Lithium attenuates ketamine-induced long-term neurotoxicity through DISC1-mediated GSK-3β/β-catenin and ERK/CREB pathways.
Ting-Ting Yang, Zi-Wen Guo, Fang Zhang, Yu Peng, Wei Yu, Guang-Qiang Gao, Hong Tian, Shu-Jun Zhang, Jia-Ren Liu
Toxicology Letters April 1, 2025 DOI: 10.1016/j.toxlet.2025.02.012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Neonatal rats |
| Interventions | Ketamine Lithium |
| Dose | 20 mg/kg b.w. ketamine; 120 mg/kg×5 b.w. lithium |
| Duration | 6-hour intervention period; cognitive function evaluated in adolescent rats |
| Topics | Ketamine Esketamine |
| Keywords | Disc1 Erk/creb pathway Gsk-3β/β-catenin pathway Neurotoxicity Pediatric anesthesia Ketamine safety Neuroprotection Brain development Molecular signaling |
| Citations | 2 |
| Key findings | Lithium mitigates ketamine-induced long-term neurotoxicity by elevating DISC1 level and activating the GSK-3β/β-catenin and ERK/CREB signaling pathways. |
Abstract
Ketamine, an antagonist of N-methyl-D-aspartate receptor, is extensively employed in pediatric anesthesia. Multiple studies have shown that repeated ketamine exposure induces neuroapoptosis, synaptic changes and cognitive deficits during neurodevelopment. Therefore, it is essential to elucidate the mechanisms of ketamine-induced neurotoxicity and develop therapies to mitigate its harmful effects. Here, we investigated the role of disrupted in Schizophrenia 1 (DISC1) in ketamine-induced long-term neurotoxicity through a ketamine-exposed neuroapoptosis model. Neonatal rats received 2-5 intraperitoneal injections of ketamine (20 mg/kg b.w.) at 90 min intervals. Another cohort of pups received five intraperitoneal injections of ketamine (20 mg/kg×5 b.w.) with or without lithium (120 mg/kg×5 b.w.) at 90 min intervals over 6 h. Neuroapoptosis, DISC1-associated proteins expression in rats treated with ketamine, lithium, or a combination of both were detected, and the cognitive function of adolescent rats was evaluated by Morris water maze test. The length of dendrites and axons of primary neurons treated with lithium and ketamine were further measured. Results showed that ketamine time-dependently downregulated the levels of DISC1, pGSK-3β, β-catenin, pERK, pCREB and PSD95 in neonatal rats. Lithium could ameliorate neuroapoptosis, cognitive deficits and neurite growth inhibition triggered by ketamine. Mechanistically, lithium upregulated the levels of DISC1, PSD95 and GSK-3β/β-catenin and ERK/CREB signaling-related proteins. Consequently, lithium mitigated ketamine-induced long-term neurotoxicity by elevating DISC1 level and activating the GSK-3β/β-catenin and ERK/CREB signaling pathways.
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
Cites 5
- Ketamine modulates disrupted in schizophrenia-1/glycogen synthase kinase-3β interaction. Frontiers in Molecular Neuroscience 2024
- Chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway Zoological Research November 18, 2022
- S-ketamine Administration in Pregnant Mice Induces ADHD- and Depression-like behaviors in Offspring Mice. Behavioural Brain Research July 1, 2022
- Chronic lithium exposure attenuates ketamine-induced mania-like behavior and c-Fos expression in the forebrain of mice. Pharmacology, Biochemistry, and Behavior January 12, 2021
- Vinpocetine halts ketamine-induced schizophrenia-like deficits in rats: impact on BDNF and GSK-3β/β-catenin pathway. Naunyn-Schmiedeberg's Archives of Pharmacology August 6, 2018