Mechanisms of cytotoxicity induced by the anesthetic isoflurane: the role of inositol 1,4,5-trisphosphate receptors

Wh, Zhai; Zhao, Juan; S-P, Huo; Xg, Chen; Yd, Li; Zl, Zhang; Ll, Yu; Song, Shuai; Wang, Qiming J.

doi:10.4238/2015.june.26.1

Cited by 4 publications

(4 citation statements)

References 38 publications

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“…It has been shown that brain development of rats at E21 is equivalent to that of human fetus at the gestational age of 12–16 weeks the second trimester [ 10 , 11 ]. In this study, pregnant SD rats at E21 were exposed to isoflurane to mimic anesthesia on pregnant woman in the second trimester; isoflurane at 1.3% and 2.0% is equivalent to 1 and 1.5 MAC, respectively [ 12 , 13 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of isoflurane exposure in pregnant rats on the learning and memory of offsprings

et al. 2018

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BackgroundAbout 2% of pregnant women receive non-obstetric surgery under general anesthesia each year. During pregnancy, general anesthetics may affect brain development of the fetus. This study aimed to investigate safe dosage range of isoflurane.MethodsForty-eight SpragueDawley (SD) pregnant rats were randomly divided into 3 groups and inhaled 1.3% isoflurane (the Iso1 group), 2.0% isoflurane (the Iso2 group) and 50% O2 alone (the control group) for 3 h, respectively. Their offsprings were subjected to Morris water maze at day 28 and day 90 after birth to evaluate learning and memory. The expression of cAMP-response element binding protein (CREB) and phosphorylated cAMP-response element binding protein (p-CREB) was detected in the hippocampus dentate gyrus.ResultsLess offsprings of Iso2 group were able to cross the platform than that of the control group (P < 0.05). Accordingly, the Iso2 offsprings expressed p-CREB mainly in the subgranular zone in contrast to the whole granular cell layer of hippocampus dentate gyrus as detected in the Iso1 and control offsprings; the expression level of pCREB was also lower in the Iso2 than Iso1 or control offsprings (P < 0.05).ConclusionInhalation of isoflurane at 1.3% during pregnancy has no significant influence on learning and memory of the offspring; exposure to isoflurane at 2.0% causes damage to spatial memory associated with inhibition of CREB phosphorylation in the granular cell layer of hippocampus dentate gyrus.

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Section: Discussionmentioning

confidence: 99%

Influence of isoflurane exposure in pregnant rats on the learning and memory of offsprings

et al. 2018

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“…Most previous studies of anesthetic effects on the ER have focused on its role in modulating cell viability ( Q.J. Wang et al, 2008 ; Zhai et al, 2015 ; Liu et al, 2016 ). Our studies are the first to analyze the functional impact of anesthetic effects on ER Ca 2+ on neuronal function in intact hippocampal neurons.…”

Section: Discussionmentioning

confidence: 99%

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Osman,

Speigel,

Patel

et al. 2023

eNeuro

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Volatile anesthetics reduce excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms which include inhibition of depolarization-evoked increases in presynaptic Ca2+concentration and blockade of postsynaptic excitatory glutamate receptors. The presynaptic sites of action leading to reduced electrically evoked increases in presynaptic Ca2+concentration and Ca2+-dependent exocytosis are unknown. Endoplasmic reticulum (ER) of Ca2+release via ryanodine receptor 1 (RyR1) and uptake by SERCA are essential for regulation intracellular Ca2+and are potential targets for anesthetic action. Mutations in sarcoplasmic reticulum release channels mediate volatile anesthetic-induced malignant hyperthermia (MH), a potentially fatal pharmacogenetic condition characterized by unregulated Ca2+release and muscle hypermetabolism. However, the impact of MH mutations on neuronal function are unknown. We used primary cultures of postnatal hippocampal neurons to analyze volatile anesthetic-induced changes in ER Ca2+dynamics using a genetically encoded ER-targeted fluorescent Ca2+sensor in both rat and mouse wild-type neurons and in mouse mutant neurons harboring theRYR1T4826I MH-susceptibility mutation. The volatile anesthetic isoflurane reduced both baseline and electrical stimulation-evoked increases in ER Ca2+concentration in neurons independent of its depression of presynaptic cytoplasmic Ca2+concentrations. Isoflurane and sevoflurane, but not propofol, depressed depolarization-evoked increases in ER Ca2+concentration significantly more in mouseRYR1T4826I mutant neurons than in wild-type neurons. TheRYR1T4826I mutant neurons also showed markedly greater isoflurane-induced reductions in presynaptic cytosolic Ca2+concentration and synaptic vesicle exocytosis. These findings implicate RyR1 as a molecular target for the effects of isoflurane on presynaptic Ca2+handling.Significance StatementDespite their essential clinical roles, the molecular and cellular mechanisms of action of general anesthetics are not fully understood. Malignant hyperthermia is a potentially fatal pharmacogenetic disorder that leads to dysregulation of intracellular Ca2+handling in response to triggering by volatile anesthetics. While research on malignant hyperthermia has focused on skeletal muscle effects, much less is known about its neuronal effects. We identify neuronal endoplasmic reticulum Ca2+regulation as a novel target for volatile anesthetic action and as a potential target in malignant hyperthermia. While depression of CNS electrical activityin vivoby anesthesia has been observed in another model of malignant hyperthermia, our study reveals fundamental presynaptic mechanisms of volatile anesthetics with implications for the development of more selective anesthetics and for prevention and treatment of malignant hyperthermia.

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“…In the nervous system of adult rats, isoflurane exposure for 1 MAC for 12 hours induced cytoxicity increased IP3R gene expression, and inhibition of IP3R activity did not completely block isoflurane-induced upregulation of IP3R mRNA expression, which was also associated with greater and faster elevation of peak (Ca2+). Sevoflurane and desflurane at equivalent exposure to isoflurane did not induce similar cytotoxicity or elevation of peak (Ca2+) [104,113] In conclusion isoflurane and sevoflurane induce cytotoxicity in the nervous system, which has significant adverse effects on neonatal and postnatal stage. In the adult effects nervous system result in increased vulnerability to cell damage.…”

Section: Role Of the Use Of Inhaled Anesthetics In Protection Againstmentioning

confidence: 97%

“…The differing effects of both anesthetics on the immature and mature nervous system have been investigated in recent years using in vitro Table 1 and in vivo murine models Table 2. The dates indicate that isoflurane and sevoflurane can inhibit NMDA receptor responses; these results suggest that both anesthetics might also be able to reduce or increase cytotoxic effects produced by excessive NMDA receptor stimulation, especially in the developing nervous system [102][103][104][105][106] In the nervous system of the developing rat, the deleterious effects of volatile anesthetics have demonstrated their greatest potential for harm between PD 0 -PD 14 [29,30,[107][108][109] Studies have determined the presence of apoptosis in the developing nervous system, as measured by expression of activated caspase-3 (CASP-3) and increases induced by the expression in proteins of cleaved CASP-3, for both isoflurane and sevoflurane [29,30,108,109].…”

Section: Role Of the Use Of Inhaled Anesthetics In Protection Againstmentioning

confidence: 97%

Effects of Excitotoxic Lesion with Inhaled Anesthetics on Nervous System Cells of Rodents

Quiroz‐Padilla

Guillazo-Blanch

Sanchez

et al. 2018

CPD

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Different anesthesia methods can variably influence excitotoxic lesion effects on the brain. The main purpose of this review is to identify potential differences in the toxicity to nervous system cells of two common inhalation anesthesia methods, isoflurane and sevoflurane, used in combination with an excitotoxic lesion procedure in rodents. The use of bioassays in animal models has provided the opportunity to examine the role of specific molecules and cellular interactions that underlie important aspects of neurotoxic effects relating to calcium homeostasis and apoptosis activation. Processes induced by NMDA antagonist drugs involve translocation of Bax protein to mitochondrial membranes, allowing extra-mitochondrial leakage of cytochrome C, followed by sequence of changes that ending in activation of CASP-3. The literature demonstrates that the use of these anesthetics in excitotoxic surgery increases neuroinflammation activity facilitating the effects of apoptosis and necrosis on nervous system cells, depending on the concentration and exposure duration of the anesthetic. High numbers of microglia and astrocytes and high levels of proinflammatory cytokines and caspase activation possibly mediate these inflammatory responses. However, it is necessary to continue studies in rodents to understand the effect of the use of inhaled anesthetics with excitotoxic lesions in different developmental stages, including newborns, juveniles and adults. Understanding the mechanisms of regulation of cell death during development can potentially provide tools to promote neuroprotection and eventually achieve the repair of the nervous system in pathological conditions.

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Mechanisms of cytotoxicity induced by the anesthetic isoflurane: the role of inositol 1,4,5-trisphosphate receptors

Cited by 4 publications

References 38 publications

Influence of isoflurane exposure in pregnant rats on the learning and memory of offsprings

Influence of isoflurane exposure in pregnant rats on the learning and memory of offsprings

Isoflurane Alters Presynaptic Endoplasmic Reticulum Calcium Dynamics in Wild-Type and Malignant Hyperthermia-Susceptible Rodent Hippocampal Neurons

Effects of Excitotoxic Lesion with Inhaled Anesthetics on Nervous System Cells of Rodents

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