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Electroconvulsive stimulation attenuates chronic neuroinflammation
Smadar Goldfarb, … , Nina Fainstein, Tamir Ben-Hur
Smadar Goldfarb, … , Nina Fainstein, Tamir Ben-Hur
Published August 11, 2020
Citation Information: JCI Insight. 2020;5(17):e137028. https://doi.org/10.1172/jci.insight.137028.
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Research Article Inflammation Neuroscience

Electroconvulsive stimulation attenuates chronic neuroinflammation

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Abstract

Electroconvulsive therapy is highly effective in resistant depression by unknown mechanisms. Microglial toxicity was suggested to mediate depression and plays key roles in neuroinflammatory and degenerative diseases, where there is critical shortage in therapies. We examined the effects of electroconvulsive seizures (ECS) on chronic neuroinflammation and microglial neurotoxicity. Electric brain stimulation inducing full tonic-clonic seizures during chronic relapsing–progressive experimental autoimmune encephalomyelitis (EAE) reduced spinal immune cell infiltration, reduced myelin and axonal loss, and prevented clinical deterioration. Using the transfer EAE model, we examined the effect of ECS on systemic immune response in donor mice versus ECS effect on CNS innate immune activity in recipient mice. ECS did not affect encephalitogenicity of systemic T cells, but it targeted the CNS directly to inhibit T cell–induced neuroinflammation. In vivo and ex vivo assays indicated that ECS suppressed microglial neurotoxicity by reducing inducible NOS expression, nitric oxide, and reactive oxygen species (ROS) production, and by reducing CNS oxidative stress. Microglia from ECS-treated EAE mice expressed less T cell stimulatory and chemoattractant factors. Our findings indicate that electroconvulsive therapy targets the CNS innate immune system to reduce neuroinflammation by attenuating microglial neurotoxicity. These findings signify a potentially novel therapeutic approach for chronic neuroinflammatory, neuropsychiatric, and neurodegenerative diseases.

Authors

Smadar Goldfarb, Nina Fainstein, Tamir Ben-Hur

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Figure 1

ECS attenuates chronic EAE.

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ECS attenuates chronic EAE.
(A and B) ECS attenuates the first EAE relap...
(A and B) ECS attenuates the first EAE relapse. Five ECS (n = 7 mice) or sham (control, n = 6 mice) treatments were performed on alternating days, starting on the first day of clinical deterioration, individually per each mouse. Average daily clinical scores show mild improvement in the clinical severity of the first relapse of EAE in ECS-treated mice. Data represent mean ± SD (A). The cumulative score of the first relapse (lasting in average 15 days) was significantly lower in ECS-treated EAE mice (B). Experiment was repeated twice. P values calculated with Student’s unpaired t test. (C–E) ECS attenuates chronic EAE. Biozzi EAE mice were treated with ECS (2.4 mC, n = 16 mice), a subthreshold current (0.4 mC, n = 8 mice), or sham treatment (control, n = 17 mice) starting before the second relapse. Treatments were given on 3 consecutive days (35–37 p.i.), followed by weekly maintenance treatments until day 95 p.i. Average daily clinical scores show that ECS (but not subthreshold stimulation) improved the clinical course of chronic EAE (C). Data represent mean ± SEM. The experiment was repeated 4 times. ECS significantly reduced the relapse rate as compared with both sham and subthreshold treatment groups. Relapse was determined by an increase of > 1 point in clinical score at any time point between day 35 and 95 p.i. (D). P values were calculated by 3-way χ2 test. ECS significantly reduced the cumulative clinical score of days 35–95 p.i. Dots represent the mean cumulative score of the 4 individual experiments (E). P value was calculated by using 1-way ANOVA followed by Tukey’s post hoc test. f(2,8) = 6.3, P = 0.023. Box-and-whisker plots show quartiles with median, and with minima and maxima at the bottom and top whiskers, respectively.

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