br Experimental br Acknowledgment This paper was financially
Acknowledgment This paper was financially supported by the Project Funded by China Postdoctoral Science Foundation (2017T100186), Natural Science Foundation of Liaoning Province (20170540858), General Scientific Research Projects of Department of Education of Liaoning Province (2017LQN05), and Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University.
Introduction Recent studies have demonstrated that exposure to anesthetics is associated with widespread apoptotic neurodegeneration in the developing brains and persistent cognitive impairment in animals (Brambrink et al., 2010; Jevtovic-Todorovic et al., 2003; Li et al., 2013; Liang et al., 2010; Shen et al., 2013). Some clinical retrospective studies have found that children younger than 4 years old exposed to surgery under general anesthesia for more than once have a higher risk of developing disabilities in reading and learning (DiMaggio et al., 2011; Ing et al., 2012). Isoflurane is a commonly used volatile anesthetic in clinical settings including infants and pregnant women. Previous studies have demonstrated that isoflurane causes severe neuroapoptosis in both developing animal brains and neuronal CGP 42112 (Jevtovic-Todorovic et al., 2003; Li et al., 2013; Liang et al., 2010). Moreover isoflurane induces significantly greater neurodegeneration than an equipotent minimum alveolar concentration of sevoflurane or desflurane (Liu et al., 2017; Tao et al., 2016). However, the comprehensive molecular mechanisms underlying the isoflurane-induced neurotoxicity remain to be elucidated. Recent studies suggested oxidative stress (Cheng et al., 2015), neuroinflammation (Wu et al., 2012), Aβ aggregation (Dong et al., 2012; Xie et al., 2008) neurotrophic factor pathway disorder (Head et al., 2009; Wu et al., 2016) and the epigenetic modulation of histone acetylation (Massara et al., 2016; Sen and Sen, 2016) are associated with anesthetics-induced neurotoxicity and cognitive dysfunction. Although neuronal apoptosis is either the principal mechanism or one of several mechanisms that accounts for neurocognitive changes after developmental anesthesia exposure remains controversial, it indeed exerted important roles in isoflurane-induced neurotoxicity (Jevtovic-Todorovic et al., 2003; Li et al., 2013; Liang et al., 2010). Mitochondrial structure injury and dysfunction, in particular, the permeabilization of the mitochondrial outer membrane (MOM) and the subsequent release of pro-apoptotic proteins from the inter membrane space of mitochondria, is the important pathological changes in anesthetics-induced neuroapoptosis (Sanchez et al., 2011; Zhang et al., 2010; Zhang et al., 2012). Mitochondria-dependent apoptosis is mediated by caspase-dependent and caspase-independent pathways (Wang and Youle, 2009). The caspase-dependent pathway is triggered by the mitochondrial intermembrane protein cytochrome c that, when released to the cytosol, initiates a cascade of caspase activating events (Li et al., 1997). The caspase-independent pathway is initiated by release of mitochondrial intermembrane protein apoptosis-inducing factor (AIF) into the cytosol and translocation to the nucleus which results in fragmentation of nuclear DNA independently of caspase recruitment. AIF is embedded in the mitochondrial inner membrane (MIM) where it exerts a vital function in bioenergetic and redox metabolism under physiological conditions (Churbanova and Sevrioukova, 2008; Vahsen et al., 2004). Upon pathological permeabilization of the MOM, mature AIF (∼62 kDa) is processed to a ∼57 kDa truncated form by activated calpains and/or cathepsins (Polster et al., 2005; Yuste et al., 2005). This isoform is then translocated to the nucleus which leads to chromatin condensation and large-scale DNA fragmentation (Otera et al., 2005; Susin et al., 1999). Calpains are a family of calcium-dependent, non-lysosomal cysteine proteases including two main isoforms, μ-calpain and m-calpain, which differ in the amount of Ca2+ (μM and mM, respectively) required to become activated. Recent research has demonstrated that μ-calpain and m-calpain are present in the mitochondrial intermembrane space (IMS) (Arrington et al., 2006; Kar et al., 2008; Ozaki et al., 2009) and contribute to AIF cleavage (Norberg et al., 2008). The release of AIF appears to occur in several steps. First, the prolonged increase in [Ca2+]i level induced by an apoptotic stimulus leads to mitochondrial Ca2+ overload, which activates mitochondrial u-calpain in the IMS. Activated mitochondrialμ-calpain truncates and releases AIF from the MIM into the IMS15,23−25. A further increase of mitochondrial Ca2+ level activates mitochondrial m-calpain leading to a truncation of voltage-dependent anion channel (VDAC) and promotes association of Bax in the MOM (Ozaki et al., 2009). AIF is then released into the cytosol through VDAC/Bax-mediated pores or Bax/Bax-mediated pores.