Isoflurane-Physiological effect, Anesthetics-Physiological effect, Neurotoxic agents, Mice-Anatomy, Brain-Degeneneration, Cofilin, RhoA
A fundamental premise of general anesthetic action is that anesthetics induce a reversible state of unconsciousness and unresponsiveness. Inherent in this premise is that the central nervous system is neurophysiologically unchanged after the exposure. Data have emerged showing widespread neurodegeneration in immature brains following general anesthesia. Isoflurane (a volatile anesthetic) is widely used to maintain general anesthesia in neonates, children, and adults. It has been suggested that some of the adverse effects might be due to the anesthetic-induced alterations in cytoskeletal dynamics. The aim of the present study is to elucidate the cellular mechanisms responsible for the morphological neurodegenerative effects of Isoflurane. We hypothesized that volatile anesthetics will induce morphological alterations of the cytoskeleton through upregulation of RhoA activity which increases LIM Kinase-1 activity thereby increasing phosphorylation of cofilin. To achieve this in vitro and in vivo mice models were used to assess how exposure to clinical concentrations of isoflurane affect the levels of expressed cofilin and phosphorylated cofilin in murine cortical tissue – since cofilin modulates cytoskeletal dynamics. Isoflurane induced morphological changes in cultured primary neurons (~DIV 14) at clinical concentrations. In time-lapse analysis most neurites responded by a slow but consistent retraction that was in most cases irreversible. In vitro exposures showed a decrease of phosphorylated cofilin relative to cofilin after 2 hrs and 4 hrs exposure .The 2hrs exposure showed a 25% decrease, as compared to the 4 hrs exposure that showed a 6% decrease. In contrast, in vivo experiments with 30-60 min isoflurane exposures in P7-P12 day old mice showed an increase in to levels as high as 160%. These results suggest that isoflurane has an impact on cell morphology and dynamics of immature brain cells through perturbation of molecular events governing cytoskeletal formation.
Nhundu, Belinda Juliana, "Exploring the neurotoxic effects of isoflurane on the cytoskeleton of developing murine neurons" (2013). Theses, Dissertations, and Projects. 181.