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Annual Review of Medicine

Volume 70, 2019

Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

Abstract

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

Keyword(s): autism spectrum disorders, ERK, fragile X syndrome, metformin, mTOR, protein synthesis
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/content/journals/10.1146/annurev-med-081117-041238
2019-01-27
2024-04-16
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Literature Cited

  1. 1.  Hagerman RJ, Berry-Kravis E, Hazlett HC et al. 2017. Fragile X syndrome. Nat. Rev. Dis. Primers 3:17065
     [Google Scholar]
  2. 2.  Berry-Kravis EM, Lindemann L, Jonch AE et al. 2018. Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome. Nat. Rev. Drug Discov. 17:280–99
     [Google Scholar]
  3. 3.  Kelleher RJ 3rd, Bear MF 2008. The autistic neuron: troubled translation?. Cell 135:401–6
     [Google Scholar]
  4. 4.  Richter JD, Bassell GJ, Klann E 2015. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat. Rev. Neurosci. 16:595–605
     [Google Scholar]
  5. 5.  Hay N, Sonenberg N 2004. Upstream and downstream of mTOR. Genes Dev 18:1926–45
     [Google Scholar]
  6. 6.  Lipton JO, Sahin M 2014. The neurology of mTOR. Neuron 84:275–91
     [Google Scholar]
  7. 7.  Dann SG, Selvaraj A, Thomas G 2007. mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med. 13:252–59
     [Google Scholar]
  8. 8.  Ryu HH, Lee YS 2016. Cell type-specific roles of RAS-MAPK signaling in learning and memory: implications in neurodevelopmental disorders. Neurobiol. Learn. Mem. 135:13–21
     [Google Scholar]
  9. 9.  Waskiewicz AJ, Flynn A, Proud CG et al. 1997. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16:1909–20
     [Google Scholar]
  10. 10.  Rauen KA 2013. The RASopathies. Annu. Rev. Genom. Hum. Genet. 14:355–69
     [Google Scholar]
  11. 11.  Wang X, Snape M, Klann E et al. 2012. Activation of the extracellular signal-regulated kinase pathway contributes to the behavioral deficit of fragile X-syndrome. J. Neurochem. 121:672–79
     [Google Scholar]
  12. 12.  Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC et al. 2012. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron 76:325–37
     [Google Scholar]
  13. 13.  Castagnola S, Bardoni B, Maurin T 2017. The search for an effective therapy to treat fragile X syndrome: dream or reality?. Front. Synaptic Neurosci. 9:15
     [Google Scholar]
  14. 14.  Sawicka K, Pyronneau A, Chao M et al. 2016. Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice. PNAS 113:E6290–97
     [Google Scholar]
  15. 15.  Gkogkas CG, Khoutorsky A, Cao R et al. 2014. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep 9:1742–55
     [Google Scholar]
  16. 16.  Dziembowska M, Pretto DI, Janusz A et al. 2013. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am. J. Med. Genet. A 161A:1897–903
     [Google Scholar]
  17. 17.  Niu M, Han Y, Dy ABC et al. 2017. Autism symptoms in fragile X syndrome. J. Child Neurol. 32:903–9
     [Google Scholar]
  18. 18.  Winden KD, Ebrahimi-Fakhari D, Sahin M 2018. Abnormal mTOR activation in autism. Annu. Rev. Neurosci. 41:1–23
     [Google Scholar]
  19. 19.  Butler MG, Dasouki MJ, Zhou XP et al. 2005. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42:318–21
     [Google Scholar]
  20. 20.  Curatolo P, Napolioni V, Moavero R 2010. Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment. J. Child Neurol. 25:873–80
     [Google Scholar]
  21. 21.  Wiznitzer M 2004. Autism and tuberous sclerosis. J. Child Neurol. 19:675–79
     [Google Scholar]
  22. 22.  Ehninger D, Han S, Shilyansky C et al. 2008. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14:843–48
     [Google Scholar]
  23. 23.  Tang G, Gudsnuk K, Kuo SH et al. 2014. Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Neuron 83:1131–43
     [Google Scholar]
  24. 24.  Tavazoie SF, Alvarez VA, Ridenour DA et al. 2005. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8:1727–34
     [Google Scholar]
  25. 25.  Zhou J, Blundell J, Ogawa S et al. 2009. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29:1773–83
     [Google Scholar]
  26. 26.  Gkogkas CG, Khoutorsky A, Ran I et al. 2013. Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493:371–77
     [Google Scholar]
  27. 27.  Bidinosti M, Botta P, Kruttner S et al. 2016. CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency. Science 351:1199–203
     [Google Scholar]
  28. 28.  Peca J, Feliciano C, Ting JT et al. 2011. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472:437–42
     [Google Scholar]
  29. 29.  Pinto D, Pagnamenta AT, Klei L et al. 2010. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466:368–72
     [Google Scholar]
  30. 30.  Weiss LA, Shen Y, Korn JM et al. 2008. Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358:667–75
     [Google Scholar]
  31. 31.  Horev G, Ellegood J, Lerch JP et al. 2011. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. PNAS 108:17076–81
     [Google Scholar]
  32. 32.  Pucilowska J, Vithayathil J, Tavares EJ et al. 2015. The 16p11.2 deletion mouse model of autism exhibits altered cortical progenitor proliferation and brain cytoarchitecture linked to the ERK MAPK pathway. J. Neurosci. 35:3190–200
     [Google Scholar]
  33. 33.  Monyak RE, Emerson D, Schoenfeld BP et al. 2016. Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Mol. Psychiatry. 22:1140–48
     [Google Scholar]
  34. 34.  Dy ABC, Tassone F, Eldeeb M et al. 2018. Metformin as targeted treatment in fragile X syndrome. Clin. Genet. 93:216–22
     [Google Scholar]
  35. 35.  Gantois I, Khoutorsky A, Popic J et al. 2017. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. Nat. Med. 23:674–77
     [Google Scholar]
  36. 36.  Witters LA 2001. The blooming of the French lilac. J. Clin. Investig. 108:1105–7
     [Google Scholar]
  37. 37.  DeFronzo RA, Goodman AM 1995. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N. Engl. J. Med. 333:541–49
     [Google Scholar]
  38. 38.  Foretz M, Guigas B, Bertrand L et al. 2014. Metformin: from mechanisms of action to therapies. Cell Metab 20:953–66
     [Google Scholar]
  39. 39.  Pernicova I, Korbonits M 2014. Metformin—mode of action and clinical implications for diabetes and cancer. Nat. Rev. Endocrinol. 10:143–56
     [Google Scholar]
  40. 40.  Gong L, Goswami S, Giacomini KM et al. 2012. Metformin pathways: pharmacokinetics and pharmacodynamics. Pharmacogenet. Genom. 22:820–27
     [Google Scholar]
  41. 41.  Liang X, Chien HC, Yee SW et al. 2015. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol. Pharm. 12:4301–10
     [Google Scholar]
  42. 42.  Jonker DM, van de Mheen C, Eilers PH et al. 2003. Anticonvulsant drugs differentially suppress individual ictal signs: a pharmacokinetic/pharmacodynamic analysis in the cortical stimulation model in the rat. Behav. Neurosci. 117:1076–85
     [Google Scholar]
  43. 43.  Koepsell H 2015. Role of organic cation transporters in drug-drug interaction. Expert Opin. Drug Metab. Toxicol. 11:1619–33
     [Google Scholar]
  44. 44.  Labuzek K, Suchy D, Gabryel B et al. 2010. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep. 62:956–65
     [Google Scholar]
  45. 45.  Owen MR, Doran E, Halestrap AP 2000. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348:3607–14
     [Google Scholar]
  46. 46.  Miller RA, Chu Q, Xie J et al. 2013. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494:256–60
     [Google Scholar]
  47. 47.  Zhou G, Myers R, Li Y et al. 2001. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Investig. 108:1167–74
     [Google Scholar]
  48. 48.  Foretz M, Hebrard S, Leclerc J et al. 2010. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Investig. 120:2355–69
     [Google Scholar]
  49. 49.  Muller S, Denet S, Candiloros H et al. 1997. Action of metformin on erythrocyte membrane fluidity in vitro and in vivo. Eur. J. Pharmacol. 337:103–10
     [Google Scholar]
  50. 50.  Inoki K, Zhu T, Guan KL 2003. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115:577–90
     [Google Scholar]
  51. 51.  Kovacic S, Soltys CL, Barr AJ et al. 2003. Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J. Biol. Chem. 278:39422–27
     [Google Scholar]
  52. 52.  Kalender A, Selvaraj A, Kim SY et al. 2010. Metformin, independent of AMPK, inhibits mTORC1 in a Rag GTPase-dependent manner. Cell Metab 11:390–401
     [Google Scholar]
  53. 53.  Ben Sahra I, Regazzetti C, Robert G et al. 2011. Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 71:4366–72
     [Google Scholar]
  54. 54.  Pearce LR, Atanassova N, Banton MC et al. 2013. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation. Cell 155:765–77
     [Google Scholar]
  55. 55.  Han YE, Hwang S, Kim JH et al. 2018. Biguanides metformin and phenformin generate therapeutic effects via AMP-activated protein kinase/extracellular-regulated kinase pathways in an in vitro model of Graves’ orbitopathy. Thyroid 28:528–36
     [Google Scholar]
  56. 56.  Dang JH, Jin ZJ, Liu XJ et al. 2017. Metformin in combination with cisplatin inhibits cell viability and induces apoptosis of human ovarian cancer cells by inactivating ERK 1/2. Oncol. Lett. 14:7557–64
     [Google Scholar]
  57. 57.  Ming M, Sinnett-Smith J, Wang J et al. 2014. Dose-dependent AMPK-dependent and independent mechanisms of berberine and metformin inhibition of mTORC1, ERK, DNA synthesis and proliferation in pancreatic cancer cells. PLOS ONE 9:e114573
     [Google Scholar]
  58. 58.  Melemedjian OK, Khoutorsky A, Sorge RE et al. 2013. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain 154:1080–91
     [Google Scholar]
  59. 59.  Kawashima I, Mitsumori T, Nozaki Y et al. 2015. Negative regulation of the LKB1/AMPK pathway by ERK in human acute myeloid leukemia cells. Exp. Hematol. 43:524–33.e1
     [Google Scholar]
  60. 60.  El-Mir MY, Detaille D, Villanueva GR et al. 2008. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J. Mol. Neurosci. 34:77–87
     [Google Scholar]
  61. 61.  Wang J, Gallagher D, DeVito LM et al. 2012. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11:23–35
     [Google Scholar]
  62. 62.  Fatt M, Hsu K, He L et al. 2015. Metformin acts on two different molecular pathways to enhance adult neural precursor proliferation/self-renewal and differentiation. Stem Cell Rep 5:988–95
     [Google Scholar]
  63. 63.  Martin-Montalvo A, Mercken EM, Mitchell SJ et al. 2013. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4:2192
     [Google Scholar]
  64. 64.  de Silva VA, Suraweera C, Ratnatunga SS et al. 2016. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry 16:341
     [Google Scholar]
  65. 65.  Anagnostou E, Aman MG, Handen BL et al. 2016. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: a randomized clinical trial. JAMA Psychiatry 73:928–37
     [Google Scholar]
  66. 66.  Wink LK, Adams R, Pedapati EV et al. 2017. Brief report: metformin for antipsychotic-induced weight gain in youth with autism spectrum disorder. J. Autism Dev. Disord. 47:2290–94
     [Google Scholar]
  67. 67.  Aman MG, Hollway JA, Veenstra-VanderWeele J et al. 2018. Effects of metformin on spatial and verbal memory in children with ASD and overweight associated with atypical antipsychotic use. J. Child Adolesc. Psychopharmacol. 28:266–73
     [Google Scholar]
  68. 68.  Arnoux I, William M, Griesche N et al. 2018. Metformin reverses early cortical network dysfunction and behavior changes in Huntington's disease. eLife 7:e38744
     [Google Scholar]
  69. 69.  Koffert JP, Mikkola K, Virtanen KA et al. 2017. Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: results from a randomized clinical trial. Diabetes Res. Clin. Pract. 131:208–16
     [Google Scholar]
  70. 70.  Rao M, Gershon MD 2016. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13:517–28
     [Google Scholar]
  71. 71.  Westmark CJ, Westmark PR, O'Riordan KJ et al. 2011. Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. PLOS ONE 6:e26549
     [Google Scholar]
  72. 72.  Hsu CC, Wahlqvist ML, Lee MS, Tsai HN 2011. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J. Alzheimers Dis. 24:485–93
     [Google Scholar]
  73. 73.  Moore EM, Mander AG, Ames D et al. 2013. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care 36:2981–87
     [Google Scholar]
  74. 74.  Li J, Deng J, Sheng W et al. 2012. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav. 101:564–74
     [Google Scholar]
  75. 75.  Ou Z, Kong X, Sun X et al. 2018. Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav. Immun. 69:351–63
     [Google Scholar]
  76. 76.  Chen Y, Zhou K, Wang R et al. 2009. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. PNAS 106:3907–12
     [Google Scholar]
  77. 77.  Lu M, Su C, Qiao C et al. 2016. Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson's disease via autophagy and mitochondrial ROS clearance. Int. J. Neuropsychopharmacol. 19:pyw047
     [Google Scholar]
  78. 78.  Wahlqvist ML, Lee MS, Chuang SY et al. 2012. Increased risk of affective disorders in type 2 diabetes is minimized by sulfonylurea and metformin combination: a population-based cohort study. BMC Med 10:150
     [Google Scholar]
  79. 79.  Patil SP, Jain PD, Ghumatkar PJ et al. 2014. Neuroprotective effect of metformin in MPTP-induced Parkinson's disease in mice. Neuroscience 277:747–54
     [Google Scholar]
  80. 80.  Ryu YK, Park HY, Go J et al. 2017. Metformin inhibits the development of l-DOPA-induced dyskinesia in a murine model of Parkinson's disease. Mol. Neurobiol. 55:5715–26
     [Google Scholar]
  81. 81.  Bayliss JA, Lemus MB, Santos VV et al. 2016. Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLOS ONE 11:e0159381
     [Google Scholar]
  82. 82.  Zhao RR, Xu XC, Xu F et al. 2014. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem. Biophys. Res. Commun. 448:414–17
     [Google Scholar]
  83. 83.  Yang Y, Zhu B, Zheng F et al. 2017. Chronic metformin treatment facilitates seizure termination. Biochem. Biophys. Res. Commun. 484:450–55
     [Google Scholar]
  84. 84.  Mehrabi S, Sanadgol N, Barati M et al. 2018. Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab. Brain Dis. 33:107–14
     [Google Scholar]
  85. 85.  Sabaratnam M, Vroegop PG, Gangadharan SK 2001. Epilepsy and EEG findings in 18 males with fragile X syndrome. Seizure 10:60–63
     [Google Scholar]
  86. 86.  Dadwal P, Mahmud N, Sinai L et al. 2015. Activating endogenous neural precursor cells using metformin leads to neural repair and functional recovery in a model of childhood brain injury. Stem Cell Rep 5:166–73
     [Google Scholar]
  87. 87.  Liu Y, Tang G, Zhang Z et al. 2014. Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion. Neurosci. Lett. 579:46–51
     [Google Scholar]
  88. 88.  Ahn MJ, Cho GW 2017. Metformin promotes neuronal differentiation and neurite outgrowth through AMPK activation in human bone marrow-mesenchymal stem cells. Biotechnol. Appl. Biochem. 64:836–42
     [Google Scholar]
  89. 89.  Williams T, Courchet J, Viollet B et al. 2011. AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. PNAS 108:5849–54
     [Google Scholar]
  90. 90. Dutch-Belg. Fragile X Consort. Bakker CE, Verheij C, Willemsen R et al. 1994. Fmr1 knockout mice: a model to study fragile X mental retardation.. Cell 78:23–33
     [Google Scholar]
  91. 91.  Kooy RF 2003. Of mice and the fragile X syndrome. Trends Genet 19:148–54
     [Google Scholar]
  92. 92.  McKinney BC, Grossman AW, Elisseou NM et al. 2005. Dendritic spine abnormalities in the occipital cortex of C57BL/6 Fmr1 knockout mice. Am. J. Med. Genet. B Neuropsychiatr. Genet. 136B:98–102
     [Google Scholar]
  93. 93.  Huber KM, Gallagher SM, Warren ST et al. 2002. Altered synaptic plasticity in a mouse model of fragile X mental retardation. PNAS 99:7746–50
     [Google Scholar]
  94. 94.  Koekkoek SK, Yamaguchi K, Milojkovic BA et al. 2005. Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome. Neuron 47:339–52
     [Google Scholar]
  95. 95.  Kazdoba TM, Leach PT, Silverman JL et al. 2014. Modeling fragile X syndrome in the Fmr1 knockout mouse. Intractable Rare Dis. Res. 3:118–33
     [Google Scholar]
  96. 96.  Mientjes EJ, Nieuwenhuizen I, Kirkpatrick L et al. 2006. The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo. Neurobiol. Dis. 21:549–55
     [Google Scholar]
  97. 97.  Gaudissard J, Ginger M, Premoli M et al. 2017. Behavioral abnormalities in the Fmr1-KO2 mouse model of fragile X syndrome: the relevance of early life phases. Autism Res 10:1584–96
     [Google Scholar]
  98. 98.  Till SM, Asiminas A, Jackson AD et al. 2015. Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. Hum. Mol. Genet. 24:5977–84
     [Google Scholar]
  99. 99.  Tian Y, Yang C, Shang S et al. 2017. Loss of FMRP impaired hippocampal long-term plasticity and spatial learning in rats. Front. Mol. Neurosci. 10:269
     [Google Scholar]
  100. 100.  Hamilton SM, Green JR, Veeraragavan S et al. 2014. Fmr1 and Nlgn3 knockout rats: novel tools for investigating autism spectrum disorders. Behav. Neurosci. 128:103–9
     [Google Scholar]
  101. 101.  Drozd M, Bardoni B, Capovilla M 2018. Modeling fragile X syndrome in Drosophila. Front. Mol. Neurosci. 11:124
     [Google Scholar]
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Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders
Annual Review of Medicine 70, 167 (2019); https://doi.org/10.1146/annurev-med-081117-041238
/content/journals/10.1146/annurev-med-081117-041238
/content/journals/10.1146/annurev-med-081117-041238
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