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.
"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. "
"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. "
"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 –. Epidemiologic studies suggest that humans are also susceptible to long-term cognitive effects after anesthesia , . "
[Show abstract][Hide abstract] 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.
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.
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.
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.
PLoS ONE 08/2014; 9(8):e105340. DOI:10.1371/journal.pone.0105340 · 3.23 Impact Factor
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