In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons

Neuroscience. 2015 Apr 2:290:31-40. doi: 10.1016/j.neuroscience.2014.12.076. Epub 2015 Jan 13.


Anesthetic doses of ketamine induce apoptosis, as well as gene expression of activity-dependent neuroprotective protein (ADNP), a putative homeodomain transcription factor in rat pups (P7). This study investigated if ketamine induced ADNP protein in a dose-dependent manner in vitro and in vivo using primary cultures of cortical neurons and neonatal pups (P7). In vivo immunohistochemistry demonstrated a sub-anesthetic dose of ketamine increased ADNP in the somatosensory cortex (SCC) which was previously identified to be damaged by repeated exposure to anesthetic doses of ketamine. Administration of low-dose ketamine prior to full sedation prevented caspase-3 activation in the hippocampus and SCC. Primary cultures of cortical neurons treated with ketamine (10 μM-10mM) at 3 days-in vitro (3 DIV) displayed a concentration-dependent decrease in expanded growth cones. Furthermore, neuronal production and localization of ADNP varied as a function of both ketamine concentration and length of exposure. Taken together, these data support the model that ADNP induction may be partially responsible for the efficacy of a low-dose ketamine pre-treatment in preventing ketamine-induced neuronal cell death.

Keywords: activity dependent protective protein; cortical neurons; growth cones; ketamine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Blotting, Western
  • Caspase 3 / metabolism
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Growth Cones / drug effects
  • Growth Cones / pathology
  • Growth Cones / physiology
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Hippocampus / physiology
  • Immunohistochemistry
  • Ketamine / pharmacology*
  • Nerve Tissue Proteins / metabolism*
  • Neurons / drug effects*
  • Neurons / pathology
  • Neurons / physiology*
  • Neuroprotective Agents / pharmacology*
  • Rats, Sprague-Dawley
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / pathology
  • Somatosensory Cortex / physiology


  • ADNP protein, rat
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Ketamine
  • Casp3 protein, rat
  • Caspase 3