Journal of Basic and Clinical Pathophysiology

Journal of Basic and Clinical Pathophysiology

Low-frequency repetitive transcranial magnetic stimulation mitigates working memory deficit and cortical malondialdehyde besides preservation of dendritic spines in valproic acid-induced model of autism spectrum disorder

Document Type : Research Paper

Authors
Masoud Afshari 1
Mehrdad Roghani 2
Hamidreza Pouretemad 1
Shahriar Gharibzadeh 1
1 Department of Cognitive Psychology, Institute for Cognitive and Brain Sciences, Shahid Beheshti University, Tehran, Iran
2 Neurophysiology Research Center, Shahed University, Tehran, Iran
10.22070/jbcp.2024.18459.1176
Abstract
Background and Objective: Autism spectrum disorder (ASD) is characterized by behavioral dysfunctions, including repetitive behaviors and impaired social interactions. Previous research has identified working memory deficits in individuals with ASD, often associated with prefrontal cortex abnormalities. Valproic acid (VPA), a well-known antiepileptic drug, has been linked to negative effects on brain development and an increased risk of ASD. This study explored the potential therapeutic impact of low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) in mitigating oxidative stress and preserving neural structures in the context of ASD induced by prenatal exposure to VPA.
Materials and Methods: Our investigation examined the role of LF-rTMS, a non-invasive brain stimulation technique, in modulating working memory (Y-maze), oxidative stress, and protecting neural structures. Oxidative stress, measured by malondialdehyde (MDA) in the prefrontal cortex, serves as a critical marker for evaluating cellular damage. Dendritic spine density was assessed using the Golgi impregnation method as a marker for neural structure protection.
Results: Our data indicated that LF-rTMS treatment significantly improves working memory function, reduces MDA level, and increases dendritic spine density in the prefrontal cortex.
Conclusion: In conclusion, our findings suggest that LF-rTMS holds promise as a neuroprotective intervention, showing potential in reducing oxidative stress and preserving neural structures in a VPA-induced ASD model.
Keywords
Autism spectrum disorder
Low-frequency repetitive transcranial magnetic stimulation
Valproic acid
Working memory
  1. Rahman MM, Shu YH, Chow T, Lurmann FW, Yu X, Martinez MP, et al. Prenatal Exposure to Air Pollution and Autism Spectrum Disorder: Sensitive Windows of Exposure and Sex Differences. Environmental Health Perspectives. 2022;130(1):017008.
  2. Hodges H, Fealko C, Soares N. Autism spectrum disorder: definition, epidemiology, causes, and clinical evaluation. Translational Pediatrics. 2020;9(S1):S55–65.
  3. Ornoy A. Valproic acid in pregnancy: How much are we endangering the embryo and fetus? Reproductive Toxicology. 2009;28(1):1–10.
  4. Han YMY, Chan MC, Chan MMY, Yeung MK, Chan AS. Effects of working memory load on frontal connectivity in children with autism spectrum disorder: a fNIRS study. Scientific Reports. 2022;12(1):1522.
  5. Borzou Z, Edalatmanesh MA. The Evaluation of Brain Derived Neurotrophic Factor and Working Memory in Valproic Acid Animal Model of Autism. The Neuroscience Journal of Shefaye Khatam. 2015;3(4):10–6.
  6. Lara AH, Wallis JD. The Role of Prefrontal Cortex in Working Memory: A Mini Review. Frontiers in Systems Neuroscience. 2015;9:173.
  7. Fereshetyan K, Chavushyan V, Danielyan M, Yenkoyan K. Assessment of behavioral, morphological and electrophysiological changes in prenatal and postnatal valproate induced rat models of autism spectrum disorder. Scientific Reports. 2021;11(1):23471.
  8. Cordiano R, Di Gioacchino M, Mangifesta R, Panzera C, Gangemi S, Minciullo PL. Malondialdehyde as a Potential Oxidative Stress Marker for Allergy-Oriented Diseases: An Update. Molecules. 2023;28(16):5979.
  9. Haro Girón S, Monserrat Sanz J, Ortega MA, Garcia-Montero C, Fraile-Martínez O, Gómez-Lahoz AM, et al. Prognostic Value of Malondialdehyde (MDA) in the Temporal Progression of Chronic Spinal Cord Injury. Journal of Personalized Medicine. 2023;13(4):626.
  10. Taleb A, Lin W, Xu X, Zhang G, Zhou QG, Naveed M, et al. Emerging mechanisms of valproic acid-induced neurotoxic events in autism and its implications for pharmacological treatment. Biomedicine & Pharmacotherapy. 2021;137:111322.
  11. Salim S. Oxidative Stress and the Central Nervous System. Journal of Pharmacology and Experimental Therapeutics. 2017;360(1):201–5.
  12. Khanal P, Hotulainen P. Dendritic Spine Initiation in Brain Development, Learning and Diseases and Impact of BAR-Domain Proteins. Cells. 2021;10(9):2392.
  13. Chail A, Saini R, Bhat P, Srivastava K, Chauhan V. Transcranial magnetic stimulation: A review of its evolution and current applications. Industrial Psychiatry Journal. 2018;27(2):172.
  14. Pascual-Leone A, Tormos JM, Keenan J, Tarazona F, Cañete C, Catalá MD. Study and modulation of human cortical excitability with transcranial magnetic stimulation. Journal of clinical neurophysiology : official publication of the American Electroencephalographic Society. 1998;15(4):333–43.
  15. Zhou X, Li K, Chen S, Zhou W, Li J, Huang Q, et al. Clinical application of transcranial magnetic stimulation in multiple sclerosis. Frontiers in Immunology. 2022;13:902658.
  16. Zahedi E, Sadr SS, Sanaeierad A, Roghani M. Chronic acetyl-L-carnitine treatment alleviates behavioral deficits and neuroinflammation through enhancing microbiota derived-SCFA in valproate model of autism. Biomedicine & Pharmacotherapy. 2023;163:114848.
  17. Tan T, Wang W, Xu H, Huang Z, Wang YT, Dong Z. Low-frequency rtms ameliorates autistic-like behaviors in rats induced by neonatal isolation through regulating the synaptic gaba transmission. Frontiers in Cellular Neuroscience. 2018;12.
  18. Weiler M, Moreno-Castilla P, Starnes HM, Melendez ELR, Stieger KC, Long JM, et al. Effects of repetitive Transcranial Magnetic Stimulation in aged rats depend on pre-treatment cognitive status: Toward individualized intervention for successful cognitive aging. Brain Stimulation. 2021;14(5):1219–25.
  19. Aguilar Diaz De Leon J, Borges CR. Evaluation of Oxidative Stress in Biological Samples Using the Thiobarbituric Acid Reactive Substances Assay. Journal of Visualized Experiments. 2020;(159):61122.
  20. Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FH, Provenzano MD, et al. Measurement of protein using bicinchoninic acid. Analytical Biochemistry. 1985;150(1):76–85.
  21. Torabi T, Azizzadeh Delshad A, Roghani M. Dietary restriction prevents dendritic changes of pyramidal neurons in hippocampal and prefrontal cortex in diabetic rat. Journal of Basic and Clinical Pathophysiology. 2019;7(2):28–32.
  22. Christensen J, Grønborg TK, Sørensen MJ, Schendel D, Parner ET, Pedersen LH, et al. Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism. Journal of the American Medical Association. 2013;309(16):1696–703.
  23. Zhao H, Wang Q, Yan T, Zhang Y, Xu H juan, Yu H peng, et al. Maternal valproic acid exposure leads to neurogenesis defects and autism-like behaviors in non-human primates. Translational Psychiatry. 2019;9(1):1–13.
  24. Sabet N, Abadi B, Moslemizadeh A, Rajizadeh MA, Arabzadeh F, Vakili Shahrbabaki SS, et al. The effect of low- and moderate-intensity interval training on cognitive behaviors of male and female rats with VPA-induced autism. Heliyon. 2023;9(10):e20641.
  25. Balderston NL, Beydler EM, Goodwin M, Deng ZD, Radman T, Luber B, et al. Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety. Translational Psychiatry. 2020;10(1):68.
  26. Huang Z, Tan T, Du Y, Chen L, Fu M, Yu Y, et al. Low-Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Function and Synaptic Plasticity in APP23/PS45 Mouse Model of Alzheimer’s Disease. Frontiers in Aging Neuroscience. 2017;9:292.
  27. Wang J, Zou L, Jiang P, Yao M, Xu Q, Hong Q, et al. Vitamin A ameliorates valproic acid-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis. NeuroToxicology.2024; S0161813X23001869
  28. Ayala A, Muñoz MF, Argüelles S. Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal. Oxidative Medicine and Cellular Longevity. 2014;2014:1–31.
  29. Ishola IO, Balogun AO, Adeyemi OO. Novel potential of metformin on valproic acid‐induced autism spectrum disorder in rats: involvement of antioxidant defence system. Fundamemntal Clinical Pharmacology. 2020;34(6):650–
  30. Bello-Medina PC, Prado-Alcalá RA, Rivas-Arancibia S. Effect of Ozone Exposure on Dendritic Spines of CA1 Pyramidal Neurons of the Dorsal Hippocampus and on Object–place Recognition Memory in Rats. Neuroscience. 2019;402:1–10.
  31. Bello-Medina PC, González-Franco DA, Vargas-Rodríguez I, Díaz-Cintra S. Oxidative stress, the immune response, synaptic plasticity, and cognition in transgenic models of Alzheimer disease. Neurologia. 2022;37(8):682–90.
  32. Mahmmoud RR, Sase S, Aher YD, Sase A, Gröger M, Mokhtar M, et al. Spatial and Working Memory Is Linked to Spine Density and Mushroom Spines. PLOS ONE. 2015;10(10):e0139739.
  33. Medina-Fernández FJ, Escribano BM, Padilla-del-Campo C, Drucker-Colín R, Pascual-Leone Á, Túnez I. Transcranial magnetic stimulation as an antioxidant. Free Radical Research. 2018;52(4):381–9.
  34. Pan J, Li H, Wang Y, Lu L, Wang Y, Zhao T, et al. Effects of low-frequency rTMS combined with antidepressants on depression in patients with post-stroke depression: a systematic review and meta-analysis. Frontiers in Neurology. 2023;14:1168333.