Central tetrahydrobiopterin concentration in neurodevelopmental disorders

Richard E Frye, Richard E Frye

Abstract

Tetrahydrobiopterin (BH(4)) is a naturally occurring cofactor essential for critical metabolic pathways. Studies suggest that BH(4) supplementation may ameliorate autism symptoms; the biological mechanism for such an effect is unknown. To help understand the relation between central BH(4) concentration and systemic metabolism and to develop a biomarker of central BH(4) concentration, the relationship between cerebrospinal fluid BH(4) concentration and serum amino acids was studied. BH(4) concentration was found to be distributed in two groups, a lower and higher BH(4) concentration group. Two serum amino acids, citrulline and methionine, differentiated these groups, and the ratio of serum citrulline-to-methionine was found to correlate with the cerebrospinal fluid BH(4) concentration (r = -0.67, p < 0.05). Both citrulline and methionine are substrates in inflammation and oxidative stress pathways - two pathways that utilize BH(4) and are abnormally activated in autism. These data suggests that central BH(4) concentration may be related to systemic inflammation and oxidative stress pathways.

Keywords: autism; inflammation; oxidative stress; serum amino acids; tetrahydrobiopterin.

Figures

Figure 1
Figure 1
The relationship between central tetrahydrobiopterin (BH4) concentration and serum citrulline and methionine concentration. (A) Citrulline was found to be higher and methionine was found to be lower in individuals in the low BH4 group as compared to individuals in the high BH4 group. (B) Scatter plot of citrulline and methionine values illustrating the separation between the low and high BH4 groups. The diagonal line illustrates the group separate. (C) The ratio of citrulline-to-methionine is significantly different between the low and high BH4 groups and (D) correlated with the central BH4 concentration.

References

    1. Anastasiadis P. Z., Bezin L., Imerman B. A., Kuhn D. M., Louie M. C., Levine R. A. (1997). Tetrahydrobiopterin as a mediator of PC12 cell proliferation induced by EGF and NGF. Eur. J. Neurosci. 9, 1831–183710.1111/j.1460-9568.1997.tb00749.x
    1. Bramham J., Ambery F., Young S., Morris R., Russell A., Xenitidis K., Asherson P., Murphy D. (2009). Executive functioning differences between adults with attention deficit hyperactivity disorder and autistic spectrum disorder in initiation, planning and strategy formation. Autism 13, 245–26410.1177/1362361309103790
    1. Castellani M. L., Conti C. M., Kempuraj D. J., Salini V., Vecchiet J., Tete S., Ciampoli C., Conti F., Cerulli G., Caraffa A., Antinolfi P., Galzio R., Shaik Y., Theoharides T. C., De Amicis D., Perrella A., Cuccurullo C., Boscolo P., Felaco M., Doyle R., Verrocchio C., Fulcheri M. (2009). Autism and immunity: revisited study. Int. J. Immunopathol. Pharmacol. 22, 15–19
    1. Corbett B. A., Constantine L. J., Hendren R., Rocke D., Ozonoff S. (2009). Examining executive functioning in children with autism spectrum disorder, attention deficit hyperactivity disorder and typical development. Psychiatry Res. 166, 210–22210.1016/j.psychres.2008.02.005
    1. Danfors T., von Knorring A. L., Hartvig P., Langstrom B., Moulder R., Stromberg B., Torstenson R., Wester U., Watanabe Y., Eeg-Olofsson O. (2005). Tetrahydrobiopterin in the treatment of children with autistic disorder: a double-blind placebo-controlled crossover study. J. Clin. Psychopharmacol. 25, 485–48910.1097/01.jcp.0000177667.35016.e9
    1. Deth R., Muratore C., Benzecry J., Power-Charnitsky V. A., Waly M. (2008). How environmental and genetic factors combine to cause autism: a redox/methylation hypothesis. Neurotoxicology 29, 190–20110.1016/j.neuro.2007.09.010
    1. Dietert R. R., Dietert J. M. (2008). Potential for early-life immune insult including developmental immunotoxicity in autism and autism spectrum disorders: focus on critical windows of immune vulnerability. J. Toxicol. Environ. Health B Crit. Rev. 11, 660–68010.1080/10937400802370923
    1. Fernell E., Watanabe Y., Adolfsson I., Tani Y., Bergstrom M., Hartvig P., Lilja A., von Knorring A. L., Gillberg C., Langstrom B. (1997). Possible effects of tetrahydrobiopterin treatment in six children with autism – clinical and positron emission tomography data: a pilot study. Dev. Med. Child. Neurol. 39, 313–318
    1. Frye R. E., Huffman L. C., Elliot G. R. (2010). Tetrahydrobiopterin as a novel therapeutic intervention for autism. Neurotherapeutics (in press).
    1. Garthwaite J. (2008). Concepts of neural nitric oxide-mediated transmission. Eur. J. Neurosci. 27, 2783–280210.1111/j.1460-9568.2008.06285.x
    1. Howells D., Hyland K. (1987). Direct analysis of tetrahydrobiopterin in cerebrospinal fluid by high-performance liquid chromatography with redox electrochemistry: prevention of autoxidation during storage and analysis. Clin. Chim. Acta 167, 23–3010.1016/0009-8981(87)90081-7
    1. Hyland K., Surtees R. A., Heales S. J., Bowron A., Howells D. W., Smith I. (1993). Cerebrospinal fluid concentrations of pterins and metabolites of serotonin and dopamine in a pediatric reference population. Pediatr. Res. 34, 10–1410.1203/00006450-199307000-00003
    1. Jahromi L. B., Kasari C. L., McCracken J. T., Lee L. S., Aman M. G., McDougle C. J., Scahill L., Tierney E., Arnold L. E., Vitiello B., Ritz L., Witwer A., Kustan E., Ghuman J., Posey D. J. (2009). Positive effects of methylphenidate on social communication and self-regulation in children with pervasive developmental disorders and hyperactivity. J. Autism Dev. Disord. 39, 395–40410.1007/s10803-008-0636-9
    1. James S. J., Cutler P., Melnyk S., Jernigan S., Janak L., Gaylor D. W., Neubrander J. A. (2004). Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 80, 1611–1617
    1. Kern J. K., Jones A. M. (2006). Evidence of toxicity, oxidative stress, and neuronal insult in autism. J. Toxicol. Environ. Health B Crit. Rev. 9, 485–49910.1080/10937400600882079
    1. Kojima S., Ona S., Iizuka I., Arai T., Mori H., Kubota K. (1995). Antioxidative activity of 5,6,7,8-tetrahydrobiopterin and its inhibitory effect on paraquat-induced cell toxicity in cultured rat hepatocytes. Free Radic. Res. 23, 419–43010.3109/10715769509065263
    1. Kolevzon A., Mathewson K. A., Hollander E. (2006). Selective serotonin reuptake inhibitors in autism: a review of efficacy and tolerability. J. Clin. Psychiatry 67, 407–41410.4088/JCP.v67n0311
    1. Koshimura K., Miwa S., Lee K., Fujiwara M., Watanabe Y. (1990). Enhancement of dopamine release in vivo from the rat striatum by dialytic perfusion of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin. J. Neurochem. 54, 1391–139710.1111/j.1471-4159.1990.tb01974.x
    1. Koshimura K., Murakami Y., Tanaka J., Kato Y. (1998). Self-protection of PC12 cells by 6R-tetrahydrobiopterin from nitric oxide toxicity. J. Neurosci. Res. 54, 664–67210.1002/(SICI)1097-4547(19981201)54:5<664::AID-JNR11>;2-U
    1. Mataga N., Imamura K., Watanabe Y. (1992). L-threo-3,4-dihydroxyphenylserine enhanced ocular dominance plasticity in adult cats. Neurosci. Lett. 142, 115–11810.1016/0304-3940(92)90352-8
    1. McDougle C. J., Kresch L. E., Goodman W. K., Naylor S. T., Volkmar F. R., Cohen D. J., Price L. H. (1995). A case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and obsessive-compulsive disorder. Am. J. Psychiatry 152, 772–777
    1. Nagahata M., Kazamatsuri H., Naruse H., Yamazaki K., Takesada M., Nakane Y., Kaihara S., Ohashi T. (1990). Clinical evaluation of aproterin hydrochloride (R-THBP. SUN 0588) on infantile autism – a multicenter cooperative study. Rinsho Iyaku 6, 1877–1899 (in Japanese).
    1. Nakane Y., Asuo T., Shimogawa S., Fujiwara T., Kawabata Y., Kubota J. (1990). Clinical efficacy and effects on physical development of long-term treatment of R-tetrahydrobiopterin (R-THBP, SUN 0588) for autism. Kiso To Rinsho 24, 4579–4598 (in Japanese).
    1. Naruse H., Hayashi T., Takesada M. (1984). “A preliminary study on clinical effect of tetrahydrobiopterin in infantile autism (in Japanese),” in Reports in 1983 for New Drug Development (Tokyo: Ministry of Health and Welfare; ), 71–81
    1. Naruse H., Takesada M., Nagahata M., Kazamatsuri H., Nakane Y., Yamazaki K. (1990b). An open clinical study of apropterin hydrochloride (R-tetrahydrobiopterin SUN 0588) in infantile autism – clinical study using a Rating Scale for Abnormal Behaviors in Children. Rinsho Iyaku 6, 1859–1875 (in Japanese).
    1. Naruse H., Takesada M., Nakane Y., Yamazaki K., Uchiyama T., Kaihara S., Ohashi T. (1990a). Clinical evaluation of R-tetrahydrobiopterin (SUN 0588) on infantile autism – a double-blind comparative study using placebo as a control. Rinsho Iyaku 6, 1343–1368 (in Japanese).
    1. Pardo C. A., Eberhart C. G. (2007). The neurobiology of autism. Brain Pathol. 17, 434–44710.1111/j.1750-3639.2007.00102.x
    1. Pardo C. A., Vargas D. L., Zimmerman A. W. (2005). Immunity, neuroglia and neuroinflammation in autism. Int. Rev. Psychiatry 17, 485–49510.1080/02646830500381930
    1. Posey D. J., Wiegand R. E., Wilkerson J., Maynard M., Stigler K. A., McDougle C. J. (2006a). Open-label atomoxetine for attention-deficit/hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders. J. Child Adolesc. Psychopharmacol. 16, 599–61010.1089/cap.2006.16.599
    1. Posey D. J., Erickson C. A., Stigler K. A., McDougle C. J. (2006b). The use of selective serotonin reuptake inhibitors in autism and related disorders. J. Child Adolesc. Psychopharmacol. 16, 181–18610.1089/cap.2006.16.181
    1. Rabier D., Kamoun P. (1995). Metabolism of citrulline in man. Amino Acids 9, 299–31610.1007/BF00807268
    1. Richdale A. L., Schreck K. A. (2009). Sleep problems in autism spectrum disorders: prevalence, nature, and possible biopsychosocial aetiologies. Sleep Med. Rev. 13, 403–41110.1016/j.smrv.2009.02.003
    1. Schnetz-Boutaud N. C., Anderson B. M., Brown K. D., Wright H. H., Abramson R. K., Cuccaro M. L., Gilbert J. R., Pericak-Vance M. A., Haines J. L. (2009). Examination of tetrahydrobiopterin pathway genes in autism. Genes Brain Behav. 8, 753–75710.1111/j.1601-183X.2009.00521.x
    1. Soorya L., Kiarashi J., Hollander E. (2008). Psychopharmacologic interventions for repetitive behaviors in autism spectrum disorders. Child Adolesc. Psychiatr. Clin. N. Am. 17, 753–77110.1016/j.chc.2008.06.003
    1. Takesada M., Naruse H., Nagahata M. (1992). “An open clinical study of sapropterin hydrochloride (R-tetrahydrobiopterin, R-THBP) in infantile autism: clinical effects and long-term follow-up,” in Neurobiology of Infantile Autism: Proceedings of the International Symposium on Neurobiology of Infantile Autism, Tokyo, 10–11 November 1990, eds Naruse H., Ornitz E. (New York: Elsevier Science Publishers; ), 355–358
    1. Tani Y., Fernell E., Watanabe Y., Kanai T., Langstrom B. (1994). Decrease in 6R-5,6,7,8-tetrahydrobiopterin content in cerebrospinal fluid of autistic patients. Neurosci. Lett. 181, 169–17210.1016/0304-3940(94)90586-X
    1. Tegenge M. A., Bicker G. (2009). Nitric oxide and cyclic GMP signal transduction positively regulates the motility of human neuronal precursor (NT2) cells. J. Neurochem. 110, 1828–184110.1111/j.1471-4159.2009.06279.x
    1. Tenu J. P., Lepoivre M., Moali C., Brollo M., Mansuy D., Boucher J. L. (1999). Effects of the new arginase inhibitor N(omega)-hydroxy-nor-L-arginine on NO synthase activity in murine macrophages. Nitric Oxide 3, 427–43810.1006/niox.1999.0255
    1. Thony B., Auerbach G., Blau N. (2000). Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem. J. 347, 1–1610.1042/0264-6021:3470001
    1. Troost P. W., Steenhuis M. P., Tuynman-Qua H. G., Kalverdijk L. J., Buitelaar J. K., Minderaa R. B., Hoekstra P. J. (2006). Atomoxetine for attention-deficit/hyperactivity disorder symptoms in children with pervasive developmental disorders: a pilot study. J. Child Adolesc. Psychopharmacol. 16, 611–61910.1089/cap.2006.16.611
    1. Willoughby R. E., Opladen T., Maier T., Rhead W., Schmiedel S., Hoyer J., Drosten C., Rupprecht C. E., Hyland K., Hoffmann G. F. (2009). Tetrahydrobiopterin deficiency in human rabies. J. Inherit. Metab. Dis. 32, 65–7210.1007/s10545-008-0949-z

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