Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

Cell Physiol Biochem. 2018;46(2):618-632. doi: 10.1159/000488630. Epub 2018 Mar 28.

Abstract

Background/aims: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats.

Methods: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3β both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult.

Results: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3β both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro.

Conclusion: We for the first time showed that simvastatin, by upregulating Akt/GSK-3β signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain.

Keywords: Akt; Caspase-3; GSK-3β; Isoflurane; Neural stem cells; Simvastatin.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chromones / pharmacology
  • Down-Regulation / drug effects
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Isoflurane / toxicity*
  • Lateral Ventricles / metabolism
  • Maze Learning / drug effects
  • Morpholines / pharmacology
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurogenesis / drug effects*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Simvastatin / pharmacology*
  • Up-Regulation / drug effects

Substances

  • Chromones
  • Morpholines
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Simvastatin
  • Isoflurane
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Caspase 3