The Effects of Neonatal Isoflurane Exposure in Mice on Brain Cell Viability, Adult Behavior, Learning, and Memory

Loepke, Andreas W.; Istaphanous, George K.; McAuliffe, John J.; Miles, Lili; Hughes, Elizabeth; McCann, John; Harlow, Kathryn E.; Kurth, C. Dean; Williams, Michael T.; Vorhees, Charles V.; Danzer, Steve C.

doi:10.1213/ane.0b013e31818cdb29

Cited by 217 publications

(180 citation statements)

References 45 publications

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“…In addition, the mice showed normal food intake behavior and normal locomotive activity. The dose of midazolam (0.83 mg/kg) used in this study was low compared with other studies that used higher concentrations of benzodiazepines such as midazolam for different experimental procedures related to neuronal toxicity and apoptosis, anesthesia, and other applications (Bittigau et al, 2002;Ikonomidou et al, 2000;Jevtovic-Todorovic et al, 2003;Loepke et al, 2009;Young et al, 2005). These results indicate promising implication of midazolam, apart from anesthesia, to enhance anticancer efficacy when applied in combination with other anticancer agents.…”

Section: Midazolam Suppressed Tumor Growth In Human Tumor Xenograft Micementioning

confidence: 82%

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

Mishra

Kang

Lee

et al. 2013

Molecules and Cells

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Midazolam is a widely used anesthetic of the benzodiazepine class that has shown cytotoxicity and apoptosisinducing activity in neuronal cells and lymphocytes. This study aims to evaluate the effect of midazolam on growth of K562 human leukemia cells and HT29 colon cancer cells. The in vivo effect of midazolam was investigated in BALB/ c-nu mice bearing K562 and HT29 cells human tumor xenografts. The results show that midazolam decreased the viability of K562 and HT29 cells by inducing apoptosis and S phase cell-cycle arrest in a concentration-dependent manner. Midazolam activated caspase-9, capspase-3 and PARP indicating induction of the mitochondrial intrinsic pathway of apoptosis. Midazolam lowered mitochondrial membrane potential and increased apoptotic DNA fragmentation. Midazolam showed reactive oxygen species (ROS) scavenging activity through inhibition of NADPH oxidase 2 (Nox2) enzyme activity in K562 cells. Midazolam caused inhibition of pERK1/2 signaling which led to inhibition of the anti-apoptotic proteins Bcl-X L and XIAP and phosphorylation activation of the pro-apoptotic protein Bid. Midazolam inhibited growth of HT29 tumors in xenograft mice. Collectively our results demonstrate that midazolam caused growth inhibition of cancer cells via activation of the mitochondrial intrinsic pathway of apoptosis and inhibited HT29 tumor growth in xenograft mice. The mechanism underlying these effects of midazolam might be suppression of ROS production leading to modulation of apoptosis and growth regulatory proteins. These findings present possible clinical implications of midazolam as an anesthetic to relieve pain during in vivo anticancer drug delivery and to enhance anticancer efficacy through its ROS-scavenging and pro-apoptotic properties.

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Section: Midazolam Suppressed Tumor Growth In Human Tumor Xenograft Micementioning

confidence: 82%

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

Mishra

Kang

Lee

et al. 2013

Molecules and Cells

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“…In initial attempts at P1-P4, before local anesthesia was introduced into the protocol, it was difficult to obtain a deep and prolonged sedation due to a narrow dose-effect window between insufficient sedation and overdose. In addition, concerns related to a neurotoxic effect of isoflurane in newborn animals have been raised [27][28][29][30] . A combination of isoflurane and the local anesthetic Bupivacaine results in a deeper and more stable anesthesia while permitting an isoflurane dose reduction by a factor of 2-3.…”

Section: Discussionmentioning

confidence: 99%

A Neonatal Mouse Spinal Cord Compression Injury Model

Züchner

Glover

Boulland

2016

JoVE

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Spinal cord injury (SCI) typically causes devastating neurological deficits, particularly through damage to fibers descending from the brain to the spinal cord. A major current area of research is focused on the mechanisms of adaptive plasticity that underlie spontaneous or induced functional recovery following SCI. Spontaneous functional recovery is reported to be greater early in life, raising interesting questions about how adaptive plasticity changes as the spinal cord develops. To facilitate investigation of this dynamic, we have developed a SCI model in the neonatal mouse. The model has relevance for pediatric SCI, which is too little studied. Because neural plasticity in the adult involves some of the same mechanisms as neural plasticity in early life 1 , this model may potentially have some relevance also for adult SCI. Here we describe the entire procedure for generating a reproducible spinal cord compression (SCC) injury in the neonatal mouse as early as postnatal (P) day 1. SCC is achieved by performing a laminectomy at a given spinal level (here described at thoracic levels 9-11) and then using a modified Yasargil aneurysm mini-clip to rapidly compress and decompress the spinal cord. As previously described, the injured neonatal mice can be tested for behavioral deficits or sacrificed for ex vivo physiological analysis of synaptic connectivity using electrophysiological and high-throughput optical recording techniques 1 . Earlier and ongoing studies using behavioral and physiological assessment have demonstrated a dramatic, acute impairment of hindlimb motility followed by a complete functional recovery within 2 weeks, and the first evidence of changes in functional circuitry at the level of identified descending synaptic connections 1 .

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“…It has been confirmed that the developing brain is susceptible to anesthetic-induced neuronal apoptosis at the peak of synaptogenesis, and the greatest vulnerability in rodents occurs predominantly from postnatal day (P) 7 to P10 (Yon et al, 2005;Rizzi et al, 2010), it was considered that anesthetic-induced acute neuronal apoptosis may be a critical contributing factor to long-term cognitive and behavioral impairment, but recent studies have demonstrated that anesthetic-induced acute neuronal apoptosis does not cause long-term cognitive impairment (Yang et al, 2014;Loepke et al, 2009). Therefore, the role of neu-ronal apoptosis in long-term cognitive impairment needs to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

et al. 2016

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-Propofol can induce acute neuronal apoptosis or long-term cognitive dysfunction when exposed at early age in rodents, but it is unclear how the neurotoxicity including neuronal apoptosis and synaptic loss will change in a dynamic manner with brain development after multiple or single exposure of propofol, and the role of neuronal apoptosis and synaptic loss in propofol-induced long-term cognitive impairment needs to be elucidated. In this study, we investigated dynamic changes of neuronal apoptosis, neuronal density, synaptic density in hippocampal CA1 region and the prelimbic cortex (PrL), and longterm cognitive function after multiple or single exposure of propofol in neonatal rats. Results showed that single exposure of propofol only induced great neuronal apoptosis and deficit at postnatal day 9(P9); while multiple exposures of propofol could induce significant neuronal apoptosis, neuronal deficit and synaptic loss at P9, P14, P21, or P35 compared with intact, and spatial learning and memory impairment from P36 to P41. Results suggest that single exposure of propofol only induces transient neuronal apoptosis and deficit, while multiple exposures of propofol induce persistent neuronal apoptosis, neuronal deficit, synaptic loss, and long-term cognitive impairment. Furthermore, persistent neuronal deficit and disturbances in synapse formation but not transient neuronal apoptosis may contribute to long-term cognitive impairment.

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The Effects of Neonatal Isoflurane Exposure in Mice on Brain Cell Viability, Adult Behavior, Learning, and Memory

Abstract: Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions in adult neuronal density or deficits in spontaneous locomotion, spatial learning, or memory function were observed.

Cited by 217 publications

References 45 publications

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

Midazolam Induces Cellular Apoptosis in Human Cancer Cells and Inhibits Tumor Growth in Xenograft Mice

A Neonatal Mouse Spinal Cord Compression Injury Model

Persistent neuronal apoptosis and synaptic loss induced by multiple but not single exposure of propofol contribute to long-term cognitive dysfunction in neonatal rats

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