Extremely low frequency electromagnetic stimulation reduces ischemic stroke volume by improving cerebral collateral blood flow

Abstract

Extremely low frequency electromagnetic stimulation (ELF-EMS) has been considered as a neuroprotective therapy for ischemic stroke based on its capacity to induce nitric oxide (NO) signaling. Here, we examined whether ELF-EMS reduces ischemic stroke volume by stimulating cerebral collateral perfusion. Moreover, the pathway responsible for ELF-EMS-induced NO production was investigated. ELF-EMS diminished infarct growth following experimental stroke in collateral-rich C57BL/6 mice, but not in collateral-scarce BALB/c mice, suggesting that decreased lesion sizes after ELF-EMS results from improved collateral blood flow. In vitro analysis demonstrated that ELF-EMS increased endothelial NO levels by stimulating the Akt-/eNOS pathway. Furthermore, ELF-EMS augmented perfusion in the hind limb of healthy mice, which was mediated by enhanced Akt-/eNOS signaling. In healthy C57BL/6 mouse brains, ELF-EMS treatment increased cerebral blood flow in a NOS-dependent manner, whereas no improvement in cerebrovascular perfusion was observed in collateral-sparse BALB/c mice. In addition, ELF-EMS enhanced cerebral blood flow in both the contra- and ipsilateral hemispheres of C57BL/6 mice subjected to experimental ischemic stroke. In conclusion, we showed that ELF-EMS enhances (cerebro)vascular perfusion by stimulating NO production, indicating that ELF-EMS could be an attractive therapeutic strategy for acute ischemic stroke by improving cerebral collateral blood flow.

Hypoxia-Preconditioned Bone Marrow Mesenchymal Stem Cells Improved Cerebral Collateral Circulation and Stroke Outcome in Mice

“…28 Previous preclinical studies have also shown that inhalation of NO, remote ischemic preconditioning, and extremely-low-frequency electromagnetic stimulation induced dilation of collaterals within the 24 hours after stroke and significantly reduced early ischemic damage. 5,29,30 We also found that H-BMSCs increased VEGF secretion and eNOS phosphorylation, leading to an early vasorelaxation before collateral remodeling.…”

“…3,4 Recent studies on collateral blood flow, including our own, highlight the promise of optimizing collateral circulation to improve outcomes in patients who have experienced an AIS. 5–7…”

“…3,4 Recent studies on collateral blood flow, including our own, highlight the promise of optimizing collateral circulation to improve outcomes in patients who have experienced an AIS. [5][6][7] Stem cells are self-renewing cells that can differentiate into various cell lineages. In the context of AIS, stem cells can respond to ischemic injury and migrate to the infarcted cerebral territory.…”

Extremely Low-Frequency Electromagnetic Stimulation (ELF-EMS) Improves Neurological Outcome and Reduces Microglial Reactivity in a Rodent Model of Global Transient Stroke

“…Cerebral ischemia/reperfusion was achieved by transient occlusion of both common carotid arteries. Animals were then either sham-exposed or treated with ELF-EMS (13.5 mT/60 Hz/20 min) for 4 consecutive days as previously established by our research group [ 13 , 14 ]. ELF-EMS significantly improved the neurological score of treated ischemic gerbils 3 days (8.0 ± 0.8 vs. 2.9 ± 0.9) and 7 days (7.67 ± 1.0 vs. 2.13 ± 1.0) after surgery ( Figure 1 C).…”

“…Our research group previously showed that in permanent stroke models, sinusoidal extremely low-frequency electromagnetic stimulation (ELF-EMS) reduced lesion size, improved neurological outcome, and enhanced cerebrovascular perfusion. It also increased eNOS activation in endothelial cells [ 13 , 14 ]. In reperfusion models, studies show a recovery of sensory motor functions [ 15 , 16 ], reduction in oxidative stress [ 17 ], and an effect on neuronal death and glia activation [ 18 ].…”