Volume 1, Issue 1, July 2013, Page: 14-21
The Role of Beta-Adrenergic Receptor Blockers in Autism
Khanh vinh quốc Lương, Vietnamese American Medical Research FoundationWestminster, California, United States
Lan Thi Hoàng Nguyễn, Vietnamese American Medical Research FoundationWestminster, California, United States
Received: Jun. 25, 2013;       Published: Aug. 10, 2013
DOI: 10.11648/j.ajpn.20130101.13      View  3203      Downloads  211
β-adrenergic receptor blockade has been demonstrated to benefit individuals with autism. Genetic studies have identified numerous factors linking β-adrenergic receptor blockade to autism spectrum disorder (ASD), including β-adrenergic receptor variants, human leukocyte antigen genes, apoptotics factor caspase-3, glycogen synthetase kinase-3β, and the reduced form of nicotinamide adenine dinucleotide phosphate. β-adrenergic receptor blockade has also been implicated in ASD via its effects on myelin basic protein, prostaglandins, cyclooxygenase-2, and nitric oxide synthase. β-adrenergic receptor blockade may have a significant role in ASD.Therefore, the characterization of β-adrenergic receptor blockade in individuals with ASD is needed.
Β-Adrenergic Receptor Blocker, Autism, Autism Spectrum Disorder, Β-Adrenergic Receptor Antagonism
To cite this article
Khanh vinh quốc Lương, Lan Thi Hoàng Nguyễn, The Role of Beta-Adrenergic Receptor Blockers in Autism, American Journal of Psychiatry and Neuroscience. Vol. 1, No. 1, 2013, pp. 14-21. doi: 10.11648/j.ajpn.20130101.13
Asanuma M, Ogawa N, Mizukawa K, Haba K, Hirata H, Mori A. Distribution of the beta-2 adrenergic receptor messenger RNA in the rat brain by in situ hybridization histochemistry: effects of chronic reserpine treatment. Neurochem Res. 1991;16:1253-6.
Nicholas AP, Pieribone VA, Hökfelt T. Cellular localization of messenger RNA for beta-1 and beta-2 adrenergic receptors in rat brain: an in situ hybridization study. Neuroscience. 1993;56:1023-39.
Zerrate MC, Pletnikov M, Connors SL, Vargas DL, Seidler FJ, et al. Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism. J PharmacolExpTher. 2007;322:16-22.
Pitzer M, Schmidt MH, Esser G, Laucht M. Child development after maternal tocolysis with beta-sympathomimetic drugs. Child Psychiatry Hum Dev. 2001;31:165-82.
Lake CR, Ziegler MG, Murphy DL. Increased norepinephrine levels and decreased dopamine-beta-hydroxylase activity in primary autism. Arch Gen Psychiatry. 1977;34:553-6.
Barthelemy C, Bruneau N, Cottet-Eymard JM, Domenech-Jouve J, Garreau B, et al. Urinary free and conjugated catecholamines and metabolites in autistic children. J Autism DevDisord. 1988;18:583-91.
Bodner KE, Beversdorf DQ, Saklayen SS, Christ SE. Noradrenergic moderation of working memory impairments in adults with autism spectrum disorder. J IntNeuropsychol Soc. 2012;18:556-64.
Ratey JJ, Bemporad J, Sorgi P, Bick P, Polakoff S, et al. Open trial effects of beta-blockers on speech and social behaviors in 8 autistic adults. J Autism DevDisord. 1987;17:439-46.
Narayanan A, White CA, Saklayen S, Scaduto MJ, Carpenter AL, et al. Effect of propranolol on functional connectivity in autism spectrum disorder--a pilot study. Brain Imaging Behav. 2010;4:189-97.
Beversdorf DQ, Saklayen S, Higgins KF, Bodner KE, Kanne SM, Christ SE. Effect of propranolol on word fluency in autism. CognBehav Neurol. 2011;24:11-7
Beversdorf DQ, Carpenter AL, Miller RF, Cios JS, Hillier A. Effect of propranolol on verbal problem solving in autism spectrum disorder. Neurocase. 2008;14:378-83.
Campbell HL, Tivarus ME, Hillier A, Beversdorf DQ. Increased task difficulty results in greater impact of noradrenergic modulation of cognitive flexibility. PharmacolBiochemBehav. 2008;88:222-9.
Connors SL, Crowell DE, Eberhart CG, Copeland J, Newschaffer CJ, et al. β2-adrenergicreceptor activation and genetic polymorphisms in autism: data from dizygotic twins. J Child Neurol. 2005;20:876-84.
Cheslack-Postava K, Fallin MD, Avramopoulos D, Connors SL, Zimmerman AW, et al. β2-Adrenergicreceptor gene variants and risk for autism in the AGRE cohort. Mol Psychiatry. 2007;12:283-91.
Ashwood P, Corbett BA, Kantor A, Schulman H, Van de Water J, Amaral DG. In search of cellular immunophenotypes in the blood of children with autism. PLoS One. 2011;6:e19299.
Warren RP, Odell JD, Warren WL, Burger RA, Maciulis A, et al. Strong association of the third hypervariable region of HLA-DR beta 1 with autism. J Neuroimmunol. 1996;67:97-102.
Torres AR, Maciulis A, Stubbs EG, Cutler A, Odell D. The transmission disequilibrium test suggests that HLA-DR4 and DR13 are linked to autism spectrum disorder. Hum Immunol. 2002;63:311-6.
Grady DL, Harxhi A, Smith M, Flodman P, Spence MA, et al. Sequence variants of the DRD4 gene in autism: further evidence that rare DRD4 7R haplotypes are ADHD specific. Am J Med Genet B Neuropsychiatr Genet. 2005;136B:33-5.
Lee LC, Zachary AA, Leffell MS, Newschaffer CJ, Matteson KJ, et al. HLA-DR4 in families with autism. Pediatr Neurol. 2006;35:303-7.
Chien YL, Wu YY, Chen CH, Gau SS, Huang YS, et al. Association of HLA-DRB1 alleles and neuropsychological function in autism. Psychiatr Genet. 2012;22:46-9.
Johnson WG, Buyske S, Mars AE, Sreenath M, Stenroos ES, et al. HLA-DR4 as a risk allele for autism acting in mothers of probands possibly during pregnancy.Arch PediatrAdolesc Med. 2009;163:542-6.
Odell D, Maciulis A, Cutler A, Warren L, McMahon WM, et al. Confirmation of the association of the C4B null allelle in autism. Hum Immunol. 2005;66:140-5
Daniels WW, Warren RP, Odell JD, Maciulis A, Burger RA, et al. Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology. 1995;32:120-3.
Limas C, Limas CJ, Boudoulas H, Bair R, Graber H, et al. Anti-beta-receptor antibodies in familial cardiomyopathy: correlation with HLA-DR and HLA-DQ gene polymorphisms. Am Heart J. 1994;127:382-6.
Limas CJ, Goldenberg IF, LimasC.Influence of anti-beta-receptor antibodies on cardiac adenylatecyclase in patients with idiopathic dilated cardiomyopathy. Am Heart J. 1990;119:1322-8.
Li Q, Milo R, Panitch H, Bever CT Jr. Effect of propranolol and IFN-beta on the induction of MHC class II expression and cytokine production by IFN-gamma IN THP-1 human monocytic cells. Immunopharmacol Immunotoxicol. 1998;20:39-61.
Shaw SM, Coppinger T, Waywell C, Dunne L, Archer LD, et al. The effect of beta-blockers on the adaptive immune system in chronic heart failure. Cardiovasc Ther. 2009;27:181-6.
Salvesen GS, Riedl SJ. Caspase mechanisms. Adv Exp Med Biol. 2008;615:13-23.
Satomoto M, Satoh Y, Terui K, Miyao H, Takishima K, et al. Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice. Anesthesiology 2009;110:628-37.
Sheikh AM, Li X, Wen G, Tauqeer Z, Brown WT, Malik M. Cathepsin D and apoptosis related proteins are elevated in the brain of autistic subjects. Neuroscience. 2010;165:363-70.
Siniscalco D, Sapone A, Giordano C, Cirillo A, de Novellis V, et al. The Expression of Caspases is Enhanced in Peripheral Blood Mononuclear Cells of Autism Spectrum Disorder Patients. J Autism Dev Disord. 2012;42:1403-10.
Zaugg M, Xu W, Lucchinetti E, Shafiq SA, Jamali NZ, Siddiqui MA. Beta-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes. Circulation. 2000 18;102:344-50.
Mak IT, Chmielinska JJ, Nedelec L, Torres A, Weglicki WB. D-propranolol attenuates lysosomal iron accumulation and oxidative injury in endothelial cells. J Pharmacol Exp Ther. 2006;317:522-8.
Mikami M, Goubaeva F, Song JH, Lee HT, Yang J.beta-Adrenoceptor blockers protect against staurosporine-induced apoptosis in SH-SY5Y neuroblastoma cells. Eur J Pharmacol. 2008;589:14-21.
Jiang H, Guo W, Liang X, Rao Y. Both the establishment and the maintenance of neuronal polarity require active mechanisms: critical roles of GSK-3beta and its upstream regulators. Cell. 2005;120:123-35.
Yuskaitis CJ, Beurel E, Jope RS. 1. Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X syndrome. Biochim Biophys Acta 2010;1802:1006-1012.
Min WW, Yuskaitis CJ, Yan Q, Sikorski C, Chen S, et al. Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential. Neuropharmacology. 2009;56:463-72.
Mines MA, Yuskaitis CJ, King MK, Beurel E, Jope RS. GSK3 influences social preference and anxiety-related behaviors during social interaction in a mouse model of fragile X syndrome and autism. PLoS One. 2010;5:e9706.
Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, et al. Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci U S A. 2008;105:1333-8.
Ciani L, Salinas PC. WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci. 2005;6:351-62.
Zhang Y, Sun Y, Wang F, Wang Z, Peng Y, Li R. Downregulating the Canonical Wnt/β-catenin Signaling Pathway Attenuates the Susceptibility to Autism-like Phenotypes by Decreasing Oxidative Stress. Neurochem Res. 2012;37:1409-19
Webb IG, Nishino Y, Clark JE, Murdoch C, Walker SJ, et al. Constitutive glycogen synthase kinase-3alpha/beta activity protects against chronic beta-adrenergicremodelling of the heart. Cardiovasc Res. 2010;87:494-503.
Dobarro M, Orejana L, Aguirre N, RamírezMJ.Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration. Int J Neuropsychopharmacol. 2012 Nov 30:1-10.
Dobarro M, Orejana L, Aguirre N, Ramírez MJ. Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. Neuropharmacology. 2013;64:137-44.
Giulivi C, Zhang YF, Omanska-Klusek A, Ross-Inta C, Wong S, et al. Mitochondrial dysfunction in autism. JAMA. 2010;304:2389-96.
Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, et al. Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity. Nutr Metab (Lond). 2011;8:34.
Adams JB, Audhya T, McDonough-Means S, Rubin RA, Quig D, et al. Effect of a vitamin/mineral supplement on children and adults with autism. BMC Pediatr. 2011;11:111.
Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, et al. The NADH-ubiquinone oxidoreductase 1 alpha subcomplex 5 (NDUFA5) gene variants are associated with autism. Acta Psychiatr Scand. 2011;123:118-24.
Sorrentino SA, Doerries C, Manes C, Speer T, Dessy C, et al. Nebivolol exerts beneficial effects on endothelial function, early endothelial progenitor cells, myocardial neovascularization, and left ventricular dysfunction early after myocardial infarction beyond conventional β1-blockade. J Am Coll Cardiol. 2011;57:601-11.
Manrique C, Lastra G, Habibi J, Pulakat L, Schneider R, et al. Nebivolol improves insulin sensitivity in the TGR(Ren2)27 rat. Metabolism. 2011;60:1757-66.
Whaley-Connell A, Habibi J, Johnson M, Tilmon R, Rehmer N, et al. Nebivolol reduces proteinuria and renal NADPH oxidase-generated reactive oxygen species in the transgenic Ren2 rat. Am J Nephrol. 2009;30:354-60.
Zhou X, Ma L, Habibi J, Whaley-Connell A, Hayden MR, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the Zucker obese rat. Hypertension. 2010;55:880-8.
Arozal W, Watanabe K, Veeraveedu PT, Ma M, Thandavarayan RA, et al. Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats. Toxicology. 2010;274:18-26.
Mollnau H, Schulz E, Daiber A, Baldus S, Oelze M, et al. Nebivolol prevents vascular NOS III uncoupling in experimental hyperlipidemia and inhibits NADPH oxidase activity in inflammatory cells. Arterioscler Thromb Vasc Biol. 2003;23:615-21.
Kobayashi N, Mita S, Yoshida K, Honda T, Kobayashi T, et al.Celiprolol activates eNOS through the PI3K-Akt pathway and inhibits VCAM-1 Via NF-kappaB induced by oxidative stress. Hypertension. 2003;42:1004-13.
Singh VK, Warren R, Averett R, Ghaziuddin M. Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatr Neurol. 1997;17:88-90.
Singh VK, Warren RP, Odell JD, Warren WL, Cole P. Antibodies to myelin basic protein in children with autistic behavior. Brain Behav Immun. 1993;7:97-103.
Stephenson DT, O'Neill SM, Narayan S, Tiwari A, Arnold E, et al.Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis. Mol Autism.2011;2:7.
Gozzi M, Nielson DM, Lenroot RK, Ostuni JL, Luckenbaugh DA, et al. A magnetization transfer imaging study of corpus callosum myelination in young children with autism. Biol Psychiatry. 2012;72:215-20.
Mostafa GA, Al-Ayadhi LY. A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children. J Neuroinflammation. 2011;8:71.
Markham JA, Herting MM, Luszpak AE, Juraska JM, Greenough WT. Myelination of the corpus callosum in male and female rats following complex environment housing during adulthood. Brain Res. 2009;1288:9-17.
Mostafa GA, El-Sayed ZA, El-Aziz MM, El-Sayed MF. Serum anti-myelin-associated glycoprotein antibodies in Egyptian autistic children. J Child Neurol. 2008;23:1413-8.
Singer HS, Morris CM, Gause CD, Gillin PK, Crawford S, Zimmerman AW. Antibodies against fetal brain in sera of mothers with autistic children. J Neuroimmunol. 2008;194:165-72.
Martin I, Gauthier J, D'Amelio M, Védrine S, Vourc'h P, et al. Transmission disequilibrium study of an oligodendrocyte and myelin glycoprotein gene allele in 431 families with an autisticproband. Neurosci Res. 2007;59:426-30.
Larocca JN, Ledeen RW, Dvorkin B, Makman MH. Muscarinic receptor binding and muscarinic receptor-mediated inhibition of adenylatecyclase in rat brain myelin. J Neurosci. 1987;7:3869-76.
Post GR, Dawson G. Characterization of a cell line derived from a human oligodendroglioma. Mol Chem Neuropathol. 1992;16:303-17.
Vroon A, Lombardi MS, Kavelaars A, Heijnen CJ. Changes in the G-protein-coupled receptor desensitization machinery during relapsing-progressive experimental allergic encephalomyelitis. J Neuroimmunol. 2003;137:79-86.
De Keyser J, Wilczak N, Walter JH, Zurbriggen A. Disappearance of β2-adrenergicreceptors on astrocytes in canine distemper encephalitis: possible implications for the pathogenesis of multiple sclerosis. Neuroreport. 2001;12:191-4.
De Keyser J, Wilczak N, Leta R, Streetland C. Astrocytes in multiple sclerosis lack beta-2 adrenergic receptors. Neurology. 1999;53:1628-33.
Tassoni D, Kaur G, Weisinger RS, Sinclair AJ. The role of eicosanoids in the brain. Asia Pac J Clin Nutr. 2008;17Suppl 1:220-8.
Tamiji J, Crawford DA. Prostaglandin E2 and misoprostol induce neurite retraction in Neuro-2a cells. Biochem Biophys Res Commun. 2010;98:450-6.
Kaufmann WE, Worley PF, Taylor CV, Bremer M, Isakson PC. Cyclooxygenase-2 expression during rat neocortical development and in Rett syndrome. Brain Dev. 1997;19:25-34.
Yoo HJ, Cho IH, Park M, Cho E, Cho SC, et al. Association between PTGS2 polymorphism and autism spectrum disorders in Korean trios. Neurosci Res. 2008;62:66-9.
Wong HP, Ho JW, Koo MW, Yu L, Wu WK, et al. Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci. 2011;88:1108-12.
Zhang D, Ma QY, Hu HT, Zhang M. β2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFκB and AP-1. Cancer Biol Ther.2010;10:19-29.
Liao X, Che X, Zhao W, Zhang D, Bi T, Wang G. The β-adrenoceptor antagonist, propranolol, induces human gastric cancer cell apoptosis and cell cycle arrest via inhibiting nuclear factor κB signaling. Oncol Rep. 2010;24:1669-76.
Liao X, Che X, Zhao W, Zhang D, Long H, et al. Effects of propranolol in combination with radiation on apoptosis and survival of gastric cancer cells in vitro. Radiat Oncol. 2010;5:98.
Glasner A, Avraham R, Rosenne E, Benish M, Zmora O, et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;184:2449-57.
Benish M, Bartal I, Goldfarb Y, Levi B, Avraham R, et al.Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol. 2008;15:2042-52.
Chauhan A, Chauhan V, Brown WT, Cohen I. Oxidative stress in autism: increased lipid peroxidation and reduced serum levels of ceruloplasmin and transferrin--the antioxidant proteins. Life Sci. 2004;75:2539-49.
González-Fraguela M, Hung M, Vera H, Maragoto C, Noris E, et al. Oxidative stress markers in children with autism spectrum disorders. British J Med Medical Res. 2013;3:307-17.
Sajdel-Sulkowska E, Lipinski B, Windom H, Audhya J, McGinnis W. Oxidative stress in autism: cerebellar 3 nitrotyrosine levels. Am J Biochem Biotechnol. 2008;4:73-84.
Rose S, Melnyk S, Pavliv O, Bai S, Nick TG, et al. Evidence of oxidative damage and inflammation associated with low glutathione redox status in the autism brain. Transl Psychiatry. 2012;2:e134
Ming X, Stein TP, Brimacombe M, Johnson WG, Lambert GH, Wagner GC. Increased excretion of a lipid peroxidation biomarker in autism. Prostaglandins Leukot Essent Fatty Acids. 2005;73:379-84.
Yao Y, Walsh WJ, McGinnis WR, Praticò D. Altered vascular phenotype in autism: correlation with oxidative stress. Arch Neurol. 2006;63:1161-4.
Yorbik O, Sayal A, Akay C, Akbiyik DI, Sohmen T. Investigation of antioxidant enzymes in children with autistic disorder. Prostaglandins LeukotEssent Fatty Acids. 2002;67:341-3.
Al-Gadani Y, El-Ansary A, Attas O, Al-Ayadhi L. Metabolic biomarkers related to oxidative stress and antioxidant status in Saudi autistic children. Clin Biochem.2009;42:1032-40.
Larson BE, Stockwell DW, Boas S, Andrews T, Wellman GC, et al. Cardiac reactive oxygen species after traumatic brain injury. J Surg Res. 2012;173:e73-81.
Habon T, Szabados E, Kesmarky G, Halmosi R, Past T, et al. The effect of carvedilol on enhanced ADP-ribosylation and red blood cell membrane damage caused by free radicals. Cardiovasc Res. 2001;52:153-60.
Kumar A, Dogra S. Neuroprotective effect of carvedilol, an adrenergic antagonist against colchicine induced cognitive impairment and oxidative damage in rat. Pharmacol Biochem Behav. 2009;92:25-31
Kumar A, Prakash A, Dogra S. Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats. Pharmacol Rep. 2011;63:915-23.
Ma L, Gul R, Habibi J, Yang M, Pulakat L, et al. Nebivolol improves diastolic dysfunction and myocardial remodeling through reductions in oxidative stress in the transgenic (mRen2) rat. Am J Physiol Heart Circ Physiol. 2012;302:H2341-51.
Park DJ, West AR. Regulation of striatal nitric oxide synthesis by local dopamine and glutamate interactions. J Neurochem. 2009;111:1457-65.
West AR, Galloway MP, Grace AA. Regulation of striatal dopamine neurotransmission by nitric oxide: effector pathways and signaling mechanisms. Synapse. 2002;44:227-45.
Söğüt S, Zoroğlu SS, Ozyurt H, Yilmaz HR, Ozuğurlu F, et al. Changes in nitric oxide levels and antioxidant enzyme activities may have a role in the pathophysiological mechanisms involved in autism. Clin Chim Acta. 2003;331:111-7.
James SJ, Melnyk S, Jernigan S, Cleves MA, Halsted CH, et al. Metabolic endophenotype and related genotypes are associated with oxidative stress in children with autism. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:947-56.
Essa MM, Guillemin GJ, Waly MI, Al-Sharbati MM, Al-Farsi YM, et al. Increased markers of oxidative stress in autistic children of the sultanate of oman. Biol Trace Elem Res. 2012;147:25-7.
Ming X, Johnson WG, Stenroos ES, Mars A, Lambert GH, Buyske S. Genetic variant of glutathione peroxidase 1 in autism. Brain Dev. 2010;32:105-9.
Bowers K, Li Q, Bressler J, Avramopoulos D, Newschaffer C, Fallin MD. Glutathione pathway gene variation and risk of autism spectrum disorders. J Neurodev Disord. 2011;3:132-43.
Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, et al. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med. 2007;161:356-61.
Osborne NN, Wood JP. Metipranolol blunts nitric oxide-induced lipid peroxidation and death of retinal photoreceptors: a comparison with other anti-glaucoma drugs. Invest Ophthalmol Vis Sci. 2004;45:3787-95.
Dai Y, Hou F, Buckmiller L, Fan CY, Saad A, et al. Decreased eNOS protein expression in involuting and propranolol-treated hemangiomas. Arch Otolaryngol Head Neck Surg. 2012;138:177-82.
Browse journals by subject