Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive therapeutic modality acknowledged for augmenting neurological function recovery following stroke. Nonetheless, uncertainties remain regarding its efficacy in promoting cognitive function recovery in patients diagnosed with vascular dementia (VD). In this study, VD was experimentally induced in a rat model utilizing the bilateral common carotid artery occlusion method. Following a recuperation period of seven days, rats were subjected to high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) at a frequency of 10 Hz. Cognitive function was assessed utilizing the Morris water maze test, and the levels of IL-6, TNF-alpha, SOD, GSH, MDA, and Fe2+ in cerebral tissue were quantitatively analyzed through enzyme-linked immunosorbent assay. Moreover, the gene and protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and glutathione peroxidase 4 (GPx4) were meticulously investigated via quantitative polymerase chain reaction (qPCR) and Western blotting techniques. The use of HF-rTMS notably augmented cognitive function in rats with VD, concomitantly reducing neuroinflammation, oxidative stress, and ferroptosis within the brain. The group subjected to HF-rTMS demonstrated an increase in the levels of both proteins and genes associated with Nrf2 and GPx4, in comparison to the VD group. These results highlight the potential of HF-rTMS treatment in enhancing cognitive function in rats diagnosed with VD through the modulation of the Nrf2/GPx4 signaling pathway. This modulation, in turn, mitigates processes linked with neuroinflammation, oxidative stress, and ferroptosis. Nevertheless, additional studies are essential to comprehensively elucidate the underlying mechanisms and clinical implications of HF-rTMS treatment in the treatment of VD.

Department of Rehabilitation Medicine Nanjing Medical University Nanjing China; Rehabilitation Medicine Center Zhejiang Chinese Medical University Affiliated Jiaxing TCM Hospital Jiaxing China

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Hobert MA, Hofmann W, Bartsch T, Peters S, Maetzler W. Diagnosis and treatment of vascular dementia. (Article in German) Z Gerontol Geriatr. 2020;53:687–698. doi: 10.1007/s00391-020-01786-3. PubMed DOI

Román GC. Vascular dementia revisited: diagnosis, pathogenesis, treatment, and prevention. Med Clin North Am. 2002;86:477–499. doi: 10.1016/S0025-7125(02)00008-1. PubMed DOI

Wolters FJ, Ikram MA. Epidemiology of Vascular Dementia. Arterioscler Thromb Vasc Biol. 2019;39:1542–1549. doi: 10.1161/ATVBAHA.119.311908. PubMed DOI

Sachdev PS, Brodaty H, Looi JC. Vascular dementia: diagnosis, management and possible prevention. Med J Aust. 1999;170:81–85. doi: 10.5694/j.1326-5377.1999.tb126889.x. PubMed DOI

Kim WJ, Rosselin C, Amatya B, Hafezi P, Khan F. Repetitive transcranial magnetic stimulation for management of post-stroke impairments: An overview of systematic reviews. J Rehabil Med. 2020;52:jrm00015. doi: 10.2340/16501977-2637. PubMed DOI

Gomes-Osman J, Indahlastari A, Fried PJ, Cabral DLF, Rice J, Nissim NR, Aksu S, et al. Non-invasive Brain Stimulation: Probing Intracortical Circuits and Improving Cognition in the Aging Brain. Front Aging Neurosci. 2018;10:177. doi: 10.3389/fnagi.2018.00177. PubMed DOI PMC

Kim J, Cha B, Lee D, Kim JM, Kim M. Effect of Cognition Recovery by Repetitive Transcranial Magnetic Stimulation on Ipsilesional Dorsolateral Prefrontal Cortex in Subacute Stroke Patients. Front Neurol. 2022;13:823108. doi: 10.3389/fneur.2022.823108. PubMed DOI PMC

Bilek E, Schäfer A, Ochs E, Esslinger C, Zangl M, Plichta MM, Braun U, et al. Application of alters human prefrontal-hippocampal functional interaction. J Neurosci. 2013;33:7050–7056. doi: 10.1523/JNEUROSCI.3081-12.2013. PubMed DOI PMC

Jeurissen D, Sack AT, Roebroeck A, Russ BE, Pascual-Leone A. TMS affects moral judgment, showing the role of DLPFC and TPJ in cognitive and emotional processing. Front Neurosci. 2014;8:18. doi: 10.3389/fnins.2014.00018. PubMed DOI PMC

Zhang N, Xing M, Wang Y, Tao H, Cheng Y. Repetitive transcranial magnetic stimulation enhances spatial learning and synaptic plasticity a the VEGF and BDNF-NMDAR pathways in a rat model of vascular dementia. Neuroscience. 2015;311:284–291. doi: 10.1016/j.neuroscience.2015.10.038. PubMed DOI

Zhang R, Xu M, Wang Y, Xie F, Zhang G, Qin X. Nrf2-a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke. Mol Neurobiol. 2017;54:6006–6017. doi: 10.1007/s12035-016-0111-0. PubMed DOI

Zhang L, Zou L, Jiang X, Cheng S, Zhang J, Qin X, Qin Z, et al. Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide nanoparticles-induced endothelial cell death. Nanotoxicology. 2021;15:779–797. doi: 10.1080/17435390.2021.1919330. PubMed DOI

Li Y, Wu J, Yu S, Zhu J, Zhou Y, Wang P, Li L, Zhao Y. Sestrin2 promotes angiogenesis to alleviate brain injury by activating Nrf2 through regulating the interaction between p62 and Keap1 following photothrombotic stroke in rats. Brain Res. 2020;1745:146948. doi: 10.1016/j.brainres.2020.146948. PubMed DOI

Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–692. doi: 10.1038/s41586-019-1705-2. PubMed DOI PMC

Yao Y, Chen Z, Zhang H, Chen C, Zeng M, Yunis J, Wei Y, et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol. 2021;22:1127–1139. doi: 10.1038/s41590-021-00996-0. PubMed DOI

Wang C, Chen S, Guo H, Jiang H, Liu H, Fu H, Wang D. Forsythoside A Mitigates Alzheimer's-like Pathology by Inhibiting Ferroptosis-mediated Neuroinflammation via Nrf2/GPX4 Axis Activation. Int J Biol Sci. 2022;18:2075–2090. doi: 10.7150/ijbs.69714. PubMed DOI PMC

Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: Pivotal roles in inflammation Fu C, Wu Y, Liu S, et al. Rehmannioside A improves cognitive impairment and alleviates ferroptosis via activating PI3K/AKT/Nrf2 and SLC7A11/GPX4 signaling pathway after ischemia. J Ethnopharmacol. 2022;289:115021. doi: 10.1016/j.jep.2022.115021. PubMed DOI

Guo T, Fang J, Tong ZY, He S, Luo Y. Transcranial Direct Current Stimulation Ameliorates Cognitive Impairment via Modulating Oxidative Stress, Inflammation, and Autophagy in a Rat Model of Vascular Dementia. Front Neurosci. 2020;14:28. doi: 10.3389/fnins.2020.00028. PubMed DOI PMC

Guo F, Lou J, Han X, Deng Y, Huang X. Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Impairment by Enhancing Neurogenesis and Suppressing Apoptosis in the Hippocampus in Rats with Ischemic Stroke. Front Physiol. 2017;8:559. doi: 10.3389/fphys.2017.00559. PubMed DOI PMC

Li H, Ma J, Zhang J, Shi WY, Mei HN, Xing Y. Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Thyroid Hormones Level and Cognition in the Recovery Stage of Stroke Patients with Cognitive Dysfunction. Med Sci Monit. 2021;27:e931914. doi: 10.12659/MSM.931914. PubMed DOI PMC

Yuan TF, Li WG, Zhang C, Wei H, Sun S, Xu N-J, Liu J, Xu T-L. Targeting neuroplasticity in patients with neurodegenerative diseases using brain stimulation techniques. Transl Neurodegener. 2020;9:44. doi: 10.1186/s40035-020-00224-z. PubMed DOI PMC

Garcia-Sanz S, Ghotme KA, Hedmont D, Arévalo-Jaimes MY, Kadosh RC, Serra-Grabulosa JM, Redolar-Ripoll D. Use of transcranial magnetic stimulation for studying the neural basis of numerical cognition: A systematic review. J Neurosci Methods. 2022;369:109485. doi: 10.1016/j.jneumeth.2022.109485. PubMed DOI

Chou YH, Ton That V, Sundman M. A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer's disease. Neurobiol Aging. 2020;86:1–10. doi: 10.1016/j.neurobiolaging.2019.08.020. PubMed DOI PMC

Di Pino G, Pellegrino G, Assenza G, Capone F, Ferreri F, Formica D, Ranieri F, et al. Modulation of brain plasticity in stroke: a novel model for neurorehabilitation. Nat Rev Neurol. 2014;10:597–608. doi: 10.1038/nrneurol.2014.162. PubMed DOI

Li X, Qi G, Yu C, Lian G, Zheng H, Wu S, Yuan T-F, Zhou D. Cortical plasticity is correlated with cognitive improvement in Alzheimer's disease patients after rTMS treatment. Brain Stimul. 2021;14:503–510. doi: 10.1016/j.brs.2021.01.012. PubMed DOI

Farina M, Vieira LE, Buttari B, Profumo E, Saso L. The Nrf2 Pathway in Ischemic Stroke: A Review. Molecules. 2021;26:5001. doi: 10.3390/molecules26165001. PubMed DOI PMC

Zhang X, Yuan M, Yang S, Chen X, Wu J, Wen M, Yan K, Bi X. Enriched environment improves post-stroke cognitive impairment and inhibits neuroinflammation and oxidative stress by activating Nrf2-ARE pathway. Int J Neurosci. 2021;131:641–649. doi: 10.1080/00207454.2020.1797722. PubMed DOI

Zhu K, Zhu X, Liu S, Yu J, Wu S, Hei M. Glycyrrhizin Attenuates Hypoxic-Ischemic Brain Damage by Inhibiting Ferroptosis and Neuroinflammation in Neonatal Rats via the HMGB1/GPX4 Pathway. Oxid Med Cell Longev. 2022;2022:8438528. doi: 10.1155/2022/8438528. PubMed DOI PMC

Moi P, Chan K, Asunis I, Cao A, Kan YW. Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci U S A. 1994;91:9926–9930. doi: 10.1073/pnas.91.21.9926. PubMed DOI PMC

Mazur A, Fangman M, Ashouri R, Arcenas A, Doré S. Nrf2 as a therapeutic target in ischemic stroke. Expert Opin Ther Targets. 2021;25:163–166. doi: 10.1080/14728222.2021.1890716. PubMed DOI

Ahmed SMU, Luo L, Namani A, Wang XJ, Tang X. Nrf2 signaling pathway: Pivotal roles in inflammation. Biochim Biophys Acta Mol Basis Dis. 2017;1863:585–597. doi: 10.1016/j.bbadis.2016.11.005. PubMed DOI

Cuadrado A, Manda G, Hassan A, Alcaraz MJ, Barbas C, Daiber A, Ghezzi P, et al. Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach. Pharmacol Rev. 2018;70:348–383. doi: 10.1124/pr.117.014753. PubMed DOI

Kerins MJ, Ooi A. The Roles of NRF2 in Modulating Cellular Iron Homeostasis. Antioxid Redox Signal. 2018;29:1756–1773. doi: 10.1089/ars.2017.7176. PubMed DOI PMC

Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072. doi: 10.1016/j.cell.2012.03.042. PubMed DOI PMC

Gou Z, Su X, Hu X, Zjou Y, Huang L, Fan Y, Li J, Lu L. Melatonin improves hypoxic-ischemic brain damage through the Akt/Nrf2/Gpx4 signaling pathway. Brain Res Bull. 2020;163:40–48. doi: 10.1016/j.brainresbull.2020.07.011. PubMed DOI

Liu Y, Fang Y, Zhang Z, Luo Y, Zhang A, Lenahan C, Chen S. Ferroptosis: An emerging therapeutic target in stroke. J Neurochem. 2022;160:64–73. doi: 10.1111/jnc.15351. PubMed DOI

Tuo QZ, Lei P, Jackman KA, Li X-L, Xiong H, Li X-L, Liuyang Z-Y, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22:1520–1530. doi: 10.1038/mp.2017.171. PubMed DOI

Ji Y, Zheng K, Li S, Ren C, Shen Y, Tian L, Zhu H, et al. Insight into the potential role of ferroptosis in neurodegenerative diseases. Front Cell Neurosci. 2022;16:1005182. doi: 10.3389/fncel.2022.1005182. PubMed DOI PMC

Li J, Cao F, Yin H-L, Huang Z-J, Lin Z-T, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis. 2020;11:88. doi: 10.1038/s41419-020-2298-2. PubMed DOI PMC

Yoo SE, Chen L, Na R, Liu Y, Rios C, Van Remmen H, Richardson A, Ran Q. Gpx4 ablation in adult mice results in a lethal phenotype accompanied by neuronal loss in brain. Free Radic Biol Med. 2012;52:1820–1827. doi: 10.1016/j.freeradbiomed.2012.02.043. PubMed DOI PMC

Zhu H, Xu G, Fu L, Li Y, Fu R, Zhao D, Ding C. The effects of repetitive transcranial magnetic stimulation on the cognition and neuronal excitability of mice. Electromagn Biol Med. 2020;39:9–19. doi: 10.1080/15368378.2019.1696358. PubMed DOI

Ayton S, Portbury S, Kalinowski P, Agarwal P, Diouf I, Schneider JA, Morris AM, Bush AI. Regional brain iron associated with deterioration in Alzheimer's disease: A large cohort study and theoretical significance. Alzheimers Dement. 2021;17:1244–1256. doi: 10.1002/alz.12282. PubMed DOI PMC

Li Y, Zhang E, Yang H, Chen Y, Tao L, Xu Y, Chen T, Shen X. Gastrodin Ameliorates Cognitive Dysfunction in Vascular Dementia Rats by Suppressing Ferroptosis via the Regulation of the Nrf2/Keap1-GPx4 Signaling Pathway. Molecules. 2022;27:6311. doi: 10.3390/molecules27196311. PubMed DOI PMC