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.

Highlights

  • Neuroinflammation is considered a major mediator of brain injury in multiple chronic neurological and neuropsychiatric disorders, and it presents an important therapeutic target for intervention [1]

  • We examined here the effects of brain stimulation by electroconvulsive seizures (ECS) on chronic active neuroinflammation using the EAE model in Biozzi mice, a model that is reminiscent of chronic multiple sclerosis (MS)

  • Our study provides the first demonstration to our knowledge that ECS inhibits neuroinflammation clinically and pathologically and that it protects from inflammation-driven neurodegeneration, reducing the extent of demyelination and axonal loss

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Summary

Introduction

Neuroinflammation is considered a major mediator of brain injury in multiple chronic neurological and neuropsychiatric disorders, and it presents an important therapeutic target for intervention [1]. The brain’s innate immune system, represented mainly by microglia, plays a leading role in chronic neuroinflammation– induced brain injury [2]. The confinement of the injurious neuroinflammatory disease process to the CNS — which is dominated by innate toxic microglia, occurring behind the blood-brain barrier (BBB) — creates a major challenge for developing targeted and effective therapies. This is exemplified in chronic-progressive multiple sclerosis (MS), in which the BBB is significantly less permeable [7], and immune pathogenesis is compartmentalized within the CNS [8,9,10]. The lack of therapies for chronic MS emphasizes the unmet need for developing treatments that target the CNS directly [13], modulating its toxic innate immune system

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