Special Issue "Neurotoxicity and General Anaesthetics in the Young"

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A special issue of Brain Sciences (ISSN 2076-3425).

Deadline for manuscript submissions: closed (31 January 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Daqing Ma (Website)

Head of Anaesthesia Research, Anaesthetics, Pain Medicine & Intensive Care Department of Surgery & Cancer, Imperial College London Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK
Interests: organoprotection (stroke, neonatal asphyxia and kidney transplant); postoperative cognitive dysfunction and Alzheimer’s disease; cancer growth and metastasis

Special Issue Information

Dear Colleague

In the early development of brain, there is an important period called the synaptogenesis period (also known as the brain growth-spurt period) which occurs in different mammalian species at different times relative to birth. In rodents, it begins a day or two before birth and ends 2 weeks after birth, whereas in humans it starts at the beginning of the third trimester and ends several years after birth. This is the critical period of neural development for establishing communications with their environment and other neurons to ensure that they develop and function appropriately; disruption at this stage by toxic agents including anaesthetic agents may compromise the normal neuronal development of the central nervous system and may cause a long term of cognitive impairment in adult stage. This special issue of BRAIN SCIENCES contains a few substantial reviews updating research advance in this area.

Prof. Dr. Daqing Ma
Guest Editor

Submission

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Keywords

  • anaesthetics
  • neuroapoptosis
  • developing brain
  • molecular mechanism

Published Papers (7 papers)

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Research

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Open AccessArticle Propofol Exposure in Pregnant Rats Induces Neurotoxicity and Persistent Learning Deficit in the Offspring
Brain Sci. 2014, 4(2), 356-375; doi:10.3390/brainsci4020356
Received: 29 January 2014 / Revised: 21 April 2014 / Accepted: 24 April 2014 / Published: 6 May 2014
Cited by 11 | PDF Full-text (2473 KB) | HTML Full-text | XML Full-text
Abstract
Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal [...] Read more.
Propofol is a general anesthetic widely used in surgical procedures, including those in pregnant women. Preclinical studies suggest that propofol may cause neuronal injury to the offspring of primates if it is administered during pregnancy. However, it is unknown whether those neuronal changes would lead to long-term behavioral deficits in the offspring. In this study, propofol (0.4 mg/kg/min, IV, 2 h), saline, or intralipid solution was administered to pregnant rats on gestational day 18. We detected increased levels of cleaved caspase-3 in fetal brain at 6 h after propofol exposure. The neuronal density of the hippocampus of offspring was reduced significantly on postnatal day 10 (P10) and P28. Synaptophysin levels were also significantly reduced on P28. Furthermore, exploratory and learning behaviors of offspring rats (started at P28) were assessed in open-field trial and eight-arm radial maze. The offspring from propofol-treated dams showed significantly less exploratory activity in the open-field test and less spatial learning in the eight-arm radial maze. Thus, this study suggested that propofol exposure during pregnancy in rat increased cleaved caspsase-3 levels in fetal brain, deletion of neurons, reduced synaptophysin levels in the hippocampal region, and persistent learning deficits in the offspring. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)
Open AccessArticle Time-Dependent Effects of Anesthetic Isoflurane on Reactive Oxygen Species Levels in HEK-293 Cells
Brain Sci. 2014, 4(2), 311-320; doi:10.3390/brainsci4020311
Received: 27 January 2014 / Revised: 4 April 2014 / Accepted: 4 April 2014 / Published: 22 April 2014
Cited by 2 | PDF Full-text (256 KB) | HTML Full-text | XML Full-text
Abstract
The inhalation anesthetic isoflurane has been reported to induce caspase activation and apoptosis, which may lead to learning and memory impairment. However, the underlying mechanisms of these effects are largely unknown. Isoflurane has been shown to induce elevation of cytosol calcium levels, [...] Read more.
The inhalation anesthetic isoflurane has been reported to induce caspase activation and apoptosis, which may lead to learning and memory impairment. However, the underlying mechanisms of these effects are largely unknown. Isoflurane has been shown to induce elevation of cytosol calcium levels, accumulation of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore, reduction in mitochondria membrane potential, and release of cytochrome c. The time course of these effects, however, remains to be determined. Therefore, we performed a pilot study to determine the effects of treatment with isoflurane for various times on ROS levels in HEK-293 cells. The cells were treated with 2% isoflurane plus 21% O2 and 5% CO2 for 15, 30, 60, or 90 min. We then used fluorescence imaging and microplate fluorometer to detect ROS levels. We show that 2% isoflurane for 60 or 90 min, but not 15 or 30 min, induced ROS accumulation in the cells. These data illustrated that isoflurane could cause time-dependent effects on ROS levels. These findings have established a system to further determine the time course effects of isoflurane on cellular and mitochondria function. Ultimately, the studies would elucidate, at least partially, the underlying mechanisms of isoflurane-induced cellular toxicity. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)

Review

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Open AccessReview The Neurodevelopmental Impact of Neonatal Morphine Administration
Brain Sci. 2014, 4(2), 321-334; doi:10.3390/brainsci4020321
Received: 1 February 2014 / Revised: 1 April 2014 / Accepted: 15 April 2014 / Published: 25 April 2014
Cited by 7 | PDF Full-text (212 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Medical management of newborn infants often necessitates recurrent painful procedures, which may alter nociceptive pathways during a critical developmental period and adversely effect neuropsychological outcomes. To mitigate the effects of repeated painful stimuli, opioid administration for peri-procedural analgesia and ICU (intensive care [...] Read more.
Medical management of newborn infants often necessitates recurrent painful procedures, which may alter nociceptive pathways during a critical developmental period and adversely effect neuropsychological outcomes. To mitigate the effects of repeated painful stimuli, opioid administration for peri-procedural analgesia and ICU (intensive care unit) sedation is common in the NICU (neonatal intensive care unit). A growing body of basic and animal evidence suggests potential long-term harm associated with neonatal opioid therapy. Morphine increases apoptosis in human microglial cells, and animal studies demonstrate long-term changes in behavior, brain function, and spatial recognition memory following morphine exposure. This comprehensive review examines existing preclinical and clinical evidence on the long-term impacts of neonatal pain and opioid therapy. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)
Open AccessReview A Double-Edged Sword: Volatile Anesthetic Effects on the Neonatal Brain
Brain Sci. 2014, 4(2), 273-294; doi:10.3390/brainsci4020273
Received: 31 January 2014 / Revised: 28 March 2014 / Accepted: 31 March 2014 / Published: 16 April 2014
Cited by 6 | PDF Full-text (399 KB) | HTML Full-text | XML Full-text
Abstract
The use of volatile anesthetics, a group of general anesthetics, is an exceedingly common practice. These anesthetics may have neuroprotective effects. Over the last decade, anesthetic induced neurotoxicity in pediatric populations has gained a certain notoriety based on pre-clinical cell and animal [...] Read more.
The use of volatile anesthetics, a group of general anesthetics, is an exceedingly common practice. These anesthetics may have neuroprotective effects. Over the last decade, anesthetic induced neurotoxicity in pediatric populations has gained a certain notoriety based on pre-clinical cell and animal studies demonstrating that general anesthetics may induce neurotoxicity, including neuroapoptosis, neurodegeneration, and long-term neurocognitive and behavioral deficits. With hundreds of millions of people having surgery under general anesthesia worldwide, and roughly six million children annually in the U.S. alone, the importance of clearly defining toxic or protective effects of general anesthetics cannot be overstated. Yet, with our expanding body of knowledge, we have come to learn that perhaps not all volatile anesthetics have the same pharmacological profiles; certain ones may have a more favorable neurotoxic profile and may actually exhibit neuroprotection in specific populations and situations. Thus far, very few clinical studies exist, and have not yet been convincing enough to alter our practice. This review will provide an update on current data regarding volatile anesthetic induced neurotoxicity and neuroprotection in neonatal and infant populations. In addition, this paper will discuss ongoing studies and the trajectory of further research over the coming years. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)
Figures

Open AccessReview Anesthesia and the Developing Brain: Relevance to the Pediatric Cardiac Surgery
Brain Sci. 2014, 4(2), 295-310; doi:10.3390/brainsci4020295
Received: 26 February 2014 / Revised: 2 April 2014 / Accepted: 5 April 2014 / Published: 16 April 2014
Cited by 5 | PDF Full-text (226 KB) | HTML Full-text | XML Full-text
Abstract
Anesthetic neurotoxicity has been a hot topic in anesthesia for the past decade. It is of special interest to pediatric anesthesiologists. A subgroup of children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are [...] Read more.
Anesthetic neurotoxicity has been a hot topic in anesthesia for the past decade. It is of special interest to pediatric anesthesiologists. A subgroup of children potentially at greater risk for anesthetic neurotoxicity, based on a prolonged anesthetic exposure early in development, are those children receiving anesthesia for surgical repair of congenital heart disease. These children have a known risk of neurologic deficit after cardiopulmonary bypass for surgical repair of congenital heart disease. Yet, the type of anesthesia used has not been considered as a potential etiology for their neurologic deficits. These children not only receive prolonged anesthetic exposure during surgical repair, but also receive repeated anesthetic exposures during a critical period of brain development. Their propensity to abnormal brain development, as a result of congenital heart disease, may modify their risk of anesthetic neurotoxicity. This review article provides an overview of anesthetic neurotoxicity from the perspective of a pediatric cardiac anesthesiologist and provides insight into basic science and clinical investigations as it relates to this unique group of children who have been studied over several decades for their risk of neurologic injury. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)
Open AccessReview Anaesthetics-Induced Neurotoxicity in Developing Brain: An Update on Preclinical Evidence
Brain Sci. 2014, 4(1), 136-149; doi:10.3390/brainsci4010136
Received: 18 December 2013 / Revised: 6 February 2014 / Accepted: 4 March 2014 / Published: 14 March 2014
Cited by 6 | PDF Full-text (202 KB) | HTML Full-text | XML Full-text
Abstract
Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in [...] Read more.
Every year millions of young people are treated with anaesthetic agents for surgery and sedation in a seemingly safe manner. However, growing and convincing preclinical evidence in rodents and nonhuman primates, together with recent epidemiological observations, suggest that exposure to anaesthetics in common clinical use can be neurotoxic to the developing brain and lead to long-term neurological sequelae. These findings have seriously questioned the safe use of general anaesthetics in obstetric and paediatric patients. The mechanisms and human applicability of anaesthetic neurotoxicity and neuroprotection have remained under intense investigation over the past decade. Ongoing pre-clinical investigation may have significant impact on clinical practice in the near future. This review represents recent developments in this rapidly emerging field. The aim is to summarise recently available laboratory data, especially those being published after 2010, in the field of anaesthetics-induced neurotoxicity and its impact on cognitive function. In addition, we will discuss recent findings in mechanisms of early-life anaesthetics-induced neurotoxicity, the role of human stem cell-derived models in detecting such toxicity, and new potential alleviating strategies. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)
Open AccessReview The Neurotoxicity of Nitrous Oxide: The Facts and “Putative” Mechanisms
Brain Sci. 2014, 4(1), 73-90; doi:10.3390/brainsci4010073
Received: 16 December 2013 / Revised: 8 January 2014 / Accepted: 16 January 2014 / Published: 28 January 2014
Cited by 6 | PDF Full-text (399 KB) | HTML Full-text | XML Full-text
Abstract
Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in [...] Read more.
Nitrous oxide is a widely used analgesic agent, used also in combination with anaesthetics during surgery. Recent research has raised concerns about possible neurotoxicity of nitrous oxide, particularly in the developing brain. Nitrous oxide is an N-methyl-d-aspartate (NMDA)-antagonist drug, similar in nature to ketamine, another anaesthetic agent. It has been linked to post-operative cardiovascular problems in clinical studies. It is also widely known that exposure to nitrous oxide during surgery results in elevated homocysteine levels in many patients, but very little work has investigated the long term effect of these increased homocysteine levels. Now research in rodent models has found that homocysteine can be linked to neuronal death and possibly even cognitive deficits. This review aims to examine the current knowledge of mechanisms of action of nitrous oxide, and to describe some pathways by which it may have neurotoxic effects. Full article
(This article belongs to the Special Issue Neurotoxicity and General Anaesthetics in the Young)

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