Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity

Walters, Jennifer L.; Paule, Merle G.

doi:10.1016/j.ntt.2016.11.005

Cited by 92 publications

(69 citation statements)

References 197 publications

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“…A growing body of preclinical as well as some retrospective clinical evidences suggests that exposure to GA during the critical periods of development has been associated with neurotoxicity and long-term behavioral impairments (Flick et al, 2011; Ing et al, 2014b; Lin et al, 2014; Rappaport et al, 2015; Pinyavat et al, 2016; Walters and Paule, 2017). Consistently, we found that isoflurane administration induced long lasting neuronal apoptosis and cognitive deficits in developing rats.…”

Section: Discussionmentioning

confidence: 99%

“…A large number of preclinical studies have raised concern about the potential of neurotoxicity and long-term cognitive impairments caused by general anesthetics in developing brains (Ing et al, 2014a; Lin et al, 2014; Rappaport et al, 2015; Walters and Paule, 2017). Due to the increasing demand for pediatric patients to have anesthesia during surgery, recent research efforts are focusing on deciphering the earliest cellular targets and mechanistic pathways of general anesthesia (GA)-induced developmental neurotoxicity so that strategies for effective ameliorating or preventing the adverse effects can be devised (Boscolo et al, 2012, 2013a; Jevtovic-Todorovic et al, 2012; Noguchi et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats

Hao

Sun

et al. 2017

Front. Cell. Neurosci.

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Mitochondria are supposed to be involved in the early pathogenesis of general anesthesia (GA)-induced neurotoxicity and long-term cognitive deficits in developing brains. However, effective pharmacologic agents targeted on mitochondria during GA exposure are lacking. This study explores the protective effects of mitochondrion-targeted antioxidant elamipretide (SS-31) on mitochondrial morphogenesis and cognition in developing rats exposed to isoflurane. Rat pups at postnatal day (PND) 7 were exposed to 1.5% isoflurane for 6 h following intraperitoneal administration of elamipretide or vehicle with 30 min interval. The hippocampus was immediately removed for biochemical assays. Histopathological studies were conducted at PND 21, and behavioral tests were performed at PND 40 or 60. We found that early exposure to isoflurane caused remarkable reactive oxygen species (ROS) accumulation, mitochondrial deformation and neuronal apoptosis in hippocampus. The injury occurrence ultimately gave rise to long-term cognitive deficits in developing rats. Interestingly, pretreatment with elamipretide not only provided protective effect against oxidative stress and mitochondrial damages, but also attenuated isoflurane-induced cognitive deficits. Our data support the notion that mitochondrial damage is an early and long lasting event of GA-induced injury and suggest that elamipretide might have clinically therapeutic benefits for pediatric patients undertaking GA.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats

Hao

Sun

et al. 2017

Front. Cell. Neurosci.

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“…Several studies have also reported that L-carnitine, and particularly ALCAR can protect the developing brain from deleterious effects of exposure to clinically used anesthetic agents [154–157]. Treatment with ALCAR protected from neuroinflammation and apoptosis resulting from anesthesia [154–157]. It is particularly important that some of these studies used newborn or very young nonhuman primates [154, 155, 157].…”

Section: Neuroprotection By Acetyl-l-carnitine (Alcar)mentioning

confidence: 99%

“…Treatment with ALCAR protected from neuroinflammation and apoptosis resulting from anesthesia [154–157]. It is particularly important that some of these studies used newborn or very young nonhuman primates [154, 155, 157]. …”

Section: Neuroprotection By Acetyl-l-carnitine (Alcar)mentioning

confidence: 99%

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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L-Carnitine functions to transport long chain fatty acyl CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalance in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer’s disease and in conditions leading to central or peripheral nervous system injury. There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury. ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory. Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury.

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“…Most retrospective epidemiological studies of patients, who had medical procedures requiring general anesthesia before 1–4 years of age, found significant subsequent neurocognitive deficiencies in late childhood or adolescence ( for review see Creeley, 2016). The possibility of anesthetic-induced developmental abnormalities is strongly supported by the results of numerous laboratory studies of healthy animals, though the full range of neonatal anesthesia-induced changes and underlying mechanisms remain poorly understood even in animal models ( for review see Walters and Paule, 2016). Many factors influence the developmental outcome of anesthetic exposure in animals, one of which is the duration of anesthesia.…”

Section: Introductionmentioning

confidence: 99%

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia

Yang

Gravenstein

et al. 2017

Psychoneuroendocrinology

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Background The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. Methods Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl− (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2 h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3 h at P10. 3–7 days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl− (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. Conclusions Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.

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Review of preclinical studies on pediatric general anesthesia-induced developmental neurotoxicity

Cited by 92 publications

References 197 publications

Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats

Elamipretide (SS-31) Ameliorates Isoflurane-Induced Long-Term Impairments of Mitochondrial Morphogenesis and Cognition in Developing Rats

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

Role of environmental stressors in determining the developmental outcome of neonatal anesthesia

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