Brief isoflurane anesthesia regulates striatal AKT-GSK3β signaling and ameliorates motor deficits in a rat model of early-stage Parkinson's disease

J Neurochem. 2017 Aug;142(3):456-463. doi: 10.1111/jnc.14066. Epub 2017 Jun 14.


Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3β (GSK3β) and neurodegene-rative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3β inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3β within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3β signaling in naïve rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3β at the inhibitory Ser9 residue, and induced phosphorylation of AKTThr308 (protein kinase B; negative regulator of GSK3β) in the striatum of naïve rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.

Keywords: anesthesia; dopamine; neurodegeneration; phosphorylation; sensorimotor test.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anesthesia / adverse effects*
  • Animals
  • Corpus Striatum / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Disease Models, Animal
  • Dopaminergic Neurons / drug effects
  • Glycogen Synthase Kinase 3 / metabolism
  • Isoflurane / administration & dosage
  • Isoflurane / pharmacology*
  • Male
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Neuroprotective Agents / pharmacology*
  • Oxidopamine / pharmacology
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Rats, Wistar
  • Signal Transduction / drug effects*
  • Substantia Nigra / metabolism*


  • Neuroprotective Agents
  • Oxidopamine
  • Isoflurane
  • Cyclic AMP-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3