Repetitive Transcranial Magnetic Stimulation of the Brain After Ischemic Stroke: Mechanisms from Animal Models

Abstract

Stroke is a common cerebrovascular disease with high morbidity, mortality, and disability worldwide. Post-stroke dysfunction is related to the death of neurons and impairment of synaptic structure, which results from cerebral ischemic damage. Currently, transcranial magnetic stimulation (TMS) techniques are available to provide clinically effective interventions and quantitative diagnostic and prognostic biomarkers. The development of TMS has been 40 years and a range of repetitive TMS (rTMS) protocols are now available to regulate neuronal plasticity in many neurological disorders, such as stroke, Parkinson disease, psychiatric disorders, Alzheimer disease, and so on. Basic studies in an animal model with ischemic stroke are significant for demonstrating potential mechanisms of neural restoration induced by rTMS. In this review, the mechanisms were summarized, involving synaptic plasticity, neural cell death, neurogenesis, immune response, and blood-brain barrier (BBB) disruption in vitro and vivo experiments with ischemic stroke models. Those findings can contribute to the understanding of how rTMS modulated function recovery and the exploration of novel therapeutic targets. The mechanisms of rTMS in treating ischemic stroke from animal models. rTMS can prompt synaptic plasticity by increasing NMDAR, AMPAR and BDNF expression; rTMS can inhibit pro-inflammatory cytokines TNF and facilitate the expression of anti-inflammatory cytokines IL-10 by shifting astrocytic phenotypes from A1 to A2, and shifting microglial phenotypes from M1 to M2; rTMS facilitated the release of angiogenesis-related factors TGFβ and VEGF in A2 astrocytes, which can contribute to vasculogenesis and angiogenesis; rTMS can suppress apoptosis by increasing Bcl-2 expression and inhibiting Bax, caspase-3 expression; rTMS can also suppress pyroptosis by decreasing caspase-1, IL-1β, ASC, GSDMD and NLRP1 expression. rTMS, repetitive transcranial magnetic stimulation; NMDAR, N-methyl-D-aspartic acid receptors; AMPAR: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors; BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor; GSDMD: cleaved Caspase-1 cleaves Gasdermin D; CBF: cerebral blood flow.

Keywords: Blood–brain barrier; Ischemic stroke; Neurogenesis; Synaptic plasticity; rTMS.

Fig. 1

Mechanisms of rTMS in synaptic plasticity after ischemic stroke. Several molecules play important roles in the modulation of synaptic plasticity. After ischemic stroke, rTMS can enhance the levels of synaptic plasticity-associated genes, such as Dlx6, Calb2, Zic1, Crhr2, and Gng4, and Grin3a; rTMS can also inhibit the overexpression of pro-inflammatory cytokines TNF, and facilitate the expression of anti-inflammatory cytokines IL-10 to improve the environment of synaptic growth; In addition, rTMS-induced MeCP2 phosphorylation facilitated the expression of BDNF and the interaction between BDNF exon IV and RACK1. Ultimately, those proteins and genes can improve the structure and function of synapses by up-regulating the levels of PSD 95, mGlu 2/3R, and synapsin-1. rTMS repetitive transcranial magnetic stimulation, NMDAR N-methyl-d-aspartic acid receptors, BDNF brain-derived neurotrophic factor, PSD 95 post-synaptic density protein 95, mGlu2/3R glutamate receptor 2/3, MeCP2 methyl CpG binding protein 2, RACK receptor for activated C kinase 1, GLU glutamate

Fig. 2

Mechanisms of rTMS in BBB after ischemic stroke. rTMS can facilitate the ischemia-induced increase of HIF-1α and A1 shift to A2 in vessel-associated astrocytes. The increased HIF-1α can promote the release of angiogenesis-related factors TGFβ and VEGF in A2 astrocytes. In addition, TMS can also facilitate the secretion of CGRP, increase the activity of Bcl-xL, and decrease the activation of Bax, caspase-1, caspase-3. Ultimately, those molecules can improve BBB function by mitigating BBB permeabilization by enhancing the expression of claudin-5, ZO-1, occludin, and caveolin-1. BBB blood–brain barrier disruption, HIF-1α hypoxia-inducible factor-1α, CGRP calcitonin gene-related peptide, VEGF vascular endothelial growth factor