Ketamine induces rapid antidepressant effects via the autophagy-NLRP3 inflammasome pathway
- 4 August 2022
- journal article
- research article
- Published by Springer Science and Business Media LLC in Psychopharmacology
- Vol. 239 (10), 3201-3212
- https://doi.org/10.1007/s00213-022-06201-w
Abstract
Background Sub-anesthetic ketamine has rapid-onset effects for the treatment of major depressive disorder (MDD). However, the mechanism underlying ketamine’s antidepressant properties remains unclear. Recent studies have reported an interrelationship between autophagy and the inflammasome, both of which are involved in the pathophysiology of MDD. In this study, we assess whether ketamine exerts its antidepressant effects via an association with the autophagy-NLRP3 inflammasome pathway. Methods We established a depressive-like rat model by treating Wistar Kyoto rats with chronic restraint stress (CRS) for 28 days. Microglial cells from newborn Sprague–Dawley rats were used for in vitro experiments. Results We found sub-anesthetic ketamine treatment reversed depressive-like behavior in CRS rats. Ketamine triggered autophagy in the microglia of prefrontal cortex (PFC) and (hippocampus) HPC, with increased levels of LC3B, decreased levels of p62 protein, and elevated autophagosomes both in vivo and in vitro. Moreover, NLRP3 inflammasome activation was also inhibited by ketamine, with reduced expression of NLRP3-ASC-CASP1 assembly and decreased IL-1β levels in cerebrospinal fluid (CSF) as well as in the serum. Increased BDNF levels and synaptophysin levels were detected in the ketamine-treated group. The rapid anti-depressive effects, elevation of autophagy, reduction in NLRP3, and neuroplasticity-related factors induced by ketamine could be significantly blocked by the autophagy inhibitor Baf A1 (0.1 mg/kg). Conclusions Our findings demonstrate that sub-anesthetic doses of ketamine exert their antidepressant-like effects by inhibiting inflammation and initiating neuroprotection via autophagy activation. These data might help expand future investigations on the antidepressant properties of ketamine.Funding Information
- National Natural Science Foundation of China (81701344)
- Natural Science Foundation of Shanghai (21ZR1455100, 20ZR1448400)
- Ministry of Science and Technology of the People's Republic of China (2016YFC0906300)
- Shanghai Municipal Health Bureau (201740115)
This publication has 38 references indexed in Scilit:
- Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemiaHaematologica, 2014
- A Review of the Clinical, Economic, and Societal Burden of Treatment-Resistant Depression: 1996–2013Psychiatric Services, 2014
- Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive ratsBrain, Behavior, and Immunity, 2014
- NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorderBrain, Behavior, and Immunity, 2014
- NLRP3 Inflammasome: A New Target in Major Depressive DisorderCNS Neuroscience & Therapeutics, 2014
- Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effectsNeuroscience & Biobehavioral Reviews, 2014
- Interleukin-1β is associated with depressive episode in major depression but not in bipolar disorderJournal of Psychiatric Research, 2013
- Ketamine Enhances Human Neural Stem Cell Proliferation and Induces Neuronal Apoptosis via Reactive Oxygen Species–Mediated Mitochondrial PathwayAnesthesia & Analgesia, 2013
- A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in RatsAnesthesiology, 2011
- Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol HomeostasisNeuropsychopharmacology, 2011