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ARTICLES: Laura K. Curran, Craig J. Newschaffer, Li-Ching Lee, Stephen O. Crawford, Michael V. Johnston, and Andrew W. Zimmerman Behaviors Associated With Fever in Children With Autism Spectrum Disorders Pediatrics 2007; 120: e1386-e1392 [Abstract] [Full text] [PDF]

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Consider NO from iNOS

David R. Whitlock   (9 December 2007)

Consider NO from iNOS 9 December 2007
David R. Whitlock, Researcher Nitroceutic LLC Send letter to journal: Re: Consider NO from iNOS dwhitlock{at}nitroceutic.com David R. Whitlock	I find this result extremely interesting, and it fits with my own (unpublished) ideas that many symptoms of the ASDs are consistent with and exacerbated by low basal nitric oxide. An acute stimulation of the immune system (as in a fever) can result in higher levels of NO through expression of iNOS. In extreme cases (septic shock), high NO levels can cause systemic vasodilation and hypotension via activation of sGC. Many of the potential mechanisms suggested by Zimmerman et. al. are regulated by NO mediated pathways. For example long term potentiation is complexly regulated by NO via sGC (Garthwaite 2006), and NO is involved in regulation of many stress proteins, through Nrf2 (Dhakshinamoorthy 2004). Because each NO "sensor" senses the sum of NO from all NO sources, there is no threshold for a change in the basal NO level to affect pathways mediated by NO. In other words, because the operating point of each NO mediated signaling pathway is already in the "active range", any change in the basal level will add to (or subtract from) the signal level and change the effect level (basal + signal = effect). With the EC50 of sGC ~20 nM/L (~0.6 ppb) (Garthwaite 2003) even small changes in NO would be expected to change the range, onset time, and duration of every NO signal. If basal levels cause systemic hypotension, they are affecting basal sGC activation in the vasculature. Before everyone rushes out and tries to raise NO levels, NO physiology is quite complex and under intense regulation. There are no generally accepted methods for raising NO levels that have been shown to work long term. Organic nitrates induce "nitrate tolerance", L-arginine induces asymmetric dimethyl arginine and arginase perhaps causing "arginine tolerance" (Cooke 2007). What this work does show is that some of the symptoms of ASDs are due to acute effects, not neuroanatomy, and that some of these effects can be reversed acutely. That implies a shifted regulatory setpoint, not injury or damage. I see this as an extremely encouraging result. Hopper RA, Garthwaite J. Tonic and phasic nitric oxide signals in hippocampal long-term potentiation. J Neurosci. 2006 Nov 8;26(45):11513- 21. Dhakshinamoorthy S, Porter AG. Nitric oxide-induced transcriptional up-regulation of protective genes by Nrf2 via the antioxidant response element counteracts apoptosis of neuroblastoma cells. J Biol Chem. 2004 May 7;279(19):20096-107. Gibb BJ, Wykes V, Garthwaite J. Properties of NO-activated guanylyl cyclases expressed in cells. Br J Pharmacol. 2003 Jul;139(5):1032-40. Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation. 2007 Jul 10;116(2):188-95. Conflict of Interest: Financial disclosure: DRW and Nitroceutic LLC are privately funded and working to commercialize the use of topical ammonia oxidizing bacteria to treat and prevent a variety of disorders associated with low basal NO, including ASDs.