Beneficial Effects of Theta-Burst Transcranial Magnetic Stimulation on Stroke Injury via Improving Neuronal Microenvironment and Mitochondrial Integrity
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Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3 h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50 Hz repeated every 200 ms, intensity at 200 G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3 h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.
KeywordsIschemic stroke Functional recovery Neuroprotection Neuroinflammation Oxidative stress Apoptosis
We would like to thank Yujiao Lu for technical support with biochemical analyses.
This study was supported by an American Heart Association Innovative Project Award 18IPA34170148 (to QZ); a Scientific Research Project of Jiangsu Provincial Commission of Health and Family Planning(Z2017016 to XZ); an Open Project Program of Jiangsu Key Laboratory of Anesthesiology (KJS1704 to XZ); and a Key Research and Development Plan of Xuzhou Science and Technology Bureau (KCI7161 to XZ).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that there is no conflict of interest.
All procedures in studies involving animals were approved and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee of the local institutes.
- 11.Ahmed ME, Tucker D, Dong Y, Lu Y, Zhao N, Wang R, et al. Methylene Blue promotes cortical neurogenesis and ameliorates behavioral deficit after photothrombotic stroke in rats. Neuroscience. 2016;336:39–48. https://doi.org/10.1016/j.neuroscience.2016.08.036.CrossRefGoogle Scholar
- 23.Strubakos CD, Malik M, Wider JM, Lee I, Reynolds CA, Mitsias P, et al. Non-invasive treatment with near-infrared light: a novel mechanisms-based strategy that evokes sustained reduction in brain injury after stroke. J Cereb Blood Flow Metab. 2019;2019:271678X19845149. https://doi.org/10.1177/0271678X19845149.Google Scholar
- 24.Ojo OB, Amoo ZA, Saliu IO, Olaleye MT, Farombi EO, Akinmoladun AC. Neurotherapeutic potential of kolaviron on neurotransmitter dysregulation, excitotoxicity, mitochondrial electron transport chain dysfunction and redox imbalance in 2-VO brain ischemia/reperfusion injury. Biomed Pharmacother. 2019;111:859–72. https://doi.org/10.1016/j.biopha.2018.12.144.CrossRefGoogle Scholar
- 27.Nataraj J, Manivasagam T, Thenmozhi AJ, Essa MM. Lutein protects dopaminergic neurons against MPTP-induced apoptotic death and motor dysfunction by ameliorating mitochondrial disruption and oxidative stress. Nutr Neurosci. 2016;19(6):237–46. https://doi.org/10.1179/1476830515Y.0000000010.CrossRefGoogle Scholar
- 29.Costa C, Tozzi A, Luchetti E, Siliquini S, Belcastro V, Tantucci M, et al. Electrophysiological actions of zonisamide on striatal neurons: selective neuroprotection against complex I mitochondrial dysfunction. Exp Neurol. 2010;221(1):217–24. https://doi.org/10.1016/j.expneurol.2009.11.002.CrossRefGoogle Scholar
- 31.Sasaki N, Mizutani S, Kakuda W, Abo M. Comparison of the effects of high- and low-frequency repetitive transcranial magnetic stimulation on upper limb hemiparesis in the early phase of stroke. J Stroke Cerebrovasc Dis. 2013;22(4):413–8. https://doi.org/10.1016/j.jstrokecerebrovasdis.2011.10.004. CrossRefGoogle Scholar
- 32.Siddiqi SH, Trapp NT, Shahim P, Hacker CD, Laumann TO, Kandala S, et al. Individualized connectome-targeted transcranial magnetic stimulation for neuropsychiatric sequelae of repetitive traumatic brain injury in a retired NFL player. J Neuropsychiatry Clin Neurosci. 2019;2019:appineuropsych18100230. https://doi.org/10.1176/appi.neuropsych.18100230.Google Scholar
- 36.Ljubisavljevic MR, Javid A, Oommen J, Parekh K, Nagelkerke N, Shehab S, et al. The effects of different repetitive transcranial magnetic stimulation (rTMS) protocols on cortical gene expression in a rat model of cerebral ischemic-reperfusion injury. PLoS One. 2015;10(10):e0139892. https://doi.org/10.1371/journal.pone.0139892.CrossRefGoogle Scholar
- 40.Lu Y, Wang R, Dong Y, Tucker D, Zhao N, Ahmed ME, et al. Low-level laser therapy for beta amyloid toxicity in rat hippocampus. Neurobiol Aging. 2017;49:165–82. https://doi.org/10.1016/j.neurobiolaging.2016.10.003.CrossRefGoogle Scholar
- 43.Caglayan AB, Beker MC, Caglayan B, Yalcin E, Caglayan A, Yulug B, et al. Acute and post-acute neuromodulation induces stroke recovery by promoting survival signaling, neurogenesis, and pyramidal tract plasticity. Front Cell Neurosci. 2019;13:144. https://doi.org/10.3389/fncel.2019.00144.CrossRefGoogle Scholar
- 44.Orosz A, Jann K, Wirth M, Wiest R, Dierks T, Federspiel A. Theta burst TMS increases cerebral blood flow in the primary motor cortex during motor performance as assessed by arterial spin labeling (ASL). NeuroImage. 2012;61(3):599–605. https://doi.org/10.1016/j.neuroimage.2012.03.084.CrossRefGoogle Scholar
- 45.Gersner R, Kravetz E, Feil J, Pell G, Zangen A. Long-term effects of repetitive transcranial magnetic stimulation on markers for neuroplasticity: differential outcomes in anesthetized and awake animals. J Neurosci. 2011;31(20):7521–6. https://doi.org/10.1523/JNEUROSCI.6751-10.2011.CrossRefGoogle Scholar
- 50.Fried PJ, Jannati A, Davila-Perez P, Pascual-Leone A. Reproducibility of single-pulse, paired-pulse, and intermittent theta-burst TMS measures in healthy aging, type-2 diabetes, and Alzheimer’s disease. Front Aging Neurosci. 2017;9:263. https://doi.org/10.3389/fnagi.2017.00263.CrossRefGoogle Scholar
- 51.Kanazawa M, Ninomiya I, Hatakeyama M, Takahashi T, Shimohata T. Microglia and monocytes/macrophages polarization reveal novel therapeutic mechanism against stroke. Int J Mol Sci. 2017;18(10). https://doi.org/10.3390/ijms18102135.
- 60.Li HP, Komuta Y, Kimura-Kuroda J, van Kuppevelt TH, Kawano H. Roles of chondroitin sulfate and dermatan sulfate in the formation of a lesion scar and axonal regeneration after traumatic injury of the mouse brain. J Neurotrauma. 2013;30(5):413–25. https://doi.org/10.1089/neu.2012.2513.CrossRefGoogle Scholar
- 61.Rocamonde B, Paradells S, Barcia JM, Barcia C, Garcia Verdugo JM, Miranda M, et al. Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. Neuroscience. 2012;224:102–15. https://doi.org/10.1016/j.neuroscience.2012.08.028.CrossRefGoogle Scholar
- 68.Moro MA, Almeida A, Bolanos JP, Lizasoain I. Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med. 2005;39(10):1291–304. https://doi.org/10.1016/j.freeradbiomed.2005.07.010.CrossRefGoogle Scholar
- 69.Margaill I, Plotkine M, Lerouet D. Antioxidant strategies in the treatment of stroke. Free Radic Biol Med. 2005;39(4):429–43. https://doi.org/10.1016/j.freeradbiomed.2005.05.003.CrossRefGoogle Scholar
- 71.Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97–112. https://doi.org/10.1146/annurev.bi.64.070195.000525.CrossRefGoogle Scholar
- 73.Yao H, Ago T, Kitazono T, Nabika T. NADPH oxidase-related pathophysiology in experimental models of stroke. Int J Mol Sci. 2017;18(10). https://doi.org/10.3390/ijms18102123.