Ketamine: Neuroprotective or Neurotoxic?

Summary

Ketamine, a drug used as an anesthetic since the 1970s, has recently gained attention for its rapid antidepressant effects. In preclinical studies, it shows both neurotoxic and neuroprotective properties depending on context. At anesthetic doses during neurodevelopmental windows, it contributes to inflammation, autophagy, apoptosis, and increased reactive oxygen species. At subanesthetic doses, it activates neurotrophic signaling cascades with neuroprotective actions that are not always dependent on its primary receptor. This review summarizes the complex intracellular signaling pathways modulated by ketamine and contrasts its protective and harmful features.

Study at a glance

Abstract

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.