PRELIMINARY FINDINGS ON THE EFFECT OF VITAMIN B6 ON ZEBRAFISH SOCIAL BEHAVIOR
Keywords:
VITAMIN B6, ZEBRAFISH, SOCIAL INTERACTION TESTAbstract
Vitamin B6 (vit. B6) is one of the most important vitamins involved in the maintenance and promotion of a good state of health and body function. Needed in multiple processes, vit. B6 is a water-soluble vitamin that actively participates in hemoglobin formation, glycogenolysis, gluconeogenesis, and the immune system. Its deficiency was many times addressed and linked with serious health issues. Some studies claim that vit. B6 could be considered an adequate treatment for autism spectrum disorder (ASD). Usually seen as a complex neurodevelopmental disorder, ASD is a long-life condition described by persistent challenges in social communication and interaction, aside from restricted interests and repetitive behavior. It is widely recognized that genetic predisposition is one of the primary risk factors for ASD; however, environmental factors should also be explored due to their particular and complex mechanisms. Materials and methods: The main goal of the present study was to determine the effect of vit. B6 on zebrafish behavior as an animal model for ASD using valproic acid (VPA), an anticonvulsant drug. For a period of five days, fish were exposed to 100 µM vit. B6, 300 µM VPA, and a mixture of 100 µM vit. B6 and 300 µM VPA. All the behavioral parameters were quantified through the EthoVision XT 11.5 software and performed using the adapted T-maze. The time spent in left arm, where the social stimulus was added, reflected the zebrafish's sociability level. Besides, data from locomotor activity was gathered. Results: No significant effect on social behavior was revealed after five days of exposure to vit. B6. Despite this, behavioral improvements were observed in groups where fish received vit. B6. Conclusions: Overall, this study provided limited evidence regarding the vitamin’s capacity, suggesting the necessity of additional studies to promote the efficiency of vitamin usage in ASD.
References
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3. Ramos RJ, Albersen M, Vringer E, et al. Discovery of pyridoxal reductase activity as part of human vitamin B6 metabolism. Biochimica et biophysica acta General subjects 2019; 1863(6): 1088-1097.
4. Calori IR, Gusmão LA, Tedesco AC. B6 vitamers as generators and scavengers of reactive oxygen species. Journal of Photochemistry and Photobiology 2021; 7:100041.
5. Parra M, Stahl S, Hellmann H. Vitamin B₆ and its role in cell metabolism and physiology. Cells 2018; 7(7): 84.
6. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. International journal of biomedical science 2008; 4(2): 89-96.
7. Boutros M, Ray SD. Oxidative stress. In: Wexler PBTE of T (Fourth E, editor. Oxford: Academic Press; 2024; 221-30.
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9. Ueland PM, McCann A, Midttun Ø, Ulvik A. Inflammation, vitamin B6 and related pathways. Molec-ular aspects of medicine 2017; 53: 10-27.
10. Stach K, Stach W, Augoff K. Vitamin B6 in health and disease. Nutrients 2021; 13(9).
11. Muhamad R, Akrivaki A, Papagiannopoulou G, Zavridis P, Zis P. The role of vitamin B6 in peripheral neuropathy: a systematic review. Nutrients 2023; 15.
12. Stover PJ, Field MS. Vitamin B6. Advances in nutrition (Bethesda, Md) 2015; 6(1): 132-133.
13. Sato K. Why is vitamin B6 effective in alleviating the symptoms of autism? Medical hypotheses 2018; 115:103-106.
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15. Coghlan S, Horder J, Inkster B, Mendez MA, Murphy DG, Nutt DJ. GABA system dysfunction in autism and related disorders: from synapse to symptoms. Neuroscience and biobehavioral reviews 2012; 36(9): 2044-2055.
16. Cellot G, Cherubini E. GABAergic signaling as therapeutic target for autism spectrum disorders. Frontiers in Pediatrics 2014; 2.
17. Zhao H, Mao X, Zhu C, et al. GABAergic system dysfunction in autism spectrum disorders. Frontiers in Cell and Developmental Biology 2022; 9.
18. Lord C, Elsabbagh M, Baird G, Veenstra-Vanderweele J. Autism spectrum disorder. Lancet (London, England) 2018; 392(10146): 508-520.
19. Al-Dewik N, Al-Jurf R, Styles M, et al. Overview and introduction to autism spectrum disorder (ASD). Advances in neurobiology 2020; 24: 3-42.
20. Wang L, Wang B, Wu C, Wang J, Sun M. Autism spectrum disorder: neurodevelopmental risk factors, biological mechanism, and precision therapy. International Journal of Molecular Sciences 2023; 24.
21. Uher R, Zwicker A. Etiology in psychiatry: embracing the reality of poly-gene-environmental causation of mental illness. World Psychiatry 2017; 16(2): 121-129.
22. Ramaswami G, Geschwind DH. Genetics of autism spectrum disorder. Handbook of clinical neurology 2018; 147: 321-329.
23. Jin T, Huang W, Pang Q, et al. Inferring the genetic effects of serum homocysteine and vitamin B levels on autism spectral disorder through Mendelian randomization. European Journal of Nutrition 2024.
24. Li Y, Luo ZY, Hu YY, et al. The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice. Microbiome 2020; 8(1): 120.
25. Chen L, Li J, Liu X, et al. Vitamin B6 deficiency induces autism-like behaviors in rats by regulating mtor-mediated autophagy in the hippocampus. Behavioural neurology 2023; 2023: 6991826.
26. Mousain-Bosc M, Roche M, Polge A, Pradal-Prat D, Rapin J, Bali JP. Improvement of neurobehav-ioral disorders in children supplemented with magnesium-vitamin B6. I. Attention deficit hyperactivity disorders. Magnesium research 2006; 19(1): 46-52.
27. Loohuis LM, Albersen M, de Jong S, et al. The alkaline phosphatase (ALPL) locus is associated with B6 vitamer levels in CSF and plasma. Genes 2018; 10(1).
28. Obara T, Ishikuro M, Tamiya G, et al. Potential identification of vitamin B6 responsiveness in autism spectrum disorder utilizing phenotype variables and machine learning methods. Scientific reports 2018; 8(1): 14840.
29. Khan F, Rahman MS, Akhter S, Momen ABI, Raihan SG. Vitamin B6 and magnesium on neurobe-havioral status of autism spectrum disorder: a randomized, double-blind, placebo controlled study. Bangladesh Journal of Medicine 2021; 32: 12-18.
30. Isla Torres FC, Guerrero Medina ACD, Gutiérrez Toribio SL, Julián Guevara KK, León Risco KB, Huamán Saavedra JJ. Therapeutic dietary approach to children with autistic spectrum disorder: Abordaje dietético terapéutico de niños con trastorno del espectro autista. Revista de la Facultad de Medicina Humana 2022; 22: 4.
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32. Santoriello C, Zon LI. Hooked! Modeling human disease in zebrafish. The Journal of clinical investi-gation 2012; 122(7): 2337-2343.
33. Li HH, Huang P, Dong W, Zhu ZY, Liu D. A brief history of zebrafish research toward biomedicine. Yi chuan = Hereditas 2013; 35(4): 410-420.
34. Dai YJ, Jia YF, Chen N, et al. Zebrafish as a model system to study toxicology. Environmental toxi-cology and chemistry 2014; 33(1): 11-17.
35. Shams S, Rihel J, Ortiz JG, Gerlai R. The zebrafish as a promising tool for modeling human brain disorders: A review based upon an IBNS Symposium. Neuroscience and biobehavioral reviews 2018; 85: 176-190.
36. Stewart AM, Nguyen M, Wong K, Poudel MK, Kalueff AV. Developing zebrafish models of autism spectrum disorder (ASD). Progress in neuro-psychopharmacology & biological psychiatry 2014; 50: 27-36.
37. Meshalkina DA, N. Kizlyk M, et al. Zebrafish models of autism spectrum disorder. Experimental Neurology 2018; 299: 207-216.
38. Rea V, Van Raay TJ. Using zebrafish to model autism spectrum disorder: a comparison of asd risk genes between zebrafish and their mammalian counterparts. Frontiers in molecular neuroscience 2020; 13: 575575.
39. Tayanloo-Beik A, Hamidpour SK, Abedi M, et al. Zebrafish modeling of autism spectrum disorders, current status and future prospective. Frontiers in Psychiatry 2022; 13.
40. Zimmermann FF, Gaspary KV, Leite CE, De Paula Cognato G, Bonan CD. Embryological exposure to valproic acid induces social interaction deficits in zebrafish (Danio rerio): A developmental behavior analysis. Neurotoxicology and teratology 2015; 52(Pt A): 36-41.
41. Liu CX, Peng XL, Hu CC, Li CY, Li Q, Xu X. Developmental profiling of ASD-related shank3 tran-scripts and their differential regulation by valproic acid in zebrafish. Development genes and evolution 2016; 226(6): 389-400.
42. Baronio D, Puttonen HAJ, Sundvik M, Semenova S, Lehtonen E, Panula P. Embryonic exposure to valproic acid affects the histaminergic system and the social behaviour of adult zebrafish (Danio rerio). British journal of pharmacology 2018; 175(5): 797-809.
43. Dougnon G, Matsui H. Modelling autism spectrum disorder (ASD) and Attention-deficit / hyperactivity disorder (ADHD) using mice and zebrafish. International journal of molecular sciences. 2022; 23(14).
44. Joseph TP, Zhou F, Sai LY, Chen H, Lin SL, Schachner M. Duloxetine ameliorates valproic acid-induced hyperactivity, anxiety-like behavior, and social interaction deficits in zebrafish. Autism re-search: official journal of the International Society for Autism Research 2022; 15(1): 27-41.
45. Saleh Hodin NA, Chong SG, Bakar NA, Fahmi MSAM, Ramlan NF, Hamid NNAZZ, et al. Toxicity and teratogenicity effects of valproic acid on zebrafish (Danio rerio) embryos in relation to autism spectrum disorder. Birth defects research 2023; 115(16): 1475-1485.
46. Li X, Feng T, Lu W. The effects of valproic acid neurotoxicity on aggressive behavior in zebrafish autism model. Comparative biochemistry and physiology, Toxicology & pharmacology 2024; 275: 109783.
47. Zhu MM, Li HL, Shi LH, Chen XP, Luo J, Zhang ZL. The pharmacogenomics of valproic acid. Jour-nal of human genetics 2017; 62(12): 1009-1014.
48. Pena IA, Roussel Y, Daniel K, Mongeon K, Johnstone D, Weinschutz Mendes H, et al. Pyridoxine-Dependent epilepsy in zebrafish caused by Aldh7a1 deficiency. Genetics 2017; 207(4): 1501-1518.
49. Adams JB, Kirby J, Audhya T, Whiteley P, Bain J. Vitamin/mineral/micronutrient supplement for autism spectrum disorders: a research survey. BMC Pediatrics 2022; 22(1): 590.
50. Zwaigenbaum L, Penner M. Autism spectrum disorder: advances in diagnosis and evaluation. BMJ (Clinical research ed) 2018; 361: k1674.
51. Adams JB, George F, Audhya T. Abnormally high plasma levels of vitamin B6 in children with autism not taking supplements compared to controls not taking supplements. Journal of alternative and complementary medicine (New York, NY). 2006; 12(1): 59-63.
52. Chelban V, Wilson MP, Warman Chardon J, Vandrovcova J, Zanetti MN, Zamba-Papanicolaou E, et al. PDXK mutations cause polyneuropathy responsive to pyridoxal 5′-phosphate supplementation. Annals of Neurology [Internet]. 2019; 86(2): 225-240 / doi: 10.1002/ana.25524.
53. Purkayastha P, Malapati A, Yogeeswari P, Sriram D. A review on GABA/glutamate pathway for therapeutic intervention of ASD and ADHD. Current medicinal chemistry 2015; 22(15): 1850-1859.
54. Puts NAJ, Wodka EL, Harris AD, et al. Reduced GABA and altered somatosensory function in chil-dren with autism spectrum disorder. Autism research: Official Journal of the International Society for Autism Research 2017; 10(4): 608-619.
55. Horder J, Petrinovic MM, Mendez MA, et al. Glutamate and GABA in autism spectrum disorder-a translational magnetic resonance spectroscopy study in man and rodent models. Translational psychi-atry 2018; 8(1): 106.
56. Field DT, Cracknell RO, Eastwood JR, et al. High-dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression. Human psycho-pharmacology 2022; 37(6): e2852.
57. Winterer G. Valproate and GABAergic system effects. Neuropsychopharmacology 2003; 28(11): 2050-2051.
58. Laeng P, Pitts RL, Lemire AL, et al. The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. Journal of neurochemistry 2004; 91(1): 238-251.
59. Sekiguchi K, Mashiko T, Koide R, Kawai K, Fujimoto S, Tanaka R. A case of long-term exposure to valproic acid mimicking tremor-dominant Parkinson’s disease. Tremor and other hyperkinetic move-ments (New York, N.Y.). England; 2023; 13: 17.
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