Expression of heat shock protein HSP-70 in the retrosplenial cortex of rat brain after administration of (R,S)-ketamine and (S)-ketamine, but not (R)-ketamine.
Zheng Tian, Chao Dong, Atsuhiro Fujita, Yuko Fujita, Kenji Hashimoto
Pharmacology, Biochemistry, and Behavior September 2018 DOI: 10.1016/j.pbb.2018.07.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rat brain, retrosplenial cortex |
| Interventions | (R S)-ketamine (S)-ketamine (R)-ketamine saline |
| Dose | (R,S)-ketamine 100 mg/kg; (S)-ketamine 25, 50, or 75 mg/kg; (R)-ketamine 25, 50, or 75 mg/kg; dizocilpine 1.0 mg/kg; saline 1 ml/kg |
| Duration | 24 h after a single administration |
| Measures | HSP-70 immunohistochemistry |
| Topics | Esketamine Ketamine |
| Keywords | Heat shock protein Neurotoxicity Retrosplenial cortex |
| Key points | A single dose of (R,S)-ketamine (100 mg/kg) or (S)-ketamine (50 and 75 mg/kg, but not 25 mg/kg) induced marked HSP-70 expression in the rat retrosplenial cortex, whereas all tested doses of (R)-ketamine (25, 50, 75 mg/kg) did not. The authors suggest this HSP-70 expression may reflect detrimental side effects and argue that (R)-ketamine is likely safer in humans than (R,S)-ketamine or (S)-ketamine. |
Abstract
The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine has robust antidepressant effects in depressed patients although it has detrimental side effects such as psychotomimetic and dissociative symptoms. (R,S)-Ketamine is known to cause the expression of heat shock protein HSP-70 (a marker for neuronal injury) in the retrosplenial cortex of rat brain, suggesting that the neuropathological changes may play a role in the detrimental side effects of (R,S)-ketamine. This study was undertaken to examine whether (R,S)-ketamine and its two enantiomers, (R)-ketamine and (S)-ketamine, causes the expression of HSP-70 in the rat retrosplenial cortex after a single administration. The HSP-70 immunohistochemistry in the rat brain was performed 24 h after intraperitoneal administration of saline (1 ml/kg), (+)-MK-801 (or dizocilpine: 1.0 mg/kg), (R,S)-ketamine (100 mg/kg), (S)-ketamine (25, 50, or 75, mg/kg), or (R)-ketamine (25, 50, or 75 mg/kg). Marked expression of HSP-70 immunoreactivity in the retrosplenial cortex was detected after administration of dizocilpine or (R,S)-ketamine (100 mg/kg). Higher does (50 and 75 mg/kg) of (S)-ketamine, but not low dose (25 mg/kg), caused expression of HSP-70 in this region. In contrast, all doses of (R)-ketamine did not induce the expression of HSP-70 in this region. These findings suggest that marked expression of HSP-70 in the retrosplenial cortex after a single dose of (R,S)-ketamine or (S)-ketamine may have detrimental side effects in the rat brain. Therefore, it is likely that (R)-ketamine is a safer compound in humans than (R,S)-ketamine and (S)-ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 29
- Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective Psychiatry and Clinical Neurosciences June 19, 2019
- Molecular mechanisms of the rapid-acting and long-lasting antidepressant actions of (R)-ketamine. Biochemical Pharmacology July 1, 2020
- Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine Molecular Psychiatry November 24, 2021
- Molecular and cellular mechanisms underlying the antidepressant effects of ketamine enantiomers and its metabolites Translational Psychiatry November 7, 2019
- Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-ketamine, (R)-ketamine, and (S)-ketamine. Pharmacology, Biochemistry, and Behavior June 1, 2019
and 24 more in the library
Cites 24
- Recent advances in the phencyclidine model of schizophrenia American Journal of Psychiatry October 1, 1991
- NMDA Antagonist Neurotoxicity: Mechanism and Prevention Science December 6, 1991
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study American Journal of Psychiatry April 16, 2018
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
and 19 more in the library