17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

Li, Jianli; Wang, Bei; Wu, Honghai; Yu, Yang; Gao, Xue; Yan-ning, Hou

doi:10.1016/j.brainres.2014.09.013

Cited by 17 publications

(27 citation statements)

References 54 publications

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“…Previous studies in our lab demonstrated that neuronal apoptosis in several major area of developing brain can be induced by multiple ketamine injections (20 mg/kg given every 2 hours for 6 times) to PND 7 rats, especially in the frontal cortex [11,34]. Ketamine-induced neuronal apoptosis has also been shown to occur in newborn rhesus monkeys [38], in fetal NHP brains [34], and primary cultured rat neurons [6,39]. Early exposure to ketamine leads to persistent cognitive defi cits, including impaired learning and memory in rodent and nonhuman primate models [12,40].…”

Section: Discussionmentioning

confidence: 88%

MicroPET/CT Assessment of Minocycline Effects on Anesthetic-Induced Neuronal Injury in Developing Rats

Zhang¹

2017

Glob J Anesth

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Ketamine is a dissociative anesthetic that is frequently used for the induction and maintenance of general anesthesia in children. It has been reported that blockade of NMDA receptors by ketamine may cause neurotoxicity in neonatal rats when given over a 12 hour period during the brain growth spurt. Noninvasive, quantitative imaging of rodent brains may allow for the detection of functional, morphological and metabolic alterations induced by ketamine. Since it is known that level of the mitochondrial translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor (PBR) increase in areas of neuronal injury following exposure to neurotoxicants, TSPOs are widely recognized as important targets for imaging using positron emission tomography (PET). In this study, the effect of ketamine on the uptake and retention of [18F]-FEPPA (a TSPO ligand) in the brains of rats and the potential protective effect of minocycline, an anti-infl ammatory agent, on anesthetic-induced neuronal cell death were investigated using microPET/CT imaging. On postnatal day 7 (PND 7), rat pups in the experimental group were exposed to 6 injections of ketamine (20 mg/kg at 2 h intervals) with or without minocycline (45mg/ kg i.p. 30 minutes prior to, and 4 hours after exposure); control pups received 6 injections of saline. On PNDs 14, 21, 28 and 35, [18F]-FEPPA (18.5 MBq) was injected into the tail vein of treated and control rats and microPET/CT images were obtained over the next 90 minutes. Radiolabeled tracer accumulation in regions of interest (ROIs) in the frontal cortex was converted into Standard Uptake Values (SUVs). In PND 14 and 21 rats the uptake of [18F]-FEPPA was signifi cantly increased and the duration of tracer wash-out was prolonged in ketamine-treated rats. The increased uptake of the tracer was attenuated by the co-administration of minocycline. As expected, no signifi cant difference in radiotracer uptake in the frontal cortex was observed at 28 or 35 days after anesthesia. This preliminary study demonstrates that microPET imaging is capable of distinguishing differences in retention of [18F]-FEPPA in the brains of rodents and suggests that this approach may provide a minimally-invasive biomarker of pathogenic process associated with neurotoxicity induced by ketamine. Minocycline effectively blocks the neuronal injury caused by ketamine anesthesia in the developing rat brain.

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Section: Discussionmentioning

confidence: 88%

MicroPET/CT Assessment of Minocycline Effects on Anesthetic-Induced Neuronal Injury in Developing Rats

Zhang¹

2017

Glob J Anesth

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“…Ketamine, a widely used anesthetic, has potential neurodegenerative and long-term cognitive deficits, affecting brain development (7,(36)(37)(38)(39). Methods of safe ketamine application is an important research goal in clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Zhou

Zhang

et al. 2020

Mol Med Report

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Ketamine is a widely used general anesthetic and has been reported to demonstrate neurotoxicity and neuroprotection. investigation into the regulatory mechanism of ketamine on influencing neural development is of importance for a better and safer way of relieving pain. reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect the critical neural associated gene expression, and flow cytometry to detect the neural differentiation effect. Hence, in the present study the underlying mechanism of ketamine (50 nM) on neural differentiation of the mouse embryonic stem cell (meSc) line 46c was investigated. The results demonstrated that a low dose of ketamine (50 nM) promoted the differentiation of meScs to neural stem cells (nScs) and activated mammalian target of rapamycin (mTor) by upregulating the expression levels of phosphorylated (p)-mTor. Furthermore, inhibition of the mTor signaling pathway by rapamycin or knockdown of mTor suppressed neural differentiation. a rescue experiment further confirmed that downregulation of mTOR inhibited the promotion of neural differentiation induced by ketamine. Taken together, the present study indicated that a low level of ketamine upregulated p-mTor expression levels, promoting neural differentiation.

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“…Ketamine, which is a non-competitive antagonist of the NMDA receptor, is a commonly used intravenous anesthetic drug, and has been in use for nearly half a century and is widely used in pediatric surgery (13). However, its use is controversial due to the reported ketamine-induced reduction in juvenile learning and memory function (14). In addition, ketamine has been reported to induce schizophrenia-like behaviors and oxidative damage in mice (15).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice

Zhang

Sha²,

Wang

et al. 2018

Mol Med Report

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Tetrahydropalmatine exerts numerous pharmacological activities, including analgesic and narcotic effects; anti-arrhythmic, blood pressure lowering and cardioprotective effects; protective effects against cerebral ischemia-reperfusion injury; inhibition of platelet aggregation; prevention of ulcerative diseases and inhibition of gastric acid secretion; antitumor effects; and beneficial effects on the withdrawal symptoms associated with drug addiction. The present study aimed to investigate the protective effects of tetrahydropalmatine against ketamine-induced learning and memory impairment in mice. The Morris water maze test and open field test were used to analyzed learning and memory impairment in mice. ELISA kits and western blotting were used to analyze oxidative stress, inflammation factors, caspease-3 and caspase-9, iNOS, glial fibrillary acidic protein (GFAP), glial cell-derived neurotrophic factor (GDNF), cytochrome c and phospholipase C (PLC)-γ1 protein expression. The results demonstrated that tetrahydropalmatine treatment significantly decreased escape latency in the learning phase and increased the number of platform site crossings in ketamine-induced mice. In addition, tetrahydropalmatine significantly inhibited oxidative stress, inflammation and acetylcholinesterase activity, and decreased acetylcholine levels in ketamine-induced mice. Tetrahydropalmatine also suppressed iNOS protein expression, weakened caspase-3 and caspase-9 activation, inhibited nuclear factor-κB, glial fibrillary acidic protein, cytochrome c and phospholipase C-γ1 protein expression, and induced glial cell-derived neurotrophic factor protein expression in ketamine-induced mice. Taken together, these results indicated that tetrahydropalmatine may protect against ketamine-induced learning and memory impairment in mice via antioxidative, anti-inflammatory and anti-apoptotic mechanisms. The present study provided an experimental basis for the clinical application of tetrahydropalmatine to reduce the severe side effects associated with ketamine therapy in future studies.

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17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

Cited by 17 publications

References 54 publications

MicroPET/CT Assessment of Minocycline Effects on Anesthetic-Induced Neuronal Injury in Developing Rats

MicroPET/CT Assessment of Minocycline Effects on Anesthetic-Induced Neuronal Injury in Developing Rats

Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR

Protective effects of tetrahydropalmatine against ketamine-induced learning and memory injury via antioxidative, anti-inflammatory and anti-apoptotic mechanisms in mice

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