Isoflurane-induced Neuroapoptosis in the Neonatal Rhesus Macaque Brain

Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.
Anesthesiology (Impact Factor: 5.88). 03/2010; 112(4):834-41. DOI: 10.1097/ALN.0b013e3181d049cd
Source: PubMed


Brief isoflurane anesthesia induces neuroapoptosis in the developing rodent brain, but susceptibility of non-human primates to the apoptogenic action of isoflurane has not been studied. Therefore, we exposed postnatal day 6 (P6) rhesus macaques to a surgical plane of isoflurane anesthesia for 5 h, and studied the brains 3 h later for histopathologic changes.
With the same intensity of physiologic monitoring typical for human neonatal anesthesia, five P6 rhesus macaques were exposed for 5 h to isoflurane maintained between 0.7 and 1.5 end-tidal Vol% (endotracheally intubated and mechanically ventilated) and five controls were exposed for 5 h to room air without further intervention. Three hours later, the brains were harvested and serially sectioned across the entire forebrain and midbrain, and stained immunohistochemically with antibodies to activated caspase-3 for detection and quantification of apoptotic neurons.
Quantitative evaluation of brain sections revealed a median of 32.5 (range, 18.0-48.2) apoptotic cells/mm of brain tissue in the isoflurane group and only 2.5 (range, 1.1-5.2) in the control group (difference significant at P = 0.008). Apoptotic neuronal profiles were largely confined to the cerebral cortex. In the control brains, they were sparse and randomly distributed, whereas in the isoflurane brains they were abundant and preferentially concentrated in specific cortical layers and regions.
The developing non-human primate brain is sensitive to the apoptogenic action of isoflurane and displays a 13-fold increase in neuroapoptosis after 5 h exposure to a surgical plane of isoflurane anesthesia.

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    • "General anesthesia can induce neurodegeneration and subsequent maladaptive behaviors in animals, including rats and primates. Its neurotoxicity in animals develops after exposure above threshold doses and durations during a critical neurodevelopmental window of maximal synaptogenesis (Brambrink et al., 2010; Hays & Deshpande, 2013). Implicated drugs include N-methyl-D-aspartate (NMDA) glutamate receptor antagonists and γ-aminobutyric acid (GABA) agonists such as midazolam, nitrous oxide, isoflurane , and ketamine. "
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    ABSTRACT: To study the association between general anesthesia exposure before age 3 years and having a later ADHD diagnosis. In a birth cohort, data were collected from a nationwide population database for children born between 1997 and 1999 who were exposed to general anesthesia before their third birthday. Age- and gender-matched enrollees without general anesthesia exposure were taken as the comparison. Groups were compared to identify the incidence of ADHD after age 4 and anesthesia-related predictive factors. Among the 1,146 exposed children, 74 ADHD cases were identified, and 158 ADHD cases were identified in 3,438 matched controls. After adjusting for comorbid conditions and possible confounding factors, if exposure on more than one occasion or ≥3 hr, an increased likelihood of having a later ADHD diagnosis was found (HR, 1.71 and 2.43, respectively). Children with multiple or ≥3 hr general anesthesia exposures before age 3 years have an increased likelihood of a later ADHD diagnosis. © 2015 SAGE Publications.
    No preview · Article · May 2015 · Journal of Attention Disorders
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    • "Isoflurane is a commonly used volatile anesthetic in pediatric surgeries (Istaphanous and Loepke, 2009). However prolonged exposure to volatile anesthetics causes neuronal apoptosis and degeneration in develop -ing brains leading to learning and memory deficits (Satomoto et al., 2009; Brambrink et al., 2010; Kong et al., 2011; Li et al., 2013a,b). Recent investigations in children less than 4 years of age, exposed to anaesthesia more than once, present to have greater risks of developing cognitive disabilities (DiMaggio et al., 2011; Ing et al., 2012) thus raising serious concerns on possible detrimental effects of anesthetics. "
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    ABSTRACT: Increasing numbers of children undergo surgery and are exposed to anesthesia that raises concerns regarding the safety of frequently employed anesthetics. Isoflurane, often used in pediatric anesthesia, has been reported to cause neurodegeneration in animal models. The study investigates the effectiveness of pterostilbene on neurodegeneration caused by isoflurane. Separate groups of neonatal mice were administered with pterostilbene at 10, 20 or 40 mg/kg from post natal day 1 (P1) to P15. On P7, rats received isoflurane at 0.75% for 6 hours. Control rats received no anesthesia or pterostilbene. Neuroapoptosis following isoflurane exposure were markedly reduced by pterostilbene, further pterostilbene down-regulated the expressions of caspase-3, Bad, phospho-JNK and phospho-c-Jun and as well improved the expressions of Bcl-xL, JNK, phospho-Bad and phospho-Akt. Pterostilbene enhanced the performance of rats in Morris water maze tests. The observations suggest that pterostilbene was able to effectively reduce isoflurane-induced neurodegeneration. © 2015, Bangladesh Pharmacological Society. All right reserved.
    Preview · Article · Mar 2015 · Bangladesh Journal of Pharmacology
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    • "Every day, anesthetics are used around the world in newborns and infants who undergo medical procedures. There is growing concern that anesthetics can significantly alter the developing brain, and animal models have shown that exposure to anesthetics at an early age lead to neuronal death and long-term cognitive dysfunction [1]–[3]. Epidemiologic studies suggest that humans are also susceptible to long-term cognitive effects after anesthesia [4], [5]. "
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    ABSTRACT: Background Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue. Methods Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition. Results Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory. Conclusion Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane.
    Full-text · Article · Aug 2014 · PLoS ONE
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