Sera from children with autism induce autistic features which can be rescued with α CNTF small peptide mimetic in rats

PLoS ONE

Volumn 10, Issue 3, 2015, Pages

  Kazim, Syed Faraz ^a,b,c   Del Carmen Cardenas Aguayo, Maria ^a   Arif, Mohammad ^a   Blanchard, Julie ^a   Fayyaz, Fatima ^a   Grundke Iqbal, Inge ^a   Iqbal, Khalid ^a,c  

^a NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

^b STATE UNIVERSITY OF NEW YORK   (United States)

^c SUNY DOWNSTATE MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BRAIN DERIVED NEUROTROPHIC FACTOR; CILIARY NEUROTROPHIC FACTOR; JANUS KINASE; PEPTIDE; PEPTIDE 6; STAT PROTEIN; UNCLASSIFIED DRUG; NEUROPROTECTIVE AGENT; PEPTIDOMIMETIC AGENT;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTISM; BLOOD SAMPLING; BRAIN CELL CULTURE; CHILD; CLINICAL ARTICLE; CLINICAL FEATURE; CONTROLLED STUDY; EMBRYO; FEMALE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; ISOLATION INDUCED ULTRASONIC VOCALIZATION TEST; MALE; MOUSE; NERVE CELL NECROSIS; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROMODULATION; NEUROTOXICITY; NONHUMAN; OXIDATIVE STRESS; PRIMARY CULTURE; PROTEIN EXPRESSION; RAT; SOCIAL INTERACTION; UPREGULATION; ANIMAL; ANIMAL BEHAVIOR; AUTISTIC DISORDER; BLOOD; CELL DEATH; CHEMISTRY; DEVELOPMENTAL DISABILITIES; DRUG EFFECTS; GENE EXPRESSION REGULATION; GENETICS; NERVE CELL; PATHOLOGY; PATHOPHYSIOLOGY; PHENOTYPE; PRESCHOOL CHILD; SOCIAL BEHAVIOR; VOCALIZATION;

RATTUS; RATTUS NORVEGICUS;

ANIMALS; AUTISTIC DISORDER; BEHAVIOR, ANIMAL; BRAIN-DERIVED NEUROTROPHIC FACTOR; CELL DEATH; CHILD, PRESCHOOL; CILIARY NEUROTROPHIC FACTOR; DEVELOPMENTAL DISABILITIES; FEMALE; GENE EXPRESSION REGULATION; HUMANS; MALE; MICE; NEURONS; NEUROPROTECTIVE AGENTS; OXIDATIVE STRESS; PEPTIDOMIMETICS; PHENOTYPE; RATS; SOCIAL BEHAVIOR; VOCALIZATION, ANIMAL;

EID: 84929498001     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0118627     Document Type: Article

References (125)

1. Polšek D, Jagatic T, Cepanec M, Hof PR, Simiæ G. Recent developments in neuropathology of autism spectrum disorder. Transl Neurosci. 2011;2:256-64. PMID: 22180840
2. Amaral DG, Schumann CM, Nordahl CW. Neuroanatomy of autism. Trends Neurosci. 2008;31:137-45. doi: 10.1016/j.tins.2007.12.005 PMID: 18258309
3. Acosta MT, Pearl PL. The neurobiology of autism: new pieces of the puzzle. Curr Neurol Neurosci Rep. 2003;3:149-56. PMID: 12583844
4. Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, et al. Mapping early brain development in autism. Neuron 2007;56:399-413. PMID: 17964254
5. Lord C, Cook EH, Leventhal BL, Amaral DG. Autism spectrum disorders. Neuron 2000;28:355-63. PMID: 11144346
6. Baio J. Prevalence of Autism Spectrum Disorders: Autism and Developmental Disabilities Monitoring Network, 14 Sites, United States, 2008. MMWR Surveill Summ. 2012;61:1-19. PMID: 23235338
7. Nickl-Jockschat T, Michel TM. The role of neurotrophic factors in autism. Mol Psychiatry 2011;16:478-90. doi: 10.1038/mp. 2010.103 PMID: 20938434
8. Chauhan A, Chauhan V. Oxidative stress in autism. Pathophysiology 2006;13:171-81. PMID: 16766163
9. Sajdel-Sulkowska EM. Oxidative stress and neurotrophin signaling in autism. In: Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation, and immune abnormalities. Florida: CRC Press Inc.; 2010. pp 47-60.
10. Courchesne E, Karns CM, Davis HR, Ziccardi R, Carper RA, Tigue ZD, et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 2001;57:245-254. PMID: 11468308
11. Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA 2003;290:337-44. PMID: 12865374
12. Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch Gen Psychiatry 2005;62:1366-76. PMID: 16330725
13. Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, et al. Brain structural abnormalities in young children with autism spectrum disorder. Neurology 2002;59:184-92. PMID: 12136055
14. Dissanayake C, Bui QM, Huggins R, Loesch DZ. Growth in stature and head circumference in highfunctioning autism and Asperger disorder during the first 3 years of life. Dev Psychopathol. 2006;18:381-93. PMID: 16600060
15. Dawson G, Munson J, Webb SJ, Nalty T, Abbott R, Toth K. Rate of head growth decelerates and symptoms worsen in the second year of life in autism. Biol Psychiatry 2007;61:458-64. PMID: 17137564
16. Kemper TL, Bauman M. Neuropathology of infantile autism. J Neuropathol Exp Neurol. 1998;57:645-52. PMID: 9690668
17. Kemper TL, Bauman M. Neuropathology of infantile autism. Mol Psychiatry 2002;7:S12-S13. PMID: 12142934
18. Bourgeron T. A synaptic trek to autism. Curr Opin Neurobiol. 2009;19:231-4. doi: 10.1016/j.conb. 2009.06.003 PMID: 19545994
19. Kaur N, Lu B, Monroe RK, Ward SM, Halvorsen SW. Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons. J Neurochem. 2005;92:1521-30. PMID: 15748169
20. Linker RA, Mäurer M, Gaupp S, Martini R, Holtmann B, Giess R, et al. CNTF is a major protective factor in demyelinating CNS disease: a neurotrophic cytokine as modulator in neuroinflammation. Nat Med. 2002;8:620-4. PMID: 12042814
21. Askvig JM, Lo DY, Sudbeck AW, Behm KE, Leiphon LJ, Watt JA. Inhibition of the JAK-STAT pathway prevents CNTF-mediated survival of axotomized oxytocinergic magnocellular neurons in organotypic cultures of the rat supraoptic nucleus. Exp Neurol. 2013;240:75-87. doi: 10.1016/j.expneurol.2012. 10.023 PMID: 23123407
22. Al-Ayadhi LY. Relationship between Sonic hedgehog protein, brain-derived neurotrophic factor and oxidative stress in autism spectrum disorders. Neurochem Res. 2012;37:394-400. doi: 10.1007/s11064-011-0624-x PMID: 21984201
23. Chen H, Tung YC, Li B, Iqbal K, Grundke-Iqbal I. Trophic factors counteract elevated FGF-2-induced inhibition of adult neurogenesis. Neurobiol Aging 2007;28:1148-62. PMID: 16859812
24. Hutter-Paier B, Grygar E, Fruhwirth M, Temmel I, Windisch M. Further evidence that Cerebrolysin protects cortical neurons from neurodegeneration in vitro. J Neural Transm Suppl. 1998;53:363-72. PMID: 9700672
25. Tatebayashi Y, Lee MH, Li L, Iqbal K, Grundke-Iqbal I. The dentate gyrus neurogenesis: a therapeutic target for Alzheimer's disease. Acta Neuropathol. 2003;105:225-32. PMID: 12557008
26. Krasnoperova MG, Bashina VM, Skvortsov IA, Simashkova NV. The effect of cerebrolysin on cognitive functions in childhood autism and in Asperger syndrome. Zh Nevrol Psikhiatr Im S S Korsakova 2003;103:15-8. PMID: 14763251
27. Chen ZY, Cao L, Wang LM, Guo C, Ye JL, Chai YF, et al. Development of neurotrophic molecules for treatment of neurodegeneration. Curr Protein Pept Sci. 2001;2:261-76. PMID: 12369936
28. Longo FM, Yang T, Knowles JK, Xie Y, Massa SM. Small molecule neurotrophin receptor ligands: novel strategies for targeting Alzheimer's disease mechanisms. Curr Alzheimer Res. 2007;4:503. 506. PMID: 18220511
29. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013;14:401-16. doi: 10.1038/nrn3505 PMID: 23674053
30. ALS CNTF Treatment Study Group. A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996;46:1244-49. PMID: 8628460
31. Chohan MO, Li B, Blanchard J, Tung YC, Heaney AT, Rabe A, et al. Enhancement of dentate gyrus neurogenesis, dendritic and synaptic plasticity and memory by a neurotrophic peptide. Neurobiol Aging 2011;32:1420-34. doi: 10.1016/j.neurobiolaging.2009.08.008 PMID: 19767127
32. Blanchard J, Wanka L, Tung YC, Cardenas-Aguayo Mdel C, La Ferla FM, Iqbal K, et al. Pharmacologic reversal of neurogenic and neuroplastic abnormalities and cognitive impairments without affecting Aβ and tau pathologies in 3xTg-AD mice. Acta Neuropathol 2010;120:605-21. doi: 10.1007/s00401-010-0734-6 PMID: 20697724
33. Blanchard J, Chohan MO, Li B, Liu F, Iqbal K, Grundke-Iqbal I. Beneficial Effect of a CNTF Tetrapeptide on Adult Hippocampal Neurogenesis, Neuronal Plasticity, and Spatial Memory in Mice. J Alzheimers Dis. 2010;21:1185-95. doi: 10.3233/JAD-2010-1000069 PMID: 20952820
34. Blanchard J, Bolognin S, Chohan MO, Rabe A, Iqbal K, Grundke-Iqbal I. Rescue of synaptic failure and alleviation of learning and memory impairments in a trisomic mouse model of down syndrome. J Neuropathol Exp Neurol. 2011;70:1070-79. doi: 10.1097/NEN.0b013e318236e9ad PMID: 22082658
35. Bolognin S, Blanchard J, Wang X, Basurto-Islas G, Tung YC, Kohlbrenner E, et al. An experimental rat model of sporadic Alzheimer's disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol. 2012;123:133-51. doi: 10.1007/s00401-011-0908-x PMID: 22083255
36. Cardenas-Aguayo Mdel C, Santa-Olalla J, Baizabal JM, Salgado LM, Covarrubias L. Growth factor deprivation induces an alternative non-apoptotic death mechanism that is inhibited by Bcl2 in cells derived from neural precursor cells. J Hematother Stem Cell Res. 2003;12:735-48. PMID: 14977482
37. Cardenas-Aguayo Mdel C, Kazim SF, Grundke-Iqbal I, Iqbal K. Neurogenic and neurotrophic effects of BDNF peptides in mouse hippocampal primary neuronal cell cultures. PLoS One 2013;8:e53596. doi: 10.1371/journal.pone.0053596 PMID: 23320097
38. Kazim SF, Blanchard J, Dai CL, Tung YC, La Ferla FM, Iqbal IG, et al. Disease modifying effect of chronic oral treatment with a neurotrophic peptidergic compound in a triple transgenic mouse model of Alzheimer's disease. Neurobiol Dis. 2014;71:110-30. doi: 10.1016/j.nbd.2014.07.001 PMID: 25046994
39. Muthaiyah B, Essa MM, Chauhan V, Chauhan A. Protective Effects of Walnut Extract Against Amyloid Beta Peptide-Induced Cell Death and Oxidative Stress in PC12 Cells. Neurochemistry Res. 2011;36:2096-2103. doi: 10.1007/s11064-011-0533-z PMID: 21706234
40. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxide in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351-58. PMID: 36810
41. Branchi I, Bichler Z, Berger-Sweeney J, Ricceri L. Animal models of mental retardation: from gene to cognitive function. Neurosci Biobehav Rev. 2003;27:141-53. PMID: 12732230
42. Hill JM, Lim MA, Stone MM. Developmental Milestones in the Newborn Mouse. Neuromethods, Neuropeptide techniques 2007;39:131-49.
43. Lubics A, Reglodi D, Tamás A, Kiss P, Szalai M, Szalontay L, et al. Neurological reflexes and early motor behavior in rats subjected to neonatal hypoxic-ischemic injury. Behav Brain Res. 2005;157:157-65. PMID: 15617782
44. Altman J, Sudarshan K. Postnatal development of locomotion in the laboratory rat. Anim Behav. 1975;23:896-920. PMID: 1200422
45. Dam K, Seidler FJ, Slotkin TA. Chlorpyrifos exposure during a critical neonatal period elicits genderselective deficits in the development of coordination skills and locomotor activity. Brain Res Dev Brain Res. 2000;121:179-87. PMID: 10876030
46. Hill JM, Gozes I, Hill JL, Fridkin M, Brenneman DE. Vasoactive intestinal peptide antagonist retards the development of neonatal behaviors in the rat. Peptides 1999;12:187-92.
47. Reglodi D, Kiss P, Tamás A, Lengvári I. The effects of PACAP and PACAP antagonist on the neurobehavioral development of newborn rats. Behav Brain Res. 2003;140:131-9. PMID: 12644286
48. Smart JL, Dobbing J. Vulnerability of developing brain. II. Effects of early nutritional deprivation on reflex ontogeny and development of behaviour in the rat. Brain Res. 1971;28:85-95. PMID: 5557887
49. Smart JL, Dobbing J. Vulnerability of developing brain. VI. Relative effects of foetal and early postnatal undernutrition on reflex ontogeny and development of behaviour in the rat. Brain Res. 1971;33:303-14. PMID: 5167446
50. Hill JM, Mervis RF, Avidor R, Moody TW, Brenneman DE. HIV envelope protein-induced neuronal damage and retardation of behavioral development in rat neonates. Brain Res. 1993;603:222-33. PMID: 8461978
51. Toso L, Cameroni I, Roberson R, Abebe D, Bissell S, Spong CY. Prevention of developmental delays in a Down syndrome mouse model. Obstet Gynecol. 2008;112:1242-51. doi: 10.1097/AOG. 0b013e31818c91dc PMID: 19037032
52. Scattoni ML, Crawley J, Ricceri L. Ultrasonic vocalizations: a tool for behavioural phenotyping of mouse models of neurodevelopmental disorders. Neurosci Biobehav Rev. 2009;33:508-15. doi: 10. 1016/j.neubiorev. 2008.08.003 PMID: 18771687
53. Young DM, Schenk AK, Yang SB, Jan YN, Jan LY. Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism. Proc Natl Acad Sci U S A. 2010;107:11074-9. doi: 10.1073/pnas. 1005620107 PMID: 20534473
54. Scattoni ML, Gandhy SU, Ricceri L, Crawley JN. Unusual repertoire of vocalizations in the BTBR T+tf/J mouse model of autism. PLoS One 2008;3:e3067. doi: 10.1371/journal.pone.0003067 PMID: 18728777
55. Shair HN. Acquisition and expression of a socially mediated separation response. Behav Brain Res. 2007;182:180-92. PMID: 17379325
56. Wöhr M, Schwarting RK. Maternal care, isolation-induced infant ultrasonic calling, and their relations to adult anxiety-related behavior in the rat. Behav Neurosci. 2008;122:310-30. doi: 10.1037/0735-7044.122.2.310 PMID: 18410171
57. Blumberg MS, Alberts JR. On the significance of similarities between ultrasonic vocalizations of infant and adult rats. Neurosci Biobehav Rev. 1991;15:383-90. PMID: 1956606
58. Bell RW, Nitschke W, Bell NJ, Zachman TA. Early experience, ultrasonic vocalizations, and maternal responsiveness in rats. Dev Psychobiol. 1974;7:235-42. PMID: 4838171
59. Allin JT, Banks EM. Effects of temperature on ultrasound production by infant albino rats. Dev Psychobiol. 1971;4:149-56. PMID: 5162545
60. Hofer MA, Shair H. Sensory processes in the control of isolation-induced ultrasonic vocalization by 2-week-old rats. J Comp Physiol Psychol. 1980;94:271-9. PMID: 7364999
61. Oswalt GL, Meier GW. Olfactory, thermal, and tactual influences on infantile ultrasonic vocalization in rats. Dev Psychobiol. 1975;8:129-35. PMID: 1225689
62. Allin JT, Banks EM. Functional aspects of ultrasound production by infant albino rats (Rattus norvegicus). Anim Behav. 1972;20:175-85. PMID: 4664924
63. Noirot E. Ultrasounds in young rodents. II. Changes with age in albino rats. Anim Behav. 1968;16:129-34. PMID: 5639891
64. Naito H, Inoue M, Makino J. Ultrasonic isolation calls in genetically high- and low-emotional rat pups. Exp Anim. 2000;49:289-94. PMID: 11109555
65. Kromkhun P, Katou M, Hashimoto H, Terada M, Moon C, Saito TR. Quantitative and qualitative analysis of rat pup ultrasonic vocalization sounds induced by a hypothermic stimulus. Lab Anim Res. 2013;29:77-83. doi: 10.5625/lar.2013.29.2.77 PMID: 23825480
66. Schwarting RK, Wöhr M. On the relationships between ultrasonic calling and anxiety-related behavior in rats. Braz J Med Biol Res. 2012;45:337-48. PMID: 22437483
67. Crawley JN, Chen T, Puri A, Washburn R, Sullivan TL, Hill JM, et al. Social approach behaviors in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments. Neuropeptides 2007;41:145-63. PMID: 17420046
68. Moy SS, Nadler JJ, Perez A, Barbaro RP, Johns JM, Magnuson TR, et al. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice. Genes Brain Behav. 2004;3:287-302. PMID: 15344922
69. Moy SS, Nadler JJ, Young NB, Perez A, Holloway LP, Barbaro RP, et al. Mouse behavioral tasks relevant to autism: phenotypes of 10 inbred strains. Behav Brain Res. 2007;176:4-20. PMID: 16971002
70. Yang M, Silverman JL, Crawley JN. Automated three-chambered social approach task for mice. Curr Protoc Neurosci. 2011; Chapter 8: Unit 8-26.
71. Crawley JN. Designing mouse behavioral tasks relevant to autistic-like behaviors. Ment Retard Dev Disabil Res Rev. 2004;10:248-58. PMID: 15666335
72. Silverman JL, Yang M, Lord C, Crawley JN. Behavioural phenotyping assays for mouse models of autism. Nat Rev Neurosci. 2010;11:490-502. doi: 10.1038/nrn2851 PMID: 20559336
73. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730-2. PMID: 559941
74. Porsolt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther. 1977;229:327-36. PMID: 596982
75. Bensadoun A, Weinstein D. Assay of proteins in the presence of interfering materials. Anal Biochem. 1976;70:241-250. PMID: 1259145
76. Schmued LC, Albertson C, Slikker W Jr. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. 1997;751:37-46. PMID: 9098566
77. Wang X, Blanchard J, Grundke-Iqbal I, Wegiel J, Deng HX, Siddique T, et al. Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection. Acta Neuropathol. 2014;127:243-56. doi: 10.1007/s00401-013-1175-9 PMID: 24136402
78. Mazur-Kolecka B, Cohen IL, Gonzalez M, Jenkins EC, Kaczmarski W, Brown WT, et al. Autoantibodies against neuronal progenitors in sera from children with autism. Brain Dev. 2014;36:322-9. doi: 10.1016/j.braindev. 2013.04.015 PMID: 23838310
79. Mazur-Kolecka B, Cohen IL, Jenkins EC, Flory M, Merz G, Ted Brown W, et al. Sera from children with autism alter proliferation of human neuronal progenitor cells exposed to oxidation. Neurotox Res. 2009;16:87-95. doi: 10.1007/s12640-009-9052-y PMID: 19526302
80. Mazur-Kolecka B, Cohen IL, Jenkins EC, Kaczmarski W, Flory M, Frackowiak J. Altered development of neuronal progenitor cells after stimulation with autistic blood sera. Brain Res. 2007;1168:11-20. PMID: 17706942
81. Fox WM. Reflex-ontogeny and behavioural development of the mouse. Anim Behav. 1965;13:234-41. PMID: 5835840
82. Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, Di Lavore PC, et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30:205-23. PMID: 11055457
83. Doussard-Roosevelt JA, Joe CM, Bazhenova OV, Porges SW. Mother-child interaction in autistic and nonautistic children: characteristics of maternal approach behaviors and child social responses. Dev Psychopathol. 2003;15:277-95. PMID: 12931828
84. Nickl-Jockschat T. Neurotrophic Factors in Autism Spectrum Disorders. In: Patel VB, Preedy VR, Martin CR, editors. Comprehensive Guide to Autism. New York: Springer; 2014. pp. 741-54.
85. Katoh-Semba R, Wakako R, Komori T, Shigemi H, Miyazaki N, Ito H, et al. Age-related changes in BDNF protein levels in human serum: differences between autism cases and normal controls. Int J Dev Neurosci. 2007;25:367-72. PMID: 17804189
86. Hashimoto K, Iwata Y, Nakamura K, Tsujii M, Tsuchiya KJ, Sekine Y, et al. Reduced serum levels of brain-derived neurotrophic factor in adult male patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 2006;30:1529-31. PMID: 16876305
87. Taurines R, Segura M, Schecklmann M, Albantakis L, Grünblatt E, Walitza S, et al. Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder. J Neural Transm. 2014;121:1117-28. doi: 10.1007/s00702-014-1162-x PMID: 24500031
88. Abdallah MW, Mortensen EL, Greaves-Lord K, Larsen N, Bonefeld-Jørgensen EC, Nørgaard-Pedersen B, et al. Neonatal levels of neurotrophic factors and risk of autism spectrum disorders. Acta Psychiatr Scand. 2013;128:61-69. doi: 10.1111/acps.12020 PMID: 23039165
89. Nelson KB, Grether JK, Croen LA, Dambrosia JM, Dickens BF, Jelliffe LL, et al. Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation. Ann Neurol. 2001;49:597-606. PMID: 11357950
90. Miyazaki K, Narita N, Sakuta R, Miyahara T, Naruse H, Okado N, et al. Serum neurotrophin concentrations in autism and mental retardation: a pilot study. Brain Dev. 2004;26:292-5. PMID: 15165668
91. Ricci S, Businaro R, Ippoliti F, Lo Vasco VR, Massoni F, Onofri E, et al. Altered cytokine and BDNF levels in autism spectrum disorder. Neurotox Res. 2013;24:491-501. doi: 10.1007/s12640-013-9393-4 PMID: 23604965
92. Correia CT, Coutinho AM, Sequeira AF, Sousa IG, Lourenço Venda L, Almeida JP, et al. Increased BDNF levels and NTRK2 gene association suggest a disruption of BDNF/TrkB signaling in autism. Genes Brain Behav. 2010;9:841-8. doi: 10.1111/j.1601-183X.2010.00627.x PMID: 20662941
93. Tsai SJ. Is autism caused by early hyperactivity of brain-derived neutrophic factor? Med. Hypotheses 2005;5:79-82.
94. Garcia KL, Yu G, Nicolini C, Michalski B, Garzon DJ, Chiu VS, et al. Altered balance of proteolytic isoforms of pro-brain-derived neurotrophic factor in autism. J Neuropathol Exp Neurol. 2012;71:289-97. doi: 10.1097/NEN.0b013e31824b27e4 PMID: 22437340
95. Moon C, Yoo JY, Matarazzo V, Sung YK, Kim EJ, Ronnett GV, et al. Leukemia inhibitory factor inhibits neuronal terminal differentiation through STAT3 activation. Proc Natl Acad Sci USA 2002;99:9015-20. PMID: 12084939
96. Metcalf D. The unsolved enigmas of leukemia inhibitory factor. Stem Cells 2003;21:5-14. PMID: 12529546
97. Bonaguidi MA, McGuire T, Hu M, Kan L, Samanta J, Kessler JA. Lif and bmp signaling generate separate and discrete types of gfap-expressing cells. Development 2005;132:5503-5514. PMID: 16314487
98. Bauer S, Patterson PH. Leukemia inhibitory factor promotes neural stem cell self-renewal in the adult brain. J Neurosci. 2006;26:12089-99. PMID: 17108182
99. Shimazaki T, Shingo T, Weiss S. The ciliary neurotrophic factor/leukemia inhibitory factor/gp130 receptor complex operates in the maintenance of mammalian forebrain neural stem cells. J Neurosci. 2001;21:7642-53. PMID: 11567054
100. Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health B Crit Rev. 2006;9:485-99. PMID: 17090484
101. 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. PMID: 15363659
102. Bailey A, Luthert P, Dean A, Harding B, Janota I, Montgomery M, et al. A clinicopathological study of autism. Brain 1998;121:889-905. PMID: 9619192
103. Guerin P, Lyon G, Barthelemy C, Sostak E, Chevrollier V, Garreau B, et al. Neuropathological study of a case of autistic syndrome with severe mental retardation. Dev Med Child Neurol. 1996;38:203-11. PMID: 8631517
104. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Ann Neurol. 2005;57:67-81. PMID: 15546155
105. Pardo-Villamizar CA, Zimmerman AW. Inflammation and neuroimmunity in the pathogenesis of autism: Neural and immune network interactions. In: Chauhan A, Chauhan V, Brown WT, editors. Autism: oxidative stress, inflammation, and immune abnormalities. Florida: CRC Press Inc; 2010. pp 225-44.
106. Fields RD, Stevens-Graham B. New insights into neuron-glia communication. Science 2002;298:556-62. PMID: 12386325
107. Murai KK, Van Meyel DJ. Neuron glial communication at synapses: insights from vertebrates and invertebrates. Neuroscientist 2007;13:657-66. PMID: 17911218
108. Laurence JA, Fatemi SH. Glial fibrillary acidic protein is elevated in superior frontal, parietal and cerebellar cortices of autistic subjects. Cerebellum 2005;4:206-10. PMID: 16147953
109. Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev. 2004;10:303-17. PMID: 15666334
110. Beversdorf DQ, Manning SE, Hillier A, Anderson SL, Nordgren RE, Walters SE, et al. Timing of prenatal stressors and autism. J Autism Dev Disord. 2005;35:471-8. PMID: 16134032
111. Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci. 2005;23:201-19. PMID: 15749246
112. Andersen SL. Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev. 2003;27:3-18. PMID: 12732219
113. Bernd P. The role of neurotrophins during early development. Gene Expr. 2008;14:241-50. PMID: 19110723
114. Holtzman DM, Mobley WC. Neurotrophic factors and neurologic disease. West J Med. 1994;161:246-54. PMID: 7975562
115. Chapleau CA, Larimore JL, Theibert A, Pozzo-Miller L. Modulation of dendritic spine development and plasticity by BDNF and vesicular trafficking: fundamental roles in neurodevelopmental disorders associated with mental retardation and autism. J Neurodev Disord. 2009;1:185-96. doi: 10.1007/s11689-009-9027-6 PMID: 19966931
116. Rola R, Zou Y, Huang TT, Fishman K, Baure J, Rosi S, et al. Lack of extracellular superoxide dismutase (EC-SOD) in the microenvironment impacts radiation-induced changes in neurogenesis. Free Radic Biol Med. 2007;42:1133-45. PMID: 17382195
117. Ishii J, Natsume A, Wakabayashi T, Takeuchi H, Hasegawa H, Kim SU, et al. The free-radical scavenger edaravone restores the differentiation of human neural precursor cells after radiation-induced oxidative stress. Neurosci Lett. 2007;423:225-30. PMID: 17709197
118. Chohan MO, Bragina O, Kazim SF, Statom G, Baazaoui N, Bragin D, et al. Enhancement of Neurogenesis and Memory by a Neurotrophic Peptide in Mild to Moderate Traumatic Brain Injury. Neurosurgery 2015;76:201-15 doi: 10.1227/NEU.0000000000000577 PMID: 25255260
119. Iqbal K, Kazim SF, Bolognin S, Blanchard J. Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions. Neural Regen Res. 2014;9:1518-9. doi: 10.4103/1673-5374.139477 PMID: 25317168
120. De Chiara TM, Vejsada R, Poueymirou WT, Acheson A, Suri C, Conover JC, et al. Mice lacking the CNTF receptor, unlike mice lacking CNTF, exhibit profound motor neuron deficits at birth. Cell 1995;83:313-22. PMID: 7585948
121. Finn TP, Kim S, Nishi R. Overexpression of ciliary neurotrophic factor in vivo rescues chick ciliary ganglion neurons from cell death. J Neurobiol. 1998;34:283-93. PMID: 9485052
122. Ebadi M, Srinivasan SK, Baxi MD. Oxidative stress and antioxidant therapy in Parkinson's disease. Prog Neurobiol. 1996;48:1-19. PMID: 8830346
123. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 2013;14:401-16. doi: 10.1038/nrn3505 PMID: 23674053
124. Wu CL, Chen SD, Hwang CS, Yang DI. Sonic hedgehog mediates BDNF-induced neuroprotection against mitochondrial inhibitor 3-nitropropionic acid. Biochem Biophys Res Commun. 2009;385:112-7. doi: 10.1016/j.bbrc.2009.04.145 PMID: 19422804
125. Wu CL, Hwang CS, Yang DI. Protective effects of brain-derived neurotrophic factor against neurotoxicity of 3-nitropropionic acid in rat cortical neurons. Neurotoxicology 2009;30:718-26. doi: 10.1016/j. neuro.2009.03.008 PMID: 19428112