Ketamine: Neuroprotective or Neurotoxic?

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.

Population Pharmacokinetics and Pharmacodynamics of the Therapeutic and Adverse Effects of Ketamine in Patients With Treatment‐Refractory Depression

“…Although the exact ketamine (and possibly metabolites) mechanism of action in depression is not clear, it appears to increase brain-derived neurotrophic factor (BDNF) expression via several mechanisms, causing changes in pre-and postsynaptic scaffolding proteins and glutamate receptors, mainly αamino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA). [32][33][34][35][36] This is associated with decreased neurogenesis and synaptic plasticity, resulting in changes in synaptic strength and communication. We believe that the turnover model, although coarse, is biologically plausible given these complex dynamic counter-balancing processes.…”

“…This was best captured by a turnover model as opposed to a distributional delay with a hypothetical effect site (e.g., the central nervous system (CNS)). Although the exact ketamine (and possibly metabolites) mechanism of action in depression is not clear, it appears to increase brain‐derived neurotrophic factor (BDNF) expression via several mechanisms, causing changes in pre‐ and postsynaptic scaffolding proteins and glutamate receptors, mainly α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) 32–36 . This is associated with decreased neurogenesis and synaptic plasticity, resulting in changes in synaptic strength and communication.…”

Combined hyperforin and lanicemine treatment instead of ketamine or imipramine restores behavioral deficits induced by chronic restraint stress and dietary zinc restriction in mice

“…For instance, ketamine is a substrate of P-glycoprotein and breast cancer resistance proteins that are responsible for drug efflux from the brain and regulation of drug concentrations in the serum and other tissues ( Ganguly et al, 2018 ). Moreover, some studies have shown that R- ketamine could alter the blood-brain barrier integrity under some conditions ( Choudhury et al, 2021 ). Therefore, tissue and brain concentrations of ketamine could be functions of at least two factors, such as expression of the drug efflux proteins and integrity of the blood-brain barrier, which can be perturbed by alterations in the Zn levels.…”

Ketamine: Is It Pro-Epileptic or Anti-Epileptic? The Debate Continues. A Narrative Review with a Case Discussion

“…8 The exact mechanisms for contradictory pro-and anti-epileptic effects are not yet known but postulated to be related to the complexity of the neuropharmacology of ketamine or molecular differences of the brain such as the number, strength, and composition of NMDA receptor containing synapses. 9,10 A study reported in 1974 on ketamine's effect on both healthy volunteers and patients with epilepsy has revealed that ketamine does not produce EEG changes suggestive of seizures or epileptic activity in both groups. 11 However new evidence is emerging on ketamine's pro epileptic and antiepileptic properties.…”