Sevoflurane neurotoxicity in neonatal rats is related to an increase in the GABAAR α1/GABAAR α2 ratio

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Sevoflurane, a type of inhalational anesthetic, has been widely used in clinical practice, especially for young children, on account of its low blood/gas ratio, minimal pungency, and short time used in onset and recovery. However, attention has been drawn to the neurotoxicity of the inhalation anesthesia since the report of Levin ED et al. in the 1990s, after which heated debates were raised regarding its mechanisms and long‐term effects when used in children (Amrock, Starner, Murphy, & Baxter, 2015; Jevtovic‐Todorovic et al., 2003; Levin, Uemura, & Bowman, 1991; Liu et al., 2015; Monteleone et al., 2014; Yu, Wang, Fritschy, Witte, & Redecker, 2006). Lots of studies provide the evidence that several hours of anesthesia exposure are associated with widespread apoptotic neurodegeneration in many regions of the developing rat brain and subsequent neurobehavioral change in rats (Piehl et al., 2010; Shih et al., 2012). One of the methods to detect neuronal apoptosis is to use cleaved poly(ADP‐ribose) polymerase‐1 protein (PARP‐1), which is a substrate cleaved by caspase‐3.
Although the neurotoxic mechanisms of sevoflurane are still unknown, possible mechanisms involved in the neurotoxicity of sevoflurane include changes in postsynaptic receptors, such as type A γ‐aminobutyric acid receptor (GABAAR) (Lim et al., 2014; Mintz, Barrett, Smith, Benson, & Harrison, 2013; Yu et al., 2006). The α1 subunit of GABAAR is the major one in the early stages of the developing central nervous system, and then the increase of the α2 subunit at a later stage transforms the effect of GABAAR from excitatory to inhibitory (Yu et al., 2006). Activation of GABA AR early in developing brain promotes an excitatory response, which facilitates synaptic development and neuronal growth. Inhibition of GABAAR excitation activity early in development will lead to neuronal death (Kanaumi, Takashima, Iwasaki, Mitsudome, & Hirose, 2006). Specifically, increases in the GABA AR α1 subunit composition may create an inhibitory environment at a developmental age when in fact an excitatory environment or a predominance of α2 receptor subunit composition is in need (Crestani, Assandri, Tauber, Martin, & Rudolph, 2003; Kralic, Korpi, O'Buckley, Homanics, & Morrow, 2002). This change in excitation may cause cell death in the immature brain based on ionic gradients (Piehl et al., 2010). As a GABAAR agonist, sevoflurane may overactivate GABAAR in developing neurons, combined with the synergistic effect of the Na+–K+–2Cl− cotransporter isoform 1 (NKCC1), and stimulate a series of cascade reactions, which may result in the death of the endogenous apoptotic programmed cell (Lim et al., 2014; McKernan & Whiting, 1996; Mintz et al., 2013). Therefore, the aim of the present study is to determine whether the neurotoxicity of sevoflurane in the developing brain has a connection with its GABAAR subunit transmission.
The neurotoxicity of anesthetics has been investigated using developing rodent models, but the real minimum alveolar concentration (MAC) of sevoflurane in neonatal rats has been controversial in the literature (Orliaguet et al., 2011; Petrenko, Tsujita, Kohno, Sakimura, & Baba, 2007; Stratmann et al., 2009). Therefore, in the present study, the MAC of sevoflurane was measured through tail‐clamp stimulation in a bracketing study design. After trials in different concentrations and durations of sevoflurane exposure, a suitable model was then decided based on blood gas analysis.

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