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

Colon luminal content and epithelial cell morphology are markedly modified in rats fed with a high protein diet.

"basal oxygen consumption of colonocytes was similar in the NP and HP groups, but ammonia was found to provoke a dose-dependent decrease of oxygen consumption in the isolated absorbing colonocytes. The activity of glutamine synthetase (which condenses ammonia and glutamate) was found to be much higher in colonocytes than in small intestine enterocytes and was 1.6-fold higher (p=0.0304) in colonocytes isolated from HP animals than NP. Glutaminase activity remained unchanged."

Read more: CiteULike: Colon luminal content and epithelial cell morphology are markedly modified in rats fed with a high protein diet.:

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:

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

Activation of Glycogen Synthase Kinase-3{beta} Is Required for Hyperdopamine and D2 Receptor-Mediated Inhibition of Synaptic NMDA Receptor Function in the Rat Prefrontal Cortex

Background: GSK-3B is an off/on switch for Nrf2.

Title: Activation of glycogen synthase kinase-3beta is required for hyperdopamine and d2 receptor-mediated inhibition of synaptic nmda receptor function in the rat prefrontal cortex.

Summary: GSK-3beta is required for the hyperdopamine/D2 receptor-mediated inhibition of NMDA receptors in the prefrontal neurons and these actions may underlie D2 receptor-mediated psychostimulant effects and hyperdopamine-dependent behaviors in the brain.

Li, Y.-C., Xi, D., Roman, J., Huang, Y.-Q., and Gao, W.-J. (2009). Activation of glycogen synthase kinase-3beta is required for hyperdopamine and d2 receptor-mediated inhibition of synaptic nmda receptor function in the rat prefrontal cortex. 29(49):15551-15563. http://www.citeulike.org/user/HEIRS/article/6347607

Cuadrado, A., Moreno-Murciano, P., and Pedraza-Chaverri, J. (2009). The transcription factor nrf2 as a new therapeutic target in parkinson's disease. Expert Opinion on Therapeutic Targets, 13(3):319-329. http://www.citeulike.org/user/HEIRS/article/4116731



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Elevated insular glutamate in fibromyalgia is associated with experimental pain.

Title: Elevated insular glutamate in fibromyalgia is associated with experimental pain.

Summary: The author concluded "enhanced glutamatergic neurotransmission resulting from higher concentrations of Glu within the posterior insula may play a role in the pathophysiology of FM and other central pain augmentation syndromes."



Harris, R. E., Sundgren, P. C., Craig, A. D., Kirshenbaum, E., Sen, A., Napadow, V., and Clauw, D. J. (2009). Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis & Rheumatism, 60(10):3146-3152.

Endogenous Peptide Protects Against Toxicants By Upregulating Nrf2/HO-1

Recent studies have shown that a peptide produced from thyroptropin-releasing hormone (TRH) in the hypothalamus called cyclo (His-Pro) (CHP) can provide neuroprotective effects against a number of toxicants including Paraquat, rotenone, glutamate and B-amyloid. The author determined that these effects are generated through the activation of Nrf2 and that the protective effects against Paraquat also involve HO-1. Knock-down of Nrf2 abolished these protective effects. Generally, the studies show evidence that CHP improves glutathione synthesis and prevented depletion and reduces the generation of ROS from these toxicants. Specifically, he notes that CHP is protective against H2O2 mediated apoptotic cell death. (Minelli) Paraquat exposure has been implicated as a risk factor for Parkinson's disease and having adverse effects on dopamine systems.

Other studies have shown that dopamine transmission is regulated by H2O2 and that H2O2 generated from respiring mitochondria are the major source of H2O2 neuronal signals. As we have noted, toxicants and other factors can lead to mitochondrial dysfunction which has been implicated in a number of health conditions including those commonly known as environmental illness. In the striatum, H2O2 controls dopamine release and it has been found that H2O2 inhibits dopamine release and activity through the activation of KATP channels.

Notes:

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  CHP is a substrate for OCT2 according to Taubert. Jonker explains that knock-down of OCT1 and OCT2 in the kidney can lead to an inhibition of excretion and excessive concentration of tetraethylammonium in the blood.  (Taubert, Jonker)

Kim Kramer
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 Citations 

 

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

HEIRS Environmental Illness Research Blog: Sickness Syndrome, CFS, Fibromyalgia, IL-10 and HO-1

Activation of MCP-1/CCl2/CCR2 by TNF-a to cause microglial neuroinflammation and alterations in neurotransmission require the presence of the TNFR1. (D' Mello) The Nrf2 pathway has been shown to modulate inflammatory mediators including Tnf-a and the glutamate antiporter system. (Lewerenz) The TNFR1 receptor is important for preconditioning in ischemia to reduce injury from subsequent ischemia through interaction with the EAAT3. The EAAT3 transporter regulates glutamate and also is involved with glutathione synthesis and is present in cortical and striatal neurons. (Suchak) It works cooperatively with xCT to prevent depletion of glutathione caused by high glutamate levels and may be useful in eventual therapy for Parkinson's. (Lewerenz)

D'Mello, C., Le, T., and Swain, M. G. (2009). Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation. J. Neurosci., 29(7):2089-2102. http://www.citeulike.org/user/HEIRS/article/4079736
Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. Suchak, S. K., Baloyianni, N. V., Perkinton, M. S., Williams, R. J., Meldrum, B. S., and Rattray, M. (2003). The 'glial' glutamate transporter, eaat2 (glt-1) accounts for high affinity glutamate uptake into adult rodent nerve endings. Journal of neurochemistry, 84(3):522-532. http://www.citeulike.org/user/HEIRS/article/5699931
Pradillo, J., Hurtado, O., Romera, C., Cardenas, A., Fernandeztome, P., Alonsoescolano, D., Lorenzo, P., Moro, M., and Lizasoain, I. (2006). Tnfr1 mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 138(4):1171-1178. http://www.citeulike.org/user/HEIRS/article/5699676
Lewerenz, J., Klein, M., and Methner, A. (2006). Cooperative action of glutamate transporters and cystine/glutamate antiporter system xc- protects from oxidative glutamate toxicity. Journal of neurochemistry, 98(3):916-925. http://www.citeulike.org/user/HEIRS/article/762845
Lewerenz, J., Albrecht, P., Tien, M.-L. T. L., Henke, N., Karumbayaram, S., Kornblum, H. I., Wiedau-Pazos, M., Schubert, D., Maher, P., and Methner, A. (2009). Induction of nrf2 and xct are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5627214
Maher, P., Lewerenz, J., Lozano, C., and Torres, J. L. L. (2008). A novel approach to enhancing cellular glutathione levels. Journal of neurochemistry, 107(3):690-700.
http://www.citeulike.org/user/HEIRS/article/3401858