Abstract
BackgroundThere are growing concerns that anaesthetic exposure can cause extensive apoptotic degeneration of neurons and the impairment of normal synaptic development and remodelling. However, little attention has been paid to exploring the possible cytotoxicity of inhalation anaesthetics, such as isoflurane, in astrocytes. In this research, we determined that prolonged exposure to an inhalation anaesthetic caused cytotoxicity in astrocytes, and we identified the underlying molecular mechanism responsible for this process.MethodsAstrocytes were exposed to isoflurane, and astrocytic survival was then measured via LDH release assays, MTT assays, and TUNEL staining. TWIK-related potassium (K+) channel-1 (TREK-1) over-expression and knockdown models were also created using lentiviruses. The levels of TREK-1 and brain-derived neurotrophic factor (BDNF) were measured via Western blot and qRT-PCR.ResultsProlonged exposure to isoflurane decreased primary astrocytic viability in a dose- and time-dependent manner. Moreover, with prolonged exposure to isoflurane, the TREK-1 level increased, and the BDNF level was reduced. TREK-1 knockdown promoted the survival of astrocytes and increased BDNF expression following isoflurane exposure.ConclusionsOverdoses of and prolonged exposure to isoflurane induce cytotoxicity in primary astrocytes. TREK-1 plays an important role in isoflurane-induced cultured astrocytic cytotoxicity by down-regulating the expression of BDNF.
Highlights
There are growing concerns that anaesthetic exposure can cause extensive apoptotic degeneration of neurons and the impairment of normal synaptic development and remodelling
Isoflurane overdoses and prolonged exposure elicited toxic effects on astrocytes To test whether extended exposure to isoflurane interfered with astrocytic viability, primary astrocytes were treated with 2.4% isoflurane for different hours (3 h, 6 h and 9 h) using MTT analysis (Fig. 1a)
The MTT assays (Fig. 1b) revealed that the astrocytic viability was reduced with increasing doses of isoflurane, and the astrocytic Lactate dehydrogenase (LDH) release was found to be increased in a dose-dependent manner (Fig. 1c)
Summary
There are growing concerns that anaesthetic exposure can cause extensive apoptotic degeneration of neurons and the impairment of normal synaptic development and remodelling. We determined that prolonged exposure to an inhalation anaesthetic caused cytotoxicity in astrocytes, and we identified the underlying molecular mechanism responsible for this process. Significant and profound cognitive impairments have been observed in nonhuman primates following exposure to anaesthetics during a critical period of brain development [6]. Researches have been mainly focused on the effects of anaesthesia-induced neurotoxicity on neurons, but not astrocytes. New evidence has revealed that application of 1.4% isoflurane for 4 h induces degenerative cytoskeletal changes in astrocytes but does not affect their survival, motility, or proliferation [7]. Recent preliminary researches indicate that isoflurane can cause significant apoptotic changes in developing oligodendroglia in vivo [12].
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