Ketamine administration causes cognitive impairment by destroying the circulation function of the glymphatic system.
Xue Wu, Gehua Wen, Lei Yan, Yexin Wang, Xinghua Ren, Guiji Li, Yu Luo, Junbo Shang, Lei Lu, Anca Hermenean, Jun Yao, Baoman Li, Yan Lü, Xu Wu
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie June 1, 2024 DOI: 10.1016/j.biopha.2024.116739 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with mouse model and cell culture Peer reviewed |
|---|---|
| Population | Mice and primary astrocytes |
| Intervention | Ketamine |
| Duration | Short-term ketamine administration |
| Topics | Ketamine Esketamine |
| Keywords | 5-ht2c Aqp4 Cognitive impairment Glymphatic system Δfosb Psychopharmacology Brain-function Drug-effects Neurochemistry |
| Citations | 11 |
| Key findings | Ketamine induces cognitive impairment by increasing 5-HT2c receptor expression in hippocampal astrocytes, leading to ΔFosb accumulation that suppresses Aqp4 expression and disrupts glymphatic system function. |
Abstract
Ketamine, as a non-competitive antagonist of N-methyl-D-aspartate (NMDA) receptors, was originally used in general anesthesia. Epidemiological data show that ketamine has become one of the most commonly abused drugs in China. Ketamine administration might cause cognitive impairment; however, its molecular mechanism remains unclear. The glymphatic system is a lymphoid system that plays a key role in metabolic waste removal and cognitive regulation in the central nervous system. Focusing on the glymphatic system, this study evaluated the behavioral performance and circulatory function of the glymphatic system by building a short-term ketamine administration model in mice, and detected the expression levels of the 5-HT2c receptor, ΔFosb, Pten, Akt, and Aqp4 in the hippocampus. Primary astrocytes were cultured to verify the regulatory relationships among related indexes using a 5-HT2c receptor antagonist, a 5-HT2c receptor short interfering RNA (siRNA), and a ΔFosb siRNA. Ketamine administration induced ΔFosb accumulation by increasing 5-HT2c receptor expression in mouse hippocampal astrocytes and primary astrocytes. ΔFosb acted as a transcription factor to recognize the AATGATTAAT bases in the 5' regulatory region of the Aqp4 gene (-1096 bp to -1087 bp), which inhibited Aqp4 expression, thus causing the circulatory dysfunction of the glymphatic system, leading to cognitive impairment. Although this regulatory mechanism does not involve the Pten/Akt pathway, this study revealed a new mechanism of ketamine-induced cognitive impairment in non-neuronal systems, and provided a theoretical basis for the safety of clinical treatment and the effectiveness of withdrawal.
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 4
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Long-lasting effects of repeated ketamine administration in adult and adolescent rats. Behavioural Brain Research September 2, 2019
- Ketamine treatment involves medial prefrontal cortex serotonin to induce a rapid antidepressant-like activity in BALB/cJ mice. Neuropharmacology January 2017
- Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3 The World Journal of Biological Psychiatry October 10, 2016