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
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