Ketamine induces hippocampal apoptosis through a mechanism associated with the caspase-1 dependent pyroptosis

Abstract

Ketamine, a pediatric anesthetic, is widely used in clinical practice. There was growing evidence showing that ketamine can promote neuronal death in developing brains of both humans and animals. In this study, we used in vivo neonatal and juvenile mouse models to induce ketamine-related neurotoxicity in the hippocampus. Active caspase-3 and -9 proteins, which are responsible for the release of cytochrome C, and the mitochondrial translocation of p53, which is associated with mitochondrial apoptosis, were found to be significantly up-regulated in the ketamine-induced hippocampal neurotoxicity. Furthermore, we demonstrated that the levels of pyroptosis-related proteins, including caspase-1 and -11, NOD-like receptor family, pyrin domain containing 3 (NLRP3), and IL-1β and IL-18, significantly increased after multiple doses of ketamine administration. We speculated that ketamine triggered the formation of NLRP3 and caspase-1 complex and its translocation to the mitochondria. In consistent with this, ketamine treatment was found to induce pyroptosis in mouse primary hippocampal neurons, which was characterized by increased pore formation and elevated lactate dehydrogenase release in mitochondria. Silencing caspase-1 with lentivirus-mediated short hairpin RNA (shRNA) significantly decreased the levels of not only pyroptosis-related proteins but also mitochondrial apoptosis-associated proteins in mouse primary hippocampal neurons. We conclude that caspase-1-dependent pyroptosis is an important event which may be an essential pathway involved in the mitochondria-associated apoptosis in ketamine-induced hippocampal neurotoxicity.

Gasdermin D serves as a key executioner of pyroptosis in experimental cerebral ischemia and reperfusion model both in vivo and in vitro

“…In this study, we focused on GSDMD‐induced pyroptosis in microglia and its potential mechanisms. Based on several reports, we hypothesize that pyroptosis in neurons can be induced after I/R injury, which will be confirmed both in vivo and in vitro in our next paper (Tan et al, ; Ye et al, ). Finally, in order to minimize the variables involved, we used only adult male rats for all the MCAO/R experiment.…”

Sevoflurane Induces Learning and Memory Impairment in Young Mice Through a Reduction in Neuronal Glucose Transporter 3

“…The effects of general anaesthetic on foetal and neonatal N-methyl-d-aspartic acid (NMDA) glutamate receptors or gamma-amino-butyric-acid type A (GABA A ) receptors activate the caspase pathway, leading to an apoptotic cascade (Satomoto et al 2009;Kodama et al 2011;Creeley et al 2014;Ye et al 2018). In addition to inducing neuroapoptosis b, c, d, e Histograms showing the results of Bax, Bcl-2, cleaved caspase-3, and cleaved PARP blots in the hippocampus and temporal lobe.…”

ALDH 2 conferred neuroprotection on cerebral ischemic injury by alleviating mitochondria-related apoptosis through JNK/caspase-3 signing pathway

“…Cell counting kit-8 (CCK-8) (from Dojindo, Japan), LDH cytotoxicity detection kit (provided by Roche, Basel, Switzerland) and Caspase-3 activity analysis (from Beyotime, China) were used as previously described [37].…”

“…Acridine orange (AO)/ propidium iodide (PI) staining was reported before [37]. PC12 cells were cultured into 24-well plates before being stained with PBS, 25 mg/ml ethidum bromide and 5 mg/ml acridine orange.…”