Abstract
Neonatal exposure to isoflurane can result in neuroapoptosis and persistent cognitive impairments. However, the underlying mechanisms remain elusive. Anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 are E3 ubiquitin ligases that play important roles in the central nervous system, including in the regulation of neuronal survival, synaptic development, and mammalian learning and memory. However, whether APC/C-Cdh1 is involved in isoflurane-induced neurotoxicity in developing rats remains unclear. In this study, postnatal day-7 (P7) rat pups and primary hippocampal neurons were exposed to 2% isoflurane for 6 h. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect neuronal apoptosis, and the expression of proteins involved in apoptosis (cleaved caspase-3, Bax and Bcl-2) was assessed by western blot. The level of Cdh1 in the hippocampus was downregulated during isoflurane-induced neuroapoptosis. Cdh1-encoding lentivirus was transfected before isoflurane-treatment to increase the level of Cdh1. Our results showed that Cdh1 overexpression by a recombinant Cdh1-encoding lentivirus reduced isoflurane-induced neuronal apoptosis. Moreover, bilateral intra-hippocampal injection with Cdh1-encoding lentivirus attenuated long-term cognitive deficits after exposure to isoflurane in developing rats. Our study indicates that Cdh1 is an important target to prevent isoflurane-induced developmental neurotoxicity.
Highlights
Many infants and children receive different types of surgery or diagnostic procedure every year
The results showed that the amount of Cdh1 in the cytosol was significantly higher in the isoflurane group than in the control group (P = 0.021, Figure 1D), while the level of Cdh1 in the nucleus was reduced after isoflurane-treatment (P = 0.032, Figure 1E)
Our findings demonstrated that exposure to 2% isoflurane for 6 h induces neuroapoptosis and significantly reduces Cdh1 expression, coinciding with the accumulation of several of its downstream substrates
Summary
Many infants and children receive different types of surgery or diagnostic procedure every year. Recent animal and clinical studies have demonstrated extended or multiple exposures to inhaled anesthetics during brain development can induce neuronal apoptosis and increase the risk of cognitive abnormalities during adulthood (Jevtovic-Todorovic et al, 2003; Zhu et al, 2010; DiMaggio et al, 2011; Cheng et al, 2015; Wu et al, 2017). Isoflurane, as a common volatile anesthetic, has been implicated in long-term developmental neurotoxicity and cognitive deficits (Stratmann et al, 2009). The mechanisms of isoflurane-induced developmental neurotoxicity are probably multifactorial. Cdh Mediates Isoflurane-Induced Developmental Neurotoxicity (Lei et al, 2012), which affects the normal development of neuronal networks, and leads to long-term neurocognitive decline. Early anesthesia exposure can disturb synapse development and potentially lead to abnormalities in synaptic plasticity (Huang et al, 2016). Whether ubiquitination activity is related to anesthesia-induced neurotoxicity is unknown
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