Electroconvulsive stimulation attenuates chronic neuroinflammation
Smadar Goldfarb, Nina Fainstein, Tamir Ben-Hur
Smadar Goldfarb, Nina Fainstein, Tamir Ben-Hur
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Research Article Inflammation Neuroscience

Electroconvulsive stimulation attenuates chronic neuroinflammation

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 6

ECS decreases microglial toxicity.

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ECS decreases microglial toxicity. (A–G) Immunofluorescence staining for...
(A–G) Immunofluorescence staining for IBA1 and iNOS in SC sections of sham-treated (control) (A) and ECS-treated (B) Biozzi ABH EAE mice at day 95 p.i. ECS significantly reduced the number of IBA1+iNOS+ cells in SC WM by 40%. Box-and-whisker plot shows quartiles with median, and with minima and maxima at the bottom and top whiskers, respectively (C). (D–G) Single-color panels of IBA1 and iNOS are shown for A (D and E, respectively) and for B (F and G, respectively). (H–O) CD11b+ cells were isolated at day 38 p.i., 24 hours after the last of 3 ECS treatments (performed on days 35–37 p.i.) and evaluated by RT-PCR, FACS analysis, and ELISAs. Experiments were repeated 3 or 4 independent times. (H–K) mRNA levels of iNos (H), Il2 (I), Cxcl9 (J) and Il1b (K) were reduced in CD11b+ cells isolated from ECS-treated as compared with sham-treated (control) Biozzi EAE mice. In all graphs, the horizontal lines (and gray zone) represent the RQ mean value (±RQ min/max) of naive, age-matched Biozzi mice. (L) FACS analysis of IBA1 expression showed marked reduction in IBA1 expression (and specifically in IBA1hi cells) in CD11b+ cells, isolated from ECS-treated spinal cords, as compared with sham-treated (control) mice (representative image). (M–O) Levels of NO (M) and ROS (N) production were decreased in isolated CD11b+ cells from ECS-treated as compared with control EAE mice, measured by ELISA reader in response to Griess Reagent or DCFDA, respectively. FACS analysis (O) of intracellular ROS (response to DCFDA) in the isolated CD11b+ cells from EAE mice showed 2 cell populations: low and high ROS–producing cells (representative image). ECS reduced the percentage of high ROS–producing CD11b+ cells. P value calculated with Student’s unpaired t test. Error bars: RQ min/max in H–K and SEM in M–O.