The Antioxidant Activity of Ketamine: Threshold-Dependent Mechanism in Treatment-Resistant Depression?

Ketamine at 25 ng/mL increased the viability of mouse hippocampal HT22 neuronal cells exposed to hydrogen peroxide, but only at the highest concentration tested (1000 µM H₂O₂). At that level, cell viability rose from 12% (±1.63%) without ketamine to 38% (±9.12%) with ketamine. This suggests a protective, nonlinear effect that depends on the intensity of oxidative stress, activating only at critical H₂O₂ overload typical of severe depression. The findings indicate a threshold antioxidant mechanism that may contribute to ketamine's antidepressant action and inform future predictive models for individualized treatment.

Study at a glance

Abstract

Abstract Aim of study: The antidepressant effect of ketamine may be at least partly due to its antioxidant activity. The aim of the study was to assess whether ketamine develops a protective effect on HT22 neuronal cells under conditions of oxidative stress (OS) induced by hydrogen peroxide (H 2 O 2 ). Material and methods The experiment was performed on an immortalized mouse hippocampal HT22 cell line. Cell viability after treatment with 25 ng/ml ketamine and 10 µM – 1000 µM H 2 O 2 for 24h was assessed by MTT assay. Results Ketamine at a concentration of 25 ng/mL increased the viability of HT22 neuronal cells under conditions of OS mimicked by H 2 O 2 , but only for a concentration of 1000 µM H 2 O 2 , which reflects the high level of OS typical of treatment-resistant depression (TRD). At 1000 µM H 2 O 2 , cell viability was 12% (± 1.63%), while after incubation with 1000 µM H 2 O 2 + 25 ng/ml ketamine, cell viability was 38% (± 9.12%). The results suggest that ketamine has a protective effect on HT22 cells, but that this effect is nonlinear and dependent on OS intensity, activated only at critical H 2 O 2 overload. Conclusions Preliminary results suggest that ketamine reverses the cytotoxicity of H 2 O 2 on HT22 cells, but only at specific, high concentrations of H 2 O 2 typical of severe subtypes of depression. This indicates a threshold, antioxidant mechanism of ketamine's antidepressant action, which could be used in further research on predictive models of response to ketamine treatment, which in the future could translate into individualized treatment and increased therapeutic success.