Cell age–specific vulnerability of neurons to anesthetic toxicity

Abstract

Objective Anesthetics have been linked to widespread neuronal cell death in neonatal animals. Epidemiological human studies have associated early childhood anesthesia with long-term neurobehavioral abnormalities, raising substantial concerns that anesthetics may cause similar cell death in young children. However, key aspects of the phenomenon remain unclear, such as why certain neurons die, whereas immediately adjacent neurons are seemingly unaffected, and why the immature brain is exquisitely vulnerable, whereas the mature brain seems resistant. Elucidating these questions is critical for assessing the phenomenon’s applicability to humans, defining the susceptible age, predicting vulnerable neuronal populations, and devising mitigating strategies. Methods This study examines the effects of anesthetic exposure on late- and adult-generated neurons in newborn, juvenile, and adult mice, and characterizes vulnerable cells using birth-dating and immunohistochemical techniques. Results We identify a critical period of cellular developmental during which neurons are susceptible to anesthesia-induced apoptosis. Importantly, we demonstrate that anesthetic neurotoxicity can extend into adulthood in brain regions with ongoing neurogenesis, such as dentate gyrus and olfactory bulb. Interpretation Our findings suggest that anesthetic vulnerability reflects the age of the neuron, not the age of the organism, and therefore may potentially not only be relevant to children but also to adults undergoing anesthesia. This observation further predicts differential heightened regional vulnerability to anesthetic neuroapoptosis to closely follow the distinct regional peaks in neurogenesis. This knowledge may help guide neurocognitive testing of specific neurological domains in humans following exposure to anesthesia, dependent on the individual’s age during exposure.

Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity

“…Exposure to isoflurane, however, led to a dramatic increase in the number of caspase-3 immunoreactive cells in the dentate gyrus ( Fig.1), consistent with previous studies. 13,14 Moreover, quantification of caspase-3 immunolabeling in GFP-expressing cells revealed a five-fold increase in double-labeled cells relative to controls. Specifically, in 21-day-old control animals, 2.05±0.75% of GFPexpressing cells co-labeled with caspase-3, while 11.03±1.75% of cells in the P21 anesthesia group expressed caspase-3 ( Fig.1; P<0.001, t-test).…”

Isoflurane but not Fentanyl Causes Apoptosis in Immature Primary Neuronal Cells

“…There seems to be a critical period of cellular development during which neurons are susceptible to anaesthesia-induced apoptosis. Vulnerability towards anaesthetics reflects the age of the neurons rather than the age of the organism [15] and is linked to ongoing neurogenesis [28]. In human infants, susceptibility to anaesthetics appears to be restricted to early ages, with very preterm infants exposed before term being at greatest risk [36,37].…”

“…In newborn rodents, pigs or non-human primates, an increase of neuronal cell death has been observed following isoflurane exposure [10 -17], with rather subtle long-term cognitive dysfunction occurring in a partially sex-disparate fashion [4,18,19]. Isoflurane-induced neuronal apoptosis appears to occur only at a certain stage of neuronal development, which is dependent on the age of the neuron but independent of the age of the animal [15]. Isoflurane, however, appears to have protective properties as well.…”

Does General Anesthesia Have Detrimental Effects on Immature Human Brain?

“…While many of the initial studies established that the window of vulnerability to these agents coincides with the peak developmental period for synaptogenesis, also known as the "brain growth spurt" period, which in rodents occurs primarily at postnatal day 7, but more recent research has shown that anesthetic neurotoxicity risk extends beyond this window (16).…”