Background: We have suggested over the past few months that multiple chemical sensitivity may result from an imbalance of metabolic processes the detoxify ammonia. This may be caused by overwhelming exposure from SIBO or genetic or environmental influences that inhibit the proper excretion of ammonia in urea. Several MCS experts, as well as patients, have found that dry sauna can be of benefit although thus far, there is no explanation of why this is so. In the past, we have written that sauna therapy is based on an ancient therapy called Waon therapy and past studies of this technique suggest it may increase the expression of Nrf2 and HO-1 and possibly influence the expression of PGC-1a. Both Nrf2 and PGC-1a have been implicated as having primary or secondary roles in mitochondrial biogenesis which of course, has benefits for health conditions where mitochondrial respiration may be impaired. Also, Nrf2 has a role in neuroprotection and may modulate the ornithine pathway which is protective against ammonia toxicity.
A recent study has demonstrated that sauna/sweat therapy may lead to the reduction of nicotinamide. Nicotinamide overload has recently been implicated as a factor in causing insulin resistance, oxidative stress by H2O2 and possibly type 2 diabetes and other studies have shown that pollution may influence the development of this disease. Other findings show skin damage and certain chemicals may reduce nicotinamide excretion. In general, nicotinamide is generally considered anti-inflammatory but at higher doses may be toxic to the liver. Nicotinamides are active inhibitors of SIRT proteins which are not only important for a number of metabolic processes but they also play a role mitochondrial biogenesis. On the other hand, higher ammonia levels can inhibit the TCA cycle which are a major producer of nicotinamides. Taking these conditions into account, we see a potential for sauna (via sweat therapy) to positively reduce the production of toxic levels of nicotinamides while reducing ammonia toxicity through elevations in Nrf2 and the ornithine pathway. The reduction of MCS symptoms could be a consequence of one or the other or both...!
For further reading:
Zhou, S.-S. S., Li, D., Sun, W.-P. P., Guo, M., Lun, Y.-Z. Z., Zhou, Y.-M. M., Xiao, F.-C. C., Jing, L.-X. X., Sun, S.-X. X., Zhang, L.-B. B., Luo, N., Bian, F.-N. N., Zou, W., Dong, L.-B. B., Zhao, Z.-G. G., Li, S.-F. F., Gong, X.-J. J., Yu, Z.-G. G., Sun, C.-B. B., Zheng, C.-L. L., Jiang, D.-J. J., and Li, Z.-N. N. (2009). Nicotinamide overload may play a role in the development of type 2 diabetes. World journal of gastroenterology : WJG, 15(45):5674-5684. http://www.citeulike.org/user/HEIRS/article/6885712
Whitaker, M. J. and Steinhardt, R. A. (1981). The relation between the increase in reduced nicotinamide nucleotides and the initiation of dna synthesis in sea urchin eggs. 25(1):95-103. http://www.citeulike.org/user/HEIRS/article/6885757
Smith, D., Wang, T., Španěl, P., and Bloor, R. (2006). The increase of breath ammonia induced by niacin ingestion quantified by selected ion flow tube mass spectrometry. Physiological Measurement, 27(6). http://www.citeulike.org/user/HEIRS/article/6885842
Katunuma, N., Okada, M., and Nish, Y. (1966). Regulation of the urea cycle and tca cycle by ammonia. Advances in Enzyme Regulation, 4:317-335. http://www.citeulike.org/user/HEIRS/article/6885732
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ReplyDeleteI am aware of his paper on the importance of sauna for benefits associated with MCS. This is what one author says in relation to Pall's conclusion of BH4 and Nrf2 and their importance on the benefits of sauna. The first one says in passing that "depletion of BH4 is not sufficient to perturb NO signaling". The second, is that an activator of Nrf2 increases bioavailable nitric oxide with reduction of reactive species. At the same time, eNOS was reduced which is dependant on HO-1 which is through Nrf2 and Nrf2 is responsible for keeping BH4 in the coupled state." Further clarifications will involve more study....
ReplyDeleteSugiyama, T., Levy, B. D., and Michel, T. (2009). Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. Journal of Biological Chemistry, 284(19):12691-12700.
http://www.citeulike.org/user/HEIRS/article/5650934
Heiss, E., Schachner, D., Werner, E., and Dirsch, V. (2009). Active nf-e2-related factor (nrf2) contributes to keep endothelial no sythase enos in the coupled state: The role of reactive oxygen species (ros)-, enos-, and heme oxygenase (ho-1) levels. JBC Papers in Press.
http://www.citeulike.org/user/HEIRS/article/6912527
Clarification - the above comment refers to the role of BH4, Nrf4 and nitric oxide - not to Pall's statements about BH4 directly....
ReplyDeleteAs we noted in previous blogs, sauna increases PGC-1a which is an important regulator of mitochondrial biogenesis. Metallotheinine is a metal scavenger that prevents uncoupling which leads to mitochondrial dysfunction, can reverse inhibition of DAHP-inhibited BH4 and can also upregulates PGC-1a. PGC-1a promotes mitochondrial biogenesis by increasing NRF1 and NRF2 which are factors regulated by Nrf2. Incidentally, the accumulation of PGC-1a also acts to inhibit GSK-3b which is the on/off switch for the Nrf2 antioxidant system that also can lead to ammonia accumulation as well as, alterations of other metabolic processes. There is not a doubt that BH4 plays a role but as we see, the players PGC-1a, nuclear factors, Nrf2 and GSK-3b do too and BH4 activity may depend on them.
ReplyDeleteCeylan-Isik, A. F., Guo, K. K., Carlson, E. C., Privratsky, J. R., Liao, S.-J., Cai, L., Chen, A. F., and Ren, J. (2009). Metallothionein abrogates gtp cyclohydrolase i inhibition-induced cardiac contractile and morphological defects: Role of mitochondrial biogenesis. Hypertension, 53(6):1023-1031.
http://www.citeulike.org/user/HEIRS/article/5663630?show_msg=already_posted
Olson, B. L., Hock, M. B., Ekholm-Reed, S., Wohlschlegel, J. A., Dev, K. K., Kralli, A., and Reed, S. I. (2008). Scfcdc4 acts antagonistically to the pgc-1 transcriptional coactivator by targeting it for ubiquitin-mediated proteolysis. Genes & Development, 22:252-264.
http://www.citeulike.org/user/HEIRS/article/6562720
Dong, F., Li, Q., Sreejayan, N., Nunn, J. M., and Ren, J. (2007). Metallothionein prevents high-fat diet–induced cardiac contractile dysfunction. Diabetes, 56(9):2201-2212.
http://www.citeulike.org/user/HEIRS/article/5631902?show_msg=already_posted
In several blogs we have discussed the value of EGCG, a compound in green tea, that is an activator of Nrf2. A recent study also demonstrates that it is upregulates the EEAT2 transporter which helps to regulate ammonia in the brain. One abstract explains that elevations of ammonia lead to alterations in glutamate transporters and that excitoxicity may be a complication shortly after injury. Because sauna elevates the expression of Nrf2 and HO-1 this provides support that it may positively influence the expression of these transporters to reduce ammonia toxicity.
ReplyDelete(2009). The changes of nrf2-are signaling path in the aging and mutant sod1g93a astrocytes.
http://www.citeulike.org/user/HEIRS/article/6925119
Yi, J. and Hazell, A. (2006). Excitotoxic mechanisms and the role of astrocytic glutamate transporters in traumatic brain injury. Neurochemistry International, 48(5):394-403.
http://www.citeulike.org/user/HEIRS/article/4207635
Rao, V. L., Dogan, A., Bowen, K. K., Todd, K. G., and Dempsey, R. J. (2001). Antisense knockdown of the glial glutamate transporter glt-1 exacerbates hippocampal neuronal damage following traumatic injury to rat brain. European Journal of Neuroscience, pages 119-128.
http://www.citeulike.org/user/HEIRS/article/6925086
Butterworth, R. F. (2002). Glutamate transporters in hyperammonemia. Neurochemistry international, 41(2-3):81-85.
http://www.citeulike.org/user/HEIRS/article/6925084
Shih, A. Y., Johnson, D. A., Wong, G., Kraft, A. D., Jiang, L., Erb, H., Johnson, J. A., and Murphy, T. H. (2003). Coordinate regulation of glutathione biosynthesis and release by nrf2-expressing glia potently protects neurons from oxidative stress. J. Neurosci., 23(8):3394-3406.
http://www.citeulike.org/user/HEIRS/article/6925062
Pall, M. L. (2009). Do sauna therapy and exercise act by raising the availability of tetrahydrobiopterin? Medical hypotheses, 73(4):610-613.
http://www.citeulike.org/user/HEIRS/article/5095856?show_msg=already_posted
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