Abstract
BackgroundMultiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. Pyroptosis is an inflammatory form of programmed cell death that has been linked to various neurological diseases. However, the role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain.MethodsTo evaluate whether ketamine caused NLRP3/caspase1-dependent pyroptosis, flow cytometry analysis, western blotting, ELISA test, histopathological analysis, Morris water maze (MWM) test, cell viability assay, and lactate dehydrogenase release (LDH) assay were carried out on PC12 cells, HAPI cells, and 7-day-old rats. In addition, the NLRP3 inhibitor MCC950 or the caspase-1 inhibitor VX-765 was used to investigate the role of the NLRP3/caspase-1 axis in ketamine-induced neurotoxicity and cognitive dysfunction.ResultsOur findings demonstrated that ketamine exposure caused cell damage and increased the levels of pyroptosis in PC12 cells, HAPI cells, and the hippocampus of neonatal rats. After continuous exposure to ketamine, targeting NLRP3 and caspase-1 with MCC950 or VX765 improved pyroptosis, reduced neuropathological damages, and alleviated cognitive dysfunction.ConclusionNLRP3/Caspase-1 axis-dependent pyroptosis is involved in ketamine-induced neuroinflammation and cognitive dysfunction, and it provides a promising strategy to treat ketamine-related neurotoxicity.
Highlights
IntroductionZhang et al J Neuroinflammation (2021) 18:239 developing brain
The developing brain is highly vulnerable to the adverse effects of clinically used general anesthetics (GAs), which include neuronal apoptosis [1,2,3], decreased synapse formation [4, 5], impaired neurogenesis [6, 7], andZhang et al J Neuroinflammation (2021) 18:239 developing brain
The results showed that pre-administration of MCC950 and VX765 decreased the loss and disorder of nerve cells caused by continuous ketamine exposure in the hippocampus (CA1, CA3, and Dentate Gyrus (DG) regions) of neonatal rats (Fig. 1A and B)
Summary
Zhang et al J Neuroinflammation (2021) 18:239 developing brain This causes apoptosis and neurotoxicity, which can lead to long-term learning and memory impairment [15, 16]. The inflammatory caspase promotes the cleavage of the gasdermin family proteins, which induces pore formation in the plasma membrane, resulting in pyroptosis-induced lytic cell death and the release of cytokines [20, 21]. Several studies have shown that continuous exposure to anesthetics activates the NLRP3 inflammasome and caspase-1 [26,27,28,29,30], whether NLRP3/caspase-1 axis is involved in ketamine-induced cognitive and behavioral dysfunction remains largely unknown. Multiple studies have revealed that repeated or long-term exposure to ketamine causes neurodegeneration and cognitive dysfunction. The role of NLRP3/caspase-1 axis-related pyroptosis in ketamine-induced neurotoxicity and cognitive dysfunction remains uncertain
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