N-stearoyl-l-tyrosine ameliorates sevoflurane induced neuroapoptosis via MEK/ERK1/2 MAPK signaling pathway in the developing brain

Wang, Wenyuan; Yang, Rui; Hu, Shuangfei; Wang, Hua; Ma, Zhiwei; Yang, Lu

doi:10.1016/j.neulet.2013.02.041

Cited by 43 publications

(42 citation statements)

References 30 publications

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“…Neuronal cultures (DIV 7) or rat pups (PND 7) were placed in a tightly sealed chamber at 37°C and treated with sevoflurane as described previously [16,17]. For in vitro study, 3 % sevoflurane was delivered by a humidified gas mixture of 95 % O 2 and 5 % CO 2 from a calibrated vaporizer.…”

Section: Sevoflurane Exposurementioning

confidence: 99%

“…Activity was measured as the total distance traveled in 10 min. The learning and memory functions of young rats were evaluated by Morris water maze (MWM) as previously described [15][16][17]. We employed place trials to evaluate the rat's ability to learn the spatial relationship between distant cues and the escape platform (submerged 1.5 cm, not visible).…”

Section: Behavior Studymentioning

confidence: 99%

“…The previous study had shown that systemic administration of the NMDA receptor antagonist to 7-day-old rats led to impaired activity of ERK1/2 and severe apoptotic neurodegeneration [14]. Recently, we have shown the essential role of ERK1/2 MAPK signaling in developmental anesthetic neurotoxicity [15][16][17]. This study was designed to investigate the distinguished roles of synaptic and extra-synaptic NMDA receptor activity in sevoflurane neurotoxicity, and the involvement of ERK1/2 MAPK pathway.…”

Section: Introductionmentioning

confidence: 99%

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Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

et al. 2014

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It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors contributed to the relief of sevoflurane neurotoxicity, and the ERK1/2 MAPK signaling may be involved in this process.

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Section: Sevoflurane Exposurementioning

confidence: 99%

Section: Behavior Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

et al. 2014

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“…The MAPK pathway has been reported to be involved in anesthetic-induced neurodegeneration (7,21). The JNK signalling pathway is involved in neuronal apoptosis triggered by several brain injury stimuli, such as ischemic reperfusion injury (43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

“…Li et al (7) reported the involvement of the JNK pathway in isoflurane-induced neurodegeneration in the hippocampi of neonatal rats. Furthermore, N-stearoyl-l-tyrosine was reported to protect the developing brain against sevoflurane-induced neurotoxicity via the ERK1/2 signalling pathway (21). Finally, Sanders et al (22) reported that dexmedetomidine upregulated ERK1/2 in brain tissues of neonatal rats exposed to isoflurane.…”

Section: Introductionmentioning

confidence: 99%

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats

Zhao

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. An increasing number of infants and children undergo surgery and are exposed to anesthesia as a part of medical care each year. Isoflurane is a commonly used anesthetic in the pediatric population. However, previous studies have reported widespread isoflurane-induced neuroapoptosis and cognitive impairments in neonatal animal models, raising concerns over the administration of isoflurane in the pediatric population. The current study investigated the effects of rutin, a flavonoid, on isoflurane-induced neuroapoptosis in a neonatal rodent model. Groups of neonatal rat pups were administered rutin at doses of 10, 20 or 40 mg/kg body weight from postnatal day 1 (P1) to P15. On P7, pups were exposed to 0.75% isoflurane for 6 h. Rat pups in the control groups did not receive rutin, and did not receive anesthesia in one group. Neuroapoptosis following isoflurane exposure was determined by TUNEL assay. The expression levels of cleaved caspase-3, apoptotic pathway proteins [Bcl2-associated agonist of cell death (Bad), phospho-Bad, Bax, B-cell lymphoma 2 (Bcl-2) and Bcl-xL and mitogen-activated protein kinases (MAPK)] signalling pathway proteins [c-Jun N-terminal kinase (JNK), phospho-JNK, extracellular-signal-regulated kinase 1/2 (ERK1/2), phosphoERK1/2, p38, phospho-p38 and phospho-c-Jun], were determined by western blot analysis. The Morris water maze test was used to assess the learning and memory of pups on P30 and P31. The present study found that rutin at the tested doses of 10, 20 and 40 mg significantly reduced (P<0.05) the isoflurane-induced elevation in apoptotic cell count. The expression levels of caspase-3, Bad, Bax and MAPK proteins, which were increased following isoflurane treatment, were rescued by rutin treatment. Furthermore, rutin prevented the increase in Bcl-xL, Bcl-2 and phospho-Bad expression following isoflurane treatment, and enhanced the memory of the rats. Rutin provided neuroprotection against isoflurane-induced neuronal apoptosis and improved the learning and memory of rats by effectively regulating the expression levels of proteins in the MAPK pathway.

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Mechanistic insight into sevoflurane-associated developmental neurotoxicity

et al. 2021

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With the development of technology, more infants receive general anesthesia for surgery, other interventions, or clinical examination at an early stage after birth. However, whether general anesthetics can affect the function and structure of the developing infant brain remains an important, complex, and controversial issue. Sevoflurane is the most-used anesthetic in infants, but this drug is potentially neurotoxic. Short or single exposure to sevoflurane has a weak effect on cognitive function, while long or repeated exposure to general anesthetics may cause cognitive dysfunction. This review focuses on the mechanisms by which sevoflurane exposure during development may induce long-lasting undesirable effects on the brain. We review neural cell death, neural cell damage, impaired assembly and plasticity of neural circuits, tau phosphorylation, and neuroendocrine effects as important mechanisms for sevoflurane-induced developmental neurotoxicity. More advanced technologies and methods should be applied to determine the underlying mechanism(s) and guide prevention and treatment of sevoflurane-induced neurotoxicity.

show abstract

N-stearoyl-l-tyrosine ameliorates sevoflurane induced neuroapoptosis via MEK/ERK1/2 MAPK signaling pathway in the developing brain

Cited by 43 publications

References 30 publications

Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling

Rutin attenuates isoflurane-induced neuroapoptosis via modulating JNK and p38 MAPK pathways in the hippocampi of neonatal rats

Mechanistic insight into sevoflurane-associated developmental neurotoxicity

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