It is also noteworthy that an excess of glutamine in the CNS is involved in ammonia neurotoxicity possibly through its detrimental effects on mitochondrial function."

CiteULike: Astroglial Glutamate Glutamine Shuttle Is Involved in Central Sensitization of Nociceptive Neurons in Rat Medullary Dorsal Horn: "Chiang, C.-Y., Wang, J., Xie, Y.-F., Zhang, S., Hu, J. W., Dostrovsky, J. O., and Sessle, B. J. (2007). Astroglial glutamate glutamine shuttle is involved in central sensitization of nociceptive neurons in rat medullary dorsal horn. J. Neurosci., 27(34):9068-9076."


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Mhalla, A., de Andrade, D. C. C., Baudic, S., Perrot, S., and Bouhassira, D. (2010). Alteration of cortical excitability in patients with fibromyalgia. Pain, 149(3):495-500.
http://www.citeulike.org/user/HEIRS/article/6962057
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Chen, P.-C., Vargas, M. R., Pani, A. K., Smeyne, R. J., Johnson, D. A., Kan, Y. W., and Johnson, J. A. (2009). Nrf2-mediated neuroprotection in the mptp mouse model of parkinson's disease: Critical role for the astrocyte. Proceedings of the National Academy of Sciences, 106(8):2933-2938. http://www.citeulike.org/user/HEIRS/article/6551224?show_msg=already_posted

Overexpression of Nrf2 Protects Striatal Neurons from Mitochondrial Dysfunction.

"these results to show that multiple methods of astrocyte-specific Nrf2 overexpression provide protection from neurotoxicity in vivo."

CiteULike: Astrocyte-Specific Overexpression of Nrf2 Protects Striatal Neurons from Mitochondrial Complex II Inhibition:

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

Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways.

Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways.: "URL: Albumin activates astrocytes and microglia through mitogen-activated protein kinase pathways.

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Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat.

Transgenic mice with astrocyte-targeted production of interleukin-6 are resistant to high-fat diet-induced increases in body weight and body fat.

Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes.

Angiotensin II activates JAK2/STAT3 pathway and induces interleukin-6 production in cultured rat brainstem astrocytes.