Superoxide dismutase reduces monosodium glutamate-induced injury in an organotypic whole hemisphere brain slice model of excitotoxicity

Rick Liao,Thomas R Wood,Elizabeth Nance

doi:10.1186/s13036-020-0226-8

Rick Liao, Thomas R Wood + Show 1 more

Open Access

https://doi.org/10.1186/s13036-020-0226-8

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Abstract

BackgroundKnowledge of glutamate excitotoxicity has increased substantially over the past few decades, with multiple proposed pathways involved in inflicting damage. We sought to develop a monosodium glutamate (MSG) exposed ex vivo organotypic whole hemisphere (OWH) brain slice model of excitotoxicity to study excitotoxic processes and screen the efficacy of superoxide dismutase (SOD).ResultsThe OWH model is a reproducible platform with high cell viability and retained cellular morphology. OWH slices exposed to MSG induced significant cytotoxicity and downregulation of neuronal excitation-related gene expression. The OWH brain slice model has enabled us to isolate and study components of excitotoxicity, distinguishing the effects of glutamate excitation, hyperosmolar stress, and inflammation. We find that extracellularly administered SOD is significantly protective in inhibiting cell death and restoring healthy mitochondrial morphology. SOD efficacy suggests that superoxide scavenging is a promising therapeutic strategy in excitotoxic injury.ConclusionsUsing OWH brain slice models, we can obtain a better understanding of the pathological mechanisms of excitotoxic injury, and more rapidly screen potential therapeutics.

Highlights

Glutamate excitotoxicity is a common hallmark in many neurological diseases, including stroke, traumatic brain injury (TBI), and depression [1,2,3]
Excessive glutamate release over-activates neuronal postsynaptic glutamatergic N-methyl-D-aspartic acid (NMDA) receptors, causing sodium and calcium to flood into the neuron, generation of reactive oxygen species (ROS), and mitochondrial damage, initiating neuronal death processes [4,5,6]
Establishment of the monosodium glutamate (MSG)-induced excitotoxicity slice model While OHC and cortical slices are widely used in the field, organotypic whole hemisphere (OWH) slices have not previously been used for studying neurological disease [18]

Summary

Introduction

Glutamate excitotoxicity is a common hallmark in many neurological diseases, including stroke, traumatic brain injury (TBI), and depression [1,2,3]. Excitotoxicity can mediate cell death through both acute necrosis due to cell swelling upon uptake of sodium and chloride, and Enzymes in their native form are actively studied for their role in managing neurological damage, involving oxidative stress [9,10,11,12]. SOD, which converts O2− into H2O2 and oxygen, has been widely studied and shows therapeutic potential in multiple disease models that exhibit. We sought to develop a monosodium glutamate (MSG) exposed ex vivo organotypic whole hemisphere (OWH) brain slice model of excitotoxicity to study excitotoxic processes and screen the efficacy of superoxide dismutase (SOD)

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