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

Extremely low-frequency electromagnetic stimulation (ELF-EMS) was demonstrated to be significantly beneficial in rodent models of permanent stroke. The mechanism involved enhanced cerebrovascular perfusion and endothelial cell nitric oxide production. However, the possible effect on the neuroinflammatory response and its efficacy in reperfusion stroke models remains unclear. To evaluate ELF-EMS effectiveness and possible immunomodulatory response, we studied neurological outcome, behavior, neuronal survival, and glial reactivity in a rodent model of global transient stroke treated with 13.5 mT/60 Hz. Next, we studied microglial cells migration and, in organotypic hippocampal brain slices, we assessed neuronal survival and microglia reactivity. ELF-EMS improved the neurological score and behavior in the ischemia-reperfusion model. It also improved neuronal survival and decreased glia reactivity in the hippocampus, with microglia showing the first signs of treatment effect. In vitro ELF-EMS decreased (Lipopolysaccharide) LPS and ATP-induced microglia migration in both scratch and transwell assay. Additionally, in hippocampal brain slices, reduced microglial reactivity, improved neuronal survival, and modulation of inflammation-related markers was observed. Our study is the first to show that an EMF treatment has a direct impact on microglial migration. Furthermore, ELF-EMS has beneficial effects in an ischemia/reperfusion model, which indicates that this treatment has clinical potential as a new treatment against ischemic stroke.

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

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.

Electromagnetic Field as a Treatment for Cerebral Ischemic Stroke.

Cerebral stroke is a leading cause of death and adult-acquired disability worldwide. To this date, treatment options are limited; hence, the search for new therapeutic approaches continues. Electromagnetic fields (EMFs) affect a wide variety of biological processes and accumulating evidence shows their potential as a treatment for ischemic stroke. Based on their characteristics, they can be divided into stationary, pulsed, and sinusoidal EMF. The aim of this review is to provide an extensive literature overview ranging from in vitro to even clinical studies within the field of ischemic stroke of all EMF types. A thorough comparison between EMF types and their effects is provided, as well as an overview of the signal pathways activated in cell types relevant for ischemic stroke such as neurons, microglia, astrocytes, and endothelial cells. We also discuss which steps have to be taken to improve their therapeutic efficacy in the frame of the clinical translation of this promising therapy.

Campo magnético de frecuencia extremadamente baja: Seguridad de su aplicación a nivel del sistema nervioso central / Magnetic field of extremely low frequency: Safety of its application at the level of the central nervous system

Introducción: La enfermedad cerebrovascular constituye un importante problema de salud a nivel mundial. En la actualidad se desarrollan investigaciones científicas dedicadas al estudio de los efectos del campo magnético de frecuencia extremadamente baja para su tratamiento. No es suficientemente clara la información acerca de su inocuidad en las dosis estudiadas. Objetivo: Estudiar la seguridad de la aplicación del campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central a través de un estudio toxicológico a dosis aguda, repetida y ensayo de micronúcleos en médula ósea. Métodos: Se conformaron tres grupos experimentales con ratas Sprague Dawley Cenp:SPRD jóvenes y sanas para los experimentos de toxicidad y ratones CENP: NMRI para la evaluación mutagénica. Se utilizaron controles negativos no tratados. En el ensayo de micronúcleos se incorporó un grupo control positivo al que se administró Ciclofosfamida por vía intraperitoneal. Se aplicó un campo magnético no homogéneo con niveles de inducción magnética de 6,5 y 15 mT, tomando como referencia el valor máximo sobre la superficie de la bobina. Para la aplicación del campo magnético la bobina estimuladora se colocó sobre la cabeza asegurando la exposición completa del encéfalo. Resultados: En ninguno de los ensayos se detectaron signos de toxicidad. Se comprobó así mismo que no se indujeron efectos genotóxicos ni citotóxicos sobre las células somáticas. Conclusiones: El tratamiento con campo magnético de frecuencia extremadamente baja a nivel del sistema nervioso central en las condiciones experimentales y dosis estudiadas es seguro(AU)

Introduction: Stroke is a major health problem all over the world. Nowadays are developed scientific researches devoted to the study of extremely low frequency magnetic field effects over this illness. The information about it safety is unclear yet. Objective: To study the safety of extremely low frequency magnetic field applied at central nervous system level wasby means ofa toxicological assay (Acute, repeated doses and micronucleus in bone marrow assay) Methods: Three experimental groups were made with Sprague Dawley Cenp: SPRD young and healthy rats for toxicity experiments and CENP: NMRI mice for mutagen evaluation. Untreated negative controls were used. In the micronucleus assay, an additional positive control group was included. This group received Cyclophosphamide by intraperitoneal administration. Was applied a non-homogenousmagnetic fieldof 6,5 and 15 mT, taken as reference the maximum value over the coil surface. The coil was positioned over the head, ensuring full exposure of brain to magnetic field. Results : In none of trials were detected any sign of toxicity. It was also found no genotoxic or cytotoxic effects induced on somatic cells. Conclusions : These results indicated the safety of treatmentwith extremely low frequency magnetic field at central nervous system level for experimental conditions and doses studied(AU)